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Sample records for neuroepithelial body microenvironment

  1. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment

    NARCIS (Netherlands)

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Kroese, A; Riccardi, Daniela; Kemp, Paul J.; Timmermans, Jean-Pierre; Adriaensen, Dirk

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells invariably accompanied by Clara-like cells. Together with NEBs, Clara-like cells form the so-called "NEB microenvironment," which recently has been assigned a potential pulmonary stem cell niche. Conclusive

  2. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment.

    Science.gov (United States)

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Kroese, Alfons B A; Riccardi, Daniela; Kemp, Paul J; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2008-08-01

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells invariably accompanied by Clara-like cells. Together with NEBs, Clara-like cells form the so-called "NEB microenvironment," which recently has been assigned a potential pulmonary stem cell niche. Conclusive data on the nature of physiological stimuli for NEBs are lacking. This study aimed at developing an ex vivo mouse lung vibratome slice model for confocal live cell imaging of physiological reactions in identified NEBs and surrounding epithelial cells. Immunohistochemistry of fixed slices demonstrated that NEBs are almost completely shielded from the airway lumen by tight junction-linked Clara-like cells. Besides the unambiguous identification of NEBs, the fluorescent dye 4-Di-2-ASP allowed microscopic identification of ciliated cells, Clara cells, and Clara-like cells in live lung slices. Using the mitochondrial uncoupler FCCP and a mitochondrial membrane potential indicator, JC-1, increases in 4-Di-2-ASP fluorescence in NEB cells and ciliated cells were shown to represent alterations in mitochondrial membrane potential. Changes in the intracellular free calcium concentration ([Ca2+](i)) in NEBs and surrounding airway epithelial cells were simultaneously monitored using the calcium indicator Fluo-4. Application (5 s) of 50 mM extracellular potassium ([K+](o)) evoked a fast and reproducible [Ca2+](i) increase in NEB cells, while Clara-like cells displayed a delayed (+/- 4 s) [Ca2+](i) increase, suggestive of an indirect, NEB-mediated activation. The presented approach opens interesting new perspectives for unraveling the functional significance of pulmonary NEBs in control lungs and disease models, and for the first time allows direct visualization of local interactions within the NEB microenvironment.

  3. Purinergic signaling in the pulmonary neuroepithelial body microenvironment unraveled by live cell imaging.

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    De Proost, Ian; Pintelon, Isabel; Wilkinson, William J; Goethals, Sofie; Brouns, Inge; Van Nassauw, Luc; Riccardi, Daniela; Timmermans, Jean-Pierre; Kemp, Paul J; Adriaensen, Dirk

    2009-04-01

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of complex sensory airway receptors involved in the regulation of breathing. Together with their surrounding Clara-like cells, they exhibit stem cell potential through their capacity to regenerate depopulated areas of the epithelium following lung injury. We have employed confocal live cell imaging microscopy and novel electrophysiological techniques in a new ex vivo lung slice model to unravel potential purinergic signaling pathways within the NEB microenvironment. Quinacrine histochemistry indicated high amounts of vesicular ATP in NEB cells. Using a "reporter-patching" method adapted to create a uniquely sensitive and selective biosensor for the direct detection of ATP release from NEBs ex vivo, we demonstrated quantal ATP release from NEBs following their depolarization. Enhancing enzymatic extracellular ATP hydrolysis or inhibiting P2 receptors confirmed the central role of ATP in paracrine interactions between NEB cells and Clara-like cells. Combined calcium imaging, pharmacology, and immunohistochemistry showed that ligand-binding to functional P2Y(2) receptors underpins the activation of Clara-like cells. Hence, NEB cells communicate with their cellular neighbors in the NEB microenvironment by releasing ATP, which rapidly evokes purinergic activation of surrounding Clara-like cells. Besides ATP acting on the P2X(3) receptor expressing vagal sensory nerve terminals between NEB cells, local paracrine purinergic signaling within this potential stem cell niche may be important to both normal airway function, airway epithelial regeneration after injury, and/or the pathogenesis of small cell lung carcinomas.

  4. Expression of functional purinergic receptors in pulmonary neuroepithelial bodies and their role in hypoxia chemotransmission.

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    Fu, Xiao Wen; Nurse, Colin A; Cutz, Ernest

    2004-01-01

    Adenine nucleotides act through specific cell surface receptors to invoke a variety of biological responses. Here we show that cells of neuroepithelial bodies (NEB), presumed O2 airway sensors in neonatal hamster lung, express functional P2X receptors (P2X-R). Positive immunostaining was detected in NEB cells using double-label immunohistochemistry with antibodies against P2X2 and P2X3 receptor subunits, which co-localized with serotonin (5-HT), a marker of NEB cells. For electrophysiological characterization of P2X2-R in NEB cells, fresh neonatal hamster lung slice preparation was used. Under whole-cell patch clamp, perfusion with ATP induced a concentration-dependent, non-desensitizing inward current (EC50=12 microM). Perfusion with alpha,beta-methylene ATP also induced a slow-desensitizing inward current (EC50=8.2 microM). Suramin (IC50 ca. 43 microM) and TNP-ATP (IC50 ca. 8 microM) blocked the currents evoked by both ATP and alpha,beta-methylene ATP. Using carbon fiber amperometry we observed that hypoxia and ATP induced 5-HT release from NEB cells and that this release was blocked by suramin. These data suggest that functional P2X2/3 heteromeric receptors are expressed in NEB cells. The possible function of these purinoreceptors in NEB cells could include modulation of hypoxia chemotransmission.

  5. Pulmonary neuroepithelial bodies are polymodal airway sensors: evidence for CO2/H+ sensing.

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    Livermore, S; Zhou, Y; Pan, J; Yeger, H; Nurse, C A; Cutz, E

    2015-04-15

    Pulmonary neuroepithelial bodies (NEB) in mammalian lungs are thought to function as airway O2 sensors that release serotonin (5-HT) in response to hypoxia. Direct evidence that NEB cells also respond to airway hypercapnia/acidosis (CO2/H(+)) is presently lacking. We tested the effects of CO2/H(+) alone or in combination with hypoxia on 5-HT release from intact NEB cells in a neonatal hamster lung slice model. For the detection of 5-HT release we used carbon fiber amperometry. Fluorescence Ca(2+) imaging method was used to assess CO2/H(+)-evoked changes in intracellular Ca(2+). Exposure to 10 and 20% CO2 or pH 6.8-7.2 evoked significant release of 5-HT with a distinct rise in intracellular Ca(2+) in hamster NEBs. This secretory response was dependent on the voltage-gated entry of extracellular Ca(2+). Moreover, the combined effects of hypercapnia and hypoxia were additive. Critically, an inhibitor of carbonic anhydrase (CA), acetazolamide, suppressed CO2/H(+)-mediated 5-HT release. The expression of mRNAs for various CA isotypes, including CAII, was identified in NEB cells from human lung, and protein expression was confirmed by immunohistochemistry using a specific anti-CAII antibody on sections of human and hamster lung. Taken together our findings provide strong evidence for CO2/H(+) sensing by NEB cells and support their role as polymodal airway sensors with as yet to be defined functions under normal and disease conditions. Copyright © 2015 the American Physiological Society.

  6. Immunohistochemical characterization of the chemosensory pulmonary neuroepithelial bodies in the naked mole-rat reveals a unique adaptive phenotype.

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    Jie Pan

    Full Text Available The pulmonary neuroepithelial bodies (NEBs constitute polymodal airway chemosensors for monitoring and signaling ambient gas concentrations (pO2, pCO2/H+ via complex innervation to the brain stem controlling breathing. NEBs produce the bioactive amine, serotonin (5-HT, and a variety of peptides with multiple effects on lung physiology and other organ systems. NEBs in mammals appear prominent and numerous during fetal and neonatal periods, and decline in the post-natal period suggesting an important role during perinatal adaptation. The naked mole-rat (NMR, Heterocephalus glaber, has adapted to the extreme environmental conditions of living in subterranean burrows in large colonies (up to 300 colony mates. The crowded, unventilated burrows are environments of severe hypoxia and hypercapnia. However, NMRs adjust readily to above ground conditions. The chemosensory NEBs of this species were characterized and compared to those of the conventional Wistar rat (WR to identify similarities and differences that could explain the NMR's adaptability to environments. A multilabel immunohistochemical analysis combined with confocal microscopy revealed that the expression patterns of amine, peptide, neuroendocrine, innervation markers and chemosensor component proteins in NEBs of NMR were similar to that of WR. However, we found the following differences: 1 NEBs in both neonatal and adult NMR lungs were significantly larger and more numerous as compared to WR; 2 NEBs in NMR had a more variable compact cell organization and exhibited significant differences in the expression of adhesion proteins; 3 NMR NEBs showed a significantly greater ratio of 5-HT positive cells with an abundance of 5-HT; 4 NEBs in NMR expressed the proliferating cell nuclear antigen (PCNA and the neurogenic gene (MASH1 indicating active proliferation and a state of persistent differentiation. Taken together our findings suggest that NEBs in lungs of NMR are in a hyperactive, functional

  7. Dysembryoplastic Neuroepithelial Tumors

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    Yeon-Lim Suh

    2015-11-01

    Full Text Available Dysembryoplastic neuroepithelial tumor (DNT is a benign glioneuronal neoplasm that most commonly occurs in children and young adults and may present with medically intractable, chronic seizures. Radiologically, this tumor is characterized by a cortical topography and lack of mass effect or perilesional edema. Partial complex seizures are the most common presentation. Three histologic subtypes of DNTs have been described. Histologically, the recognition of a unique, specific glioneuronal element in brain tumor samples from patients with medically intractable, chronic epilepsy serves as a diagnostic feature for complex or simple DNT types. However, nonspecific DNT has diagnostic difficulty because its histology is indistinguishable from conventional gliomas and because a specific glioneuronal element and/or multinodularity are absent. This review will focus on the clinical, radiographic, histopathological, and immunohistochemical features as well as the molecular genetics of all three variants of DNTs. The histological and cytological differential diagnoses for this lesion, especially the nonspecific variant, will be discussed.

  8. Human body micro-environment: The benefits of controlling airflow interaction

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor

    2015-01-01

    This paper focuses on the micro-environment around a human body, and especially on its interaction with the surrounding environment. Research on the free convection flow generated by a human body (including the convective boundary layer around the body and the thermal plume above the body), its...

  9. Air temperature investigation in microenvironment around a human body

    DEFF Research Database (Denmark)

    Licina, Dusan; Melikov, Arsen Krikor; Sekhar, Chandra

    2015-01-01

    The aim of this study is to investigate the temperature boundary layer around a human body in a quiescent indoor environment. The air temperature, mean in time and standard deviation of the temperature fluctuations around a breathing thermal manikin are examined in relation to the room temperature...... to the surface of the body. The large standard deviation of air temperature fluctuations, up to 1.2°C, was recorded in the region of the chest, and up to 2.9°C when the exhalation was applied. The manikin leaned backwards increased the air temperature in the breathing zone, which was opposite from the forward...... body inclination. Exhalation through the mouth created a steady air temperature drop with increased distance from the mouth without disturbing the region of the chest. Exhalation through the nose did not affect the air temperature in front of the chest due to physics of the jets flow from the nose...

  10. Impacts of exhalation flow on the microenvironment around the human body under different room temperatures

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    Jafari, Mohammad Javad; Gharari, Noradin; Azari, Mansour Rezazade; Ashrafi, Khosro

    2017-10-01

    Exhalation flow and room temperature can have a considerable effect on the microenvironment in the vicinity of human body. In this study, impacts of exhalation flow and room temperature on the microenvironment around a human body were investigated using a numerical simulation. For this purpose, a computational fluid dynamic program was applied to study thermal plume around a sitting human body at different room temperatures of a calm indoor room by considering the exhalation flow. The simulation was supported by some experimental measurements. Six different room temperatures (18 to 28 °C) with two nose exhalation modes (exhalation and non-exhalation) were investigated. Overhead and breathing zone velocities and temperatures were simulated in different scenarios. This study finds out that the exhalation through the nose has a significant impact on both quantitative and qualitative features of the human microenvironment in different room temperatures. At a given temperature, the exhalation through the nose can change the location and size of maximum velocity at the top of the head. In the breathing zone, the effect of exhalation through the nose on velocity and temperature distribution was pronounced for the point close to mouth. Also, the exhalation through the nose strongly influences the thermal boundary layer on the breathing zone while it only minimally influences the convective boundary layer on the breathing zone. Overall results demonstrate that it is important to take the exhalation flow into consideration in all areas, especially at a quiescent flow condition with low temperature.

  11. MR findings of dysembryoplastic neuroepithelial tumor

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    Shin, Joo Yong; Chang, Jong Wun; Joo, Yang Gu [Keimyung Univ. College of Medicine, Taegu (Korea, Republic of)

    1997-09-01

    Dysembryoplastic neuroepithelial tumor (DNET) is a newly described, pathologically benign tumor arising within the supratentorial cortex. We reviewed the MR appearance of five patients with DNET, emphasizing the clinical and radiologic features. MR images in the five patients (three male and two female) with a history of epileptic seizure and pathologically-proven DNET were retrospectively reviewed. We analyzed the location, configuration, signal intensity, contrast enhancement, vasogenic edema and calcifications of these tomors. The tumors were located mainly in the cortical to subcortical area with very little perifocal mass effect on MR imaging. They were essentially hypointense on T1-weighted imaging, and showed a hyperintense well circumscribed mass on T2-weighted imaging and a thick gyrus-like configuration was retained within the lesions. On contrast enhanced study, focal nodular enhancement was seen in one patient, and multifocal nodular enhancement in two. DNET is rare benign tumor resulting in often medically intractable epileptic seizure and shows a characteristic gyriform configuration, well-described lobular tumor margins and sometimes multifocal nodular enhancement. These radiologic features may aid in differentiating DNET from ganglioglioma and other gliomas.=20.

  12. Occupant body movement and seat occupancy rate for design of desk micro-environment

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor; Pokora, Petr

    2014-01-01

    . In average occupants left the desk 4.6 times during the day and stayed away in average for 20 min. The average distance between the PC monitor and the occupant body was 0.63 m and changed mainly from 0.48 m to 0.72 m. 78% of the time the length of occupants’ body movement to the left/right direction was less...... than 0.225 m, with maximum span of the whole interval up to 0.75 m. In average the frequency of body position change was 4.9 times per minute, with minimum frequency of 0.6 times per minute and maximum frequency of 11.9 times per minute. The collected data are discussed and requirements for optimal...

  13. The fitness costs and benefits of antibiotic resistance in drug-free microenvironments encountered in the human body.

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    Maharjan, Ram; Ferenci, Thomas

    2017-10-01

    The relationship between bacterial drug resistance and growth fitness is a contentious topic, but some antibiotic resistance mutations clearly have a fitness cost in the laboratory. Whether these costs translate into deleterious effects in natural habitats is less certain however. Previously, fitness effects of resistance mutations were mostly characterized in nutrient-rich, fast-growth conditions, which bacteria rarely encounter in natural habitats. Carbon, phosphate, iron or oxygen limitations are conditions met by bacterial pathogens in various compartments of the human body. Here, we measured the fitness of four different rpoB mutations commonly found in rifampicin-resistant bacterial isolates. The fitness properties and the emergence of these and other alleles were studied in Escherichia coli populations growing under nutrient excess and in four different nutrient-limited states. Consistent with previous findings, all four mutations exhibited deleterious fitness effects under nutrient-rich conditions. In stark contrast, we found positive or neutral fitness effects under nutrient-limited conditions. Two particular rpoB alleles had a remarkable fitness increase under phosphate limitation and these alleles arose to high frequencies specifically under phosphate limitation. These findings suggest that it is not meaningful to draw general conclusions on fitness costs without considering bacterial microenvironments in humans and other animals. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

  14. Diffuse Ependymal Dysembryoplastic Neuroepithelial Tumor Causing Spinal Drop Metastases: A Case Report

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    Kim, Seul Kee; Jeong, Min Young; Kang, Heoung Keun; Yoon, Woong [Chonnam National University Hospital, Gwangju (Korea, Republic of); Jung, Tae Young [Chonnam National University Hwasun Hospital, Hwasun (Korea, Republic of)

    2012-07-15

    Dysembryoplastic neuroepithelial tumors (DNETs) arise mostly in the supratentorial cerebral cortex. A very rare case of intraventricular DNET with diffuse ependymal involvement, which causes spinal drop metastasis, is presented.

  15. Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells.

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    Fish, Jennifer L; Kosodo, Yoichi; Enard, Wolfgang; Pääbo, Svante; Huttner, Wieland B

    2006-07-05

    The ASPM (abnormal spindle-like microcephaly-associated) protein has previously been implicated in the determination of human cerebral cortical size, but the cell biological basis of this regulation has not been studied. Here we investigate the role of Aspm in mouse embryonic neuroepithelial (NE) cells, the primary stem and progenitor cells of the mammalian brain. Aspm was found to be concentrated at mitotic spindle poles of NE cells and to be down-regulated with their switch from proliferative to neurogenic divisions. Upon RNA interference in telencephalic NE cells, Aspm mRNA is reduced, mitotic spindle poles lack Aspm protein, and the cleavage plane of NE cells is less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation of NE cells increases the probability that these highly polarized cells undergo asymmetric division, i.e., that apical plasma membrane is inherited by only one of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a larger proportion of NE cell progeny is found in the neuronal layer, implying a reduction in the number of NE progenitor cells upon Aspm knock-down relative to control. Our results demonstrate that Aspm is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative divisions of NE cells during brain development. These data provide a cell biological explanation of the primary microcephaly observed in humans with mutations in ASPM, which also has implications for the evolution of mammalian brains.

  16. Pediatric brain tumors of neuroepithelial tissue; Hirntumoren des neuroepithelialen Gewebes im Kindesalter

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    Papanagiotou, P.; Politi, M. [Klinikum Bremen-Mitte/Bremen-Ost, Klinik fuer Diagnostische und Interventionelle Neuroradiologie, Bremen (Germany); Bergmann, M. [Klinikum Bremen-Mitte, Institut fuer Klinische Neuropathologie, Bremen (Germany); Pekrun, A. [Klinikum Bremen-Mitte, Klinik fuer Kinder- und Jugendmedizin, paed. Haematologie/Onkologie, Neonatologie, Bremen (Germany); Juergens, K.U. [Klinikum Bremen-Mitte, ZEMODI-Zentrum fuer moderne Diagnostik, MRT, Nuklearmedizin und PET-CT, Bremen (Germany)

    2014-08-15

    Tumors of neuroepithelial tissue represent the largest group of pediatric brain tumors by far and has therefore been divided into several discrete tumor subtypes each corresponding to a specific component of the neuropil. The neuropil contains several subtypes of glial cells, including astrocytes, oligodendrocytes, ependymal cells and modified ependymal cells that form the choroid plexus. This review discusses the imaging aspects of the most common pediatric tumors of neuroepithelial tissue. (orig.) [German] Tumoren des neuroepithelialen Gewebes stellen die mit Abstand groesste Gruppe der paediatrischen Hirntumoren dar und werden je nach deren Ursprung in diversen Subtypen unterteilt. Das Neuropil beinhaltet diverse Subtypen von Gliazellen: Astrozyten, Oligodendrozyten, ependymale Zellen und modifizierte ependymale Zellen, die den Plexus choroideus formen. In diesem Review werden die bildgebenden Aspekte mittels CT und MRT der haeufigsten Tumoren des neuroepithelialen Gewebes diskutiert. (orig.)

  17. Salvage gamma knife radiosurgery in the management of dysembryoplastic neuroepithelial tumors

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    Sinclair, Georges; Martin, Heather; Shamikh, Alia

    2017-01-01

    BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNT/DNET) are rare epileptogenic tumors. Microsurgery remains the best treatment option, although case reports exist on the use of gamma knife radiosurgery (GKRS) in selected cases. We investigated the long-term outcome of GKRS-treated DNTs....... No adverse radiation effects were recorded. Prospective studies are warranted to establish the role of GKRS in the treatment of DNTs....

  18. Multifocal Dysembryoplastic Neuroepithelial Tumour with Intradural Spinal Cord Lipomas: Report of a Case

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    Richard D. White

    2011-01-01

    Full Text Available We report a case of temporal lobe epilepsy and incomplete Brown-Sequard syndrome of the thoracic cord. Computed tomography and magnetic resonance (MR imaging showed multiple supratentorial masses with the classical radiological appearances of multifocal dysembryoplastic neuroepithelial tumour (DNET. Spinal MR imaging revealed intradural lipomas, not previously reported in association with multifocal DNET. Presentation and imaging findings are discussed along with classification and natural history of the tumour.

  19. Basolateral rather than apical primary cilia on neuroepithelial cells committed to delamination.

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    Wilsch-Bräuninger, Michaela; Peters, Jula; Paridaen, Judith T M L; Huttner, Wieland B

    2012-01-01

    Delamination of neural progenitors from the apical adherens junction belt of the neuroepithelium is a hallmark of cerebral cortex development and evolution. Specific cell biological processes preceding this delamination are largely unknown. Here, we identify a novel, pre-delamination state of neuroepithelial cells in mouse embryonic neocortex. Specifically, in a subpopulation of neuroepithelial cells that, like all others, exhibit apical-basal polarity and apical adherens junctions, the re-establishing of the primary cilium after mitosis occurs at the basolateral rather than the apical plasma membrane. Neuroepithelial cells carrying basolateral primary cilia appear at the onset of cortical neurogenesis, increase in abundance with its progression, selectively express the basal (intermediate) progenitor marker Tbr2, and eventually delaminate from the apical adherens junction belt to become basal progenitors, translocating their nucleus from the ventricular to the subventricular zone. Overexpression of insulinoma-associated 1, a transcription factor known to promote the generation of basal progenitors, increases the proportion of basolateral cilia. Basolateral cilia in cells delaminating from the apical adherens junction belt are preferentially found near spot-like adherens junctions, suggesting that the latter provide positional cues to basolateral ciliogenesis. We conclude that re-establishing a basolateral primary cilium constitutes the first known cell biological feature preceding neural progenitor delamination.

  20. Distinct roles of neuroepithelial-like and radial glia-like progenitor cells in cerebellar regeneration.

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    Kaslin, Jan; Kroehne, Volker; Ganz, Julia; Hans, Stefan; Brand, Michael

    2017-04-15

    Zebrafish can regenerate after brain injury, and the regenerative process is driven by resident stem cells. Stem cells are heterogeneous in the vertebrate brain, but the significance of having heterogeneous stem cells in regeneration is not understood. Limited availability of specific stem cells might impair the regeneration of particular cell lineages. We studied regeneration of the adult zebrafish cerebellum, which contains two major stem and progenitor cell types: ventricular zone and neuroepithelial cells. Using conditional lineage tracing we demonstrate that cerebellar regeneration depends on the availability of specific stem cells. Radial glia-like cells are thought to be the predominant stem cell type in homeostasis and after injury. However, we find that radial glia-like cells play a minor role in adult cerebellar neurogenesis and in recovery after injury. Instead, we find that neuroepithelial cells are the predominant stem cell type supporting cerebellar regeneration after injury. Zebrafish are able to regenerate many, but not all, cell types in the cerebellum, which emphasizes the need to understand the contribution of different adult neural stem and progenitor cell subtypes in the vertebrate central nervous system. © 2017. Published by The Company of Biologists Ltd.

  1. Dysembryoplastic neuroepithelial tumor and probable sudden unexplained death in epilepsy: a case report

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    Sîrbu Carmen-Adella

    2011-09-01

    Full Text Available Abstract Introduction This is the first report of the case of a patient with a natural history of dysembryoplastic neuroepithelial tumor associated with probable sudden unexplained death in epilepsy. These tumors are benign, arising within the supratentorial cortex. Over 100 cases have been reported in the literature since the first description by Daumas-Duport in 1988. Case presentation A 24- year-old Caucasian woman had a long period of intractable complex partial seizures, sometimes with tonic-clonic generalization and neuropsychological abnormalities. Magnetic resonance imaging showed a cortico-subcortical parietal tumor with all the characteristics of these types of tumors. After 14 years of evolution, our patient died suddenly during sleep. Conclusion To the best of our knowledge, this is the first case of probable sudden unexplained death in symptomatic epilepsy due to dysembryoplastic neuroepithelial tumor with natural history. Early and complete excision, with functional studies before and during the surgery, leads to better control of seizures, avoiding neuropsychological changes and the risk of death. Patients with refractory epilepsy should be evaluated for any sleep disorders and should have complete cardiology assessments including electrocardiographic evaluation of cardiac rhythm disturbances.

  2. A Robust Single Primate Neuroepithelial Cell Clonal Expansion System for Neural Tube Development and Disease Studies

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    Xiaoqing Zhu

    2016-02-01

    Full Text Available Developing a model of primate neural tube (NT development is important to promote many NT disorder studies in model organisms. Here, we report a robust and stable system to allow for clonal expansion of single monkey neuroepithelial stem cells (NESCs to develop into miniature NT-like structures. Single NESCs can produce functional neurons in vitro, survive, and extensively regenerate neuron axons in monkey brain. NT formation and NESC maintenance depend on high metabolism activity and Wnt signaling. NESCs are regionally restricted to a telencephalic fate. Moreover, single NESCs can turn into radial glial progenitors (RGPCs. The transition is accurately regulated by Wnt signaling through regulation of Notch signaling and adhesion molecules. Finally, using the “NESC-TO-NTs” system, we model the functions of folic acid (FA on NT closure and demonstrate that FA can regulate multiple mechanisms to prevent NT defects. Our system is ideal for studying NT development and diseases.

  3. Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem Cells

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    Anna S. Monzel

    2017-05-01

    Full Text Available Research on human brain development and neurological diseases is limited by the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Here, we describe a robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. These human midbrain organoids contain spatially organized groups of dopaminergic neurons, which make them an attractive model for the study of Parkinson’s disease. Midbrain organoids are characterized in detail for neuronal, astroglial, and oligodendrocyte differentiation. Furthermore, we show the presence of synaptic connections and electrophysiological activity. The complexity of this model is further highlighted by the myelination of neurites. The present midbrain organoid system has the potential to be used for advanced in vitro disease modeling and therapy development.

  4. Targeting the tumor microenvironment

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    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  5. Biological stoichiometry in tumor micro-environments.

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    Irina Kareva

    Full Text Available Tumors can be viewed as evolving ecological systems, in which heterogeneous populations of cancer cells compete with each other and somatic cells for space and nutrients within the ecosystem of the human body. According to the growth rate hypothesis (GRH, increased phosphorus availability in an ecosystem, such as the tumor micro-environment, may promote selection within the tumor for a more proliferative and thus potentially more malignant phenotype. The applicability of the GRH to tumor growth is evaluated using a mathematical model, which suggests that limiting phosphorus availability might promote intercellular competition within a tumor, and thereby delay disease progression. It is also shown that a tumor can respond differently to changes in its micro-environment depending on the initial distribution of clones within the tumor, regardless of its initial size. This suggests that composition of the tumor as a whole needs to be evaluated in order to maximize the efficacy of therapy.

  6. The diagnostic value of high-frequency power-based diffusion-weighted imaging in prediction of neuroepithelial tumour grading.

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    Chen, Zhiye; Zhou, Peng; Lv, Bin; Liu, Mengqi; Wang, Yan; Wang, Yulin; Lou, Xin; Gui, Qiuping; He, Huiguang; Ma, Lin

    2017-12-01

    To retrospectively evaluate the diagnostic value of high-frequency power (HFP) compared with the minimum apparent diffusion coefficient (MinADC) in the prediction of neuroepithelial tumour grading. Diffusion-weighted imaging (DWI) data were acquired on 115 patients by a 3.0-T MRI system, which included b0 images and b1000 images over the whole brain in each patient. The HFP values and MinADC values were calculated by an in-house script written on the MATLAB platform. There was a significant difference among each group excluding grade I (G1) vs. grade II (G2) (P = 0.309) for HFP and among each group for MinADC. ROC analysis showed a higher discriminative accuracy between low-grade glioma (LGG) and high-grade glioma (HGG) for HFP with area under the curve (AUC) value 1 compared with that for MinADC with AUC 0.83 ± 0.04 and also demonstrated a higher discriminative ability among the G1-grade IV (G4) group for HFP compared with that for MinADC except G1 vs. G2. HFP could provide a simple and effective optimal tool for the prediction of neuroepithelial tumour grading based on diffusion-weighted images in routine clinical practice. • HFP shows positive correlation with neuroepithelial tumour grading. • HFP presents a good diagnostic efficacy for LGG and HGG. • HFP is helpful in the selection of brain tumour boundary.

  7. Tumor disembrioplástico neuroepitelial: relato de caso Dysembryoplastic neuroepithelial tumor: case report

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    Luiz Fernando Bleggi Torres

    1997-09-01

    Full Text Available O tumor disembrioplástico neuroepitelial (TDN é entidade tumoral relativamente nova que foi descrita pela primeira vez por Daumas-Duport et al. em 1988 e foi incorporado à classificação de tumores cerebrais da Organização Mundial da Saúde em 1993. Os autores apresentam o primeiro caso de TDN relatado na literatura latino-americana. Trata-se de paciente de sexo feminino, com 16 anos, que começou a ter crises convulsivas tipo parciais complexas com generalização secundária aos cinco anos de idade. Usou diversas drogas anti-convulsivas mas nunca obteve total controle clínico das crises epiléticas. O exame físico era normal e não havia alterações neurológicas focais ou de cognição. O exame por ressonância nuclear magnética do crânio mostrou tumor no lobo temporal esquerdo. A paciente foi submetida a craniotomia e a ressecção tumoral foi completa. Os cortes histológicos apresentavam proliferação neuroglial atípica condizente ao TDN. O estudo imunohistoquímico pela técnica de avidina-biotina peroxidase revelou positividade para proteína glial fibrilar ácida e proteína S 100 no componente astrocitário e enolase neurônio específica e sinaptofisina no componente neuronal.Dysembryoplastic neuroepithelial tumor (DNT is a relatively new neuroepithelial neoplasm that was first described by Daumas-Duport et al. in 1988. It was incorporated in the revised World Health Organization classification of brain tumors in 1993. The authors present the first case of DNT reported in the Latin-American literature. A 16-year-old woman had been found at age of five years to have complex partial seizures accompanied by secondary generalization. She was treated with various anti-epileptic drugs but always with incomplete control of seizures activity. Neurological examination was normal. Magnetic resonance imaging demonstrated a lesion in the left temporal lobe. She underwent a craniotomy with complete resection of the tumor. Histological

  8. Cytopatholologic features of gliosarcoma with areas of primitive neuroepithelial differentiation of the brain in squash smears.

    Science.gov (United States)

    Hayashi, Toshitetsu; Kushida, Yoshio; Kadota, Kyuichi; Katsuki, Naomi; Bando, Kenji; Miyai, Yumi; Funamoto, Yasunobu; Haba, Reiji

    2009-12-01

    Gliosarcoma with areas of primitive neuroepithelial differentiation (GSPNED) is an extremely rare neoplasm. A case is presented here in which squash smears of a left temporal lobe tumor in a 76-year-old male demonstrated two distinct and easily recognizable cellular populations, i.e., densely hyperchromatic cells of a primitive nature in a fibrillary background and pleomorphic spindle-shaped cells. Occasional pseudo-rosette formations and nuclear cannibalism suggestive of neuroendocrine differentiation were also found. A cytologic diagnosis of a malignant tumor was suggested, and histochemical and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Reticulin stain highlighted increased intercellular collagen and reticulin deposition within the spindled regions, whereas nodules with primitive cells were reticulin-poor. There was a diffuse and strong reactivity to neuron specific enolase, synaptophysin and CD56 immunostains. A stain for glial fibrillary acidic protein and S-100 protein demonstrated a subset of tumor cells including elongated cytoplasmic processes. The spindled component was positive for vimentin and smooth muscle actin, whereas the primitive-appearing tumor cells were negative. The diagnosis of GSPNED was confirmed based on cytopathologic, histopathological and immunohistochemical results. The cytomorphologic features of this distinctive tumor are illustrated, and the adjunctival value of squash smears for frozen-section diagnosis is also discussed. This is the first presentation of a cytopathologic analysis that provides an important clue to an accurate diagnosis of GSPNED.

  9. Simple and complex dysembryoplastic neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology

    Energy Technology Data Exchange (ETDEWEB)

    Campos, Alexandre R.; Clusmann, Hans; Lehe, Marec von; Schramm, Johannes [University of Bonn Medical Center, Department of Neurosurgery, Bonn (Germany); Niehusmann, Pitt; Becker, Albert J. [University of Bonn Medical Center, Department of Neuropathology, Bonn (Germany); Urbach, Horst [University of Bonn Medical Center, Department of Radiology, Bonn (Germany)

    2009-07-15

    Dysembryoplastic neuroepithelial tumors (DNTs) are long-term epilepsy associated tumors subdivided into simple and complex variants. The purpose of this study was to relate different DNT components identified on magnetic resonance imaging (MRI) to histopathological features and to test the hypothesis that glial nodules as a histopathological feature of complex variants induce an occasional glioma misdiagnosis. Clinical, MRI, and histopathologic features of DNTs operated between 1988 and 2008 were reviewed. From a total of 61 DNTs, 48 simple and 13 complex variants were identified. Multiple or single pseudocysts in a cortical/subcortical location with small cysts sometimes separated from the tumor represented the glioneuronal element and were found in all DNTs. FLAIR hyperintense tissue was found between pseudocysts but - in neocortical DNTs - also circumscript in deeper tumor parts. Calcification and hemorrhages in this location occurred in four of 13 complex variants, and one of these patients was also the only one with tumor growth. Patients with complex variants had earlier seizure onset, and complex variants were more often located outside the temporal lobe. Although complex variants represented a higher diagnostic challenge, misdiagnoses also occurred in simple variants. One of five of DNTs showed contrast enhancement, which varied on follow-up studies with enhancing parts becoming nonenhancing and vice versa. The glioneuronal element is readily identifiable on MRI and should be considered to support the DNT diagnosis. Complex DNT variants have a different clinical profile and a more variable histopathological and MRI appearance; however, misdiagnoses occasionally also occur in simple variants. (orig.)

  10. Concerted action of neuroepithelial basal shrinkage and active epithelial migration ensures efficient optic cup morphogenesis

    Science.gov (United States)

    Sidhaye, Jaydeep; Norden, Caren

    2017-01-01

    Organ formation is a multi-scale event that involves changes at the intracellular, cellular and tissue level. Organogenesis often starts with the formation of characteristically shaped organ precursors. However, the cellular mechanisms driving organ precursor formation are often not clear. Here, using zebrafish, we investigate the epithelial rearrangements responsible for the development of the hemispherical retinal neuroepithelium (RNE), a part of the optic cup. We show that in addition to basal shrinkage of RNE cells, active migration of connected epithelial cells into the RNE is a crucial player in its formation. This cellular movement is driven by progressive cell-matrix contacts and actively translocates prospective RNE cells to their correct location before they adopt neuroepithelial fate. Failure of this migration during neuroepithelium formation leads to ectopic determination of RNE cells and consequently impairs optic cup formation. Overall, this study illustrates how spatiotemporal coordination between morphogenic movements and fate determination critically influences organogenesis. DOI: http://dx.doi.org/10.7554/eLife.22689.001 PMID:28372636

  11. Bioprinting the Cancer Microenvironment.

    Science.gov (United States)

    Zhang, Yu Shrike; Duchamp, Margaux; Oklu, Rahmi; Ellisen, Leif W; Langer, Robert; Khademhosseini, Ali

    2016-10-10

    Cancer is intrinsically complex, comprising both heterogeneous cellular compositions and microenvironmental cues. During the various stages of cancer initiation, development, and metastasis, cell-cell interactions (involving vascular and immune cells besides cancerous cells) as well as cell-extracellular matrix (ECM) interactions (e.g., alteration in stiffness and composition of the surrounding matrix) play major roles. Conventional cancer models both two- and three-dimensional (2D and 3D) present numerous limitations as they lack good vascularization and cannot mimic the complexity of tumors, thereby restricting their use as biomimetic models for applications such as drug screening and fundamental cancer biology studies. Bioprinting as an emerging biofabrication platform enables the creation of high-resolution 3D structures and has been extensively used in the past decade to model multiple organs and diseases. More recently, this versatile technique has further found its application in studying cancer genesis, growth, metastasis, and drug responses through creation of accurate models that recreate the complexity of the cancer microenvironment. In this review we will focus first on cancer biology and limitations with current cancer models. We then detail the current bioprinting strategies including the selection of bioinks for capturing the properties of the tumor matrices, after which we discuss bioprinting of vascular structures that are critical toward construction of complex 3D cancer organoids. We finally conclude with current literature on bioprinted cancer models and propose future perspectives.

  12. Tumor Biology and Microenvironment Research

    Science.gov (United States)

    Part of NCI's Division of Cancer Biology's research portfolio, research in this area seeks to understand the role of tumor cells and the tumor microenvironment (TME) in driving cancer initiation, progression, maintenance and recurrence.

  13. BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas.

    Science.gov (United States)

    Lee, Dakeun; Cho, Young Hye; Kang, So Young; Yoon, Nara; Sung, Chang Ohk; Suh, Yeon-Lim

    2015-03-01

    BRAF mutation has received a great deal of attention in neuro-oncology field, recently. This study aimed to investigate the incidence and the clinical significance of BRAF(V600E) in low-grade glial tumors. An institutional cohort of 105 brain tumors (51 dysembryoplastic neuroepithelial tumors (DNTs), 14 subependymal giant cell astrocytomas (SEGAs), 12 glioblastoma with neuronal marker expression (GBM-N), and 28 pleomorphic xanthoastrocytomas (PXAs)) from 100 patients were investigated for the presence of BRAF(V600E) by direct sequencing. We found frequent BRAF(V600E) in DNTs (26/51, 51%), SEGAs (6/14, 42.9%), and PXAs (14/28, 50%). In DNTs, BRAF(V600E) was more commonly detected in tumors with extra-temporal location (68.2% vs. 37.9%; P = 0.032). The diagnostic subgroups of tuberous sclerosis complex were not correlated with BRAF(V600E) in patients with SEGA (P = 0.533). One PXA case revealed a unique duplication mutation (p.Thr599dup) of codon 599. All GMB-N cases did not carry BRAF mutation. Our data indicate that BRAF(V600E) is a common genetic alteration in low-grade glial tumors with neuronal component or differentiation. High frequency of BRAF(V600E) in DNTs and SEGAs would be useful in the differential diagnosis, and also offers a potential specific treatment targeting BRAF(V600E) . © 2014 Wiley Periodicals, Inc.

  14. [Clinicopathologic features of infant dysembryoplastic neuroepithelial tumor: a case report and literature review].

    Science.gov (United States)

    Wang, H; Ye, J T; Yao, H X; Li, D; Dong, Y

    2017-10-18

    Dysembryoplastic neuroepithelial tumor (DNT) has traditionally been viewed as rare benign tumors that present with seizure widely considered curable with surgery alone. Most DNTs occur in childhood and young adults. However, rare reported cases occur in infants. This paper reported an infant case of DNT and its diagnosis, differential diagnosis, treatment, molecular features and prognosis based on the review of current literatures. The age onset of this patient was only 11 months old. The clinical manifestations were partial seizures and the imaging data untypical; CT and MRI were all supportive of astrocytoma. Typical glioneuronal element histologic features could be seen, which contained oligodendrocyte-like cells attached to bundles of axons and neurons floating in a myxoid interstitial fluid. Meanwhile, some atypical regions could also be seen. These atypical regions showed a mixture of oligodendrocyte-like cells and neurons without a myxoid interstitial fluid, which were easily misdiagnosed. The BRAFV600E mutation was not detected. This patient had a good response to drug therapy. Totally surgical resection of the tumor was conducted. The patient had been seizures free for 6 months. In conclusion, DNT is a rare and well prognostic tumor (WHO grade I), which most often arise in children in the setting of medically refractory epilepsy. The most common tumor location was temporal. Because clinical symptoms, imaging and histological features of DNT and other low-grade gliomas broadly overlap such as ganglioglioma, pilocytic astrocytomas and oligodendroglioma et al., differential diagnosis should be made carefully. The glioneuronal element was the histopathological hallmark of DNT. In addition, some untypical regions should also be called attention. Although BRAFV600E mutation didn't exist in this case, it played a role in differential diagnosis because it has been previously recorded that BRAFV600E mutation was a common feature of DNT. Infant patients have their

  15. Dysembryoplastic neuroepithelial tumor (DNT). Neuroradiological features; Dysembryoplastischer neuroepithelialer Tumor (DNT). Neuroradiologische Befundmuster

    Energy Technology Data Exchange (ETDEWEB)

    Reiche, W. [Abt. fuer Neuroradiologie, Radiologische Klinik, Universitaet des Saarlandes, Homburg/Saar (Germany); Kolles, H. [Abt. fuer Neuropathologie, Inst. fuer Pathologie, Universitaet des Saarlandes, Homburg/Saar (Germany); Eymann, R. [Neurochirurgische Klinik, Universitaet des Sarlandes, Homburg/Saar (Germany); Feiden, W. [Abt. fuer Neuropathologie, Inst. fuer Pathologie, Universitaet des Saarlandes, Homburg/Saar (Germany)

    1996-11-01

    Dysembryoplastic neuroepithelial tumors (DNT) were first described as a new tumor entity by Daumas-Duport et al. in 1988 and were introduced into the revised WHO classification of brain tumors in 1993. The purpose of this study was to work out neuroradiological CT and MRT patterns of DNT. Five patients, aged 11-61 years (three female, two male) underwent complete presurgical neuroradiological exploration (5 CT, 4 MRT investigations, 2 angiography) because of brain tumor. Four cases complained of seizures and one of occipital-located headache. Total microsurgical excision was achieved in two cases. Two further lesions were resected subtotally after stereotactic biopsy diagnosis. In one case, stereotactic biopsy alone was carried out. All DNTs were localized cortically: Two frontobasal medial in the gyrus rectus, two temporobasal in the gyrus occipitotemporalis lateralis and one infratentorial in the lobus caudalis cerebelli. They were sharply demarcated from the surrounding brain tissue. Cortical localization was better visualized by MRT, especially on coronal and sagittal images. CT scans showed a hypodense lesion, MRT a high-signal intensity in T{sub 2}, low signal in T{sub 1} and in proton-weighted images a hyperintense rim with a slightly hyperintense small cyst. The multinodular tumor architecture was best seen in MRT. Two DNTs presented partial contrast enhancement, while three DNTs did not take up contrast. In two lesions there were focal calcifications. The infratentorial DNT was associated with a bony defect of the tabula interna into which the tumor expanded. Two angiographies showed no pathological tumor neovascularization. A hypodense, sharply demarcated lesion with a multinodular pattern in MRT with cortical location and without space-occupying signs is, in combination with the clinical symptom of epileptic seizures, highly suggestive of DNT. As our results demonstrate, DNT can also occur in the infratentorial space. (orig.) [Deutsch] Die Gruppe der

  16. Leukocyte trafficking in tumor microenvironment.

    Science.gov (United States)

    Del Prete, Annalisa; Schioppa, Tiziana; Tiberio, Laura; Stabile, Helena; Sozzani, Silvano

    2017-08-01

    The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of soluble mediators. Different types of tumors have specific tumor microenvironments characterized by distinct chemokines and chemotactic factors that influence leukocyte recruitment. The immune cell infiltrate continuously interacts with stroma cells and influence tumor growth. Emerging evidence suggests that the regulation of the composition and the metabolic state of tumor-associated leukocytes may represent a new promising intervention strategy. Here we summarize the current knowledge on the role of tumor-associated immune cells in tumor growth and dissemination, with a specific focus on the nature of the chemotactic factors responsible for their accumulation and activation in tumors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Macrophages in Mildly Acid Microenvironment

    African Journals Online (AJOL)

    acid caused by anaerobic glycolysis in hypoxia, seem to be the main cause. In consequence, pH. 6.6 and 6.8 were used as experimental group to present the mildly acid microenvironment of tumor tissues, and pH 7.2 was taken as control group in our study. Table 1: Effect of TP concentration and time on the proliferation of ...

  18. Biomimetic microenvironments for regenerative endodontics.

    Science.gov (United States)

    Kaushik, Sagar N; Kim, Bogeun; Walma, Alexander M Cruz; Choi, Sung Chul; Wu, Hui; Mao, Jeremy J; Jun, Ho-Wook; Cheon, Kyounga

    2016-01-01

    Regenerative endodontics has been proposed to replace damaged and underdeveloped tooth structures with normal pulp-dentin tissue by providing a natural extracellular matrix (ECM) mimicking environment; stem cells, signaling molecules, and scaffolds. In addition, clinical success of the regenerative endodontic treatments can be evidenced by absence of signs and symptoms; no bony pathology, a disinfected pulp, and the maturation of root dentin in length and thickness. In spite of the various approaches of regenerative endodontics, there are several major challenges that remain to be improved: a) the endodontic root canal is a strong harbor of the endodontic bacterial biofilm and the fundamental etiologic factors of recurrent endodontic diseases, (b) tooth discolorations are caused by antibiotics and filling materials, (c) cervical root fractures are caused by endodontic medicaments, (d) pulp tissue is not vascularized nor innervated, and (e) the dentin matrix is not developed with adequate root thickness and length. Generally, current clinical protocols and recent studies have shown a limited success of the pulp-dentin tissue regeneration. Throughout the various approaches, the construction of biomimetic microenvironments of pulp-dentin tissue is a key concept of the tissue engineering based regenerative endodontics. The biomimetic microenvironments are composed of a synthetic nano-scaled polymeric fiber structure that mimics native pulp ECM and functions as a scaffold of the pulp-dentin tissue complex. They will provide a framework of the pulp ECM, can deliver selective bioactive molecules, and may recruit pluripotent stem cells from the vicinity of the pulp apex. The polymeric nanofibers are produced by methods of self-assembly, electrospinning, and phase separation. In order to be applied to biomedical use, the polymeric nanofibers require biocompatibility, stability, and biodegradability. Therefore, this review focuses on the development and application of the

  19. The external microenvironment of healing skin wounds

    DEFF Research Database (Denmark)

    Kruse, Carla R; Nuutila, Kristo; Lee, Cameron Cy

    2015-01-01

    The skin wound microenvironment can be divided into two main components that influence healing: the external wound microenvironment, which is outside the wound surface; and the internal wound microenvironment, underneath the surface, to which the cells within the wound are exposed. Treatment...... and carbon dioxide), pH, and anti-microbial treatment on the wound. These factors are well described in the literature and can be modified with treatment methods available in the clinic. Understanding the roles of these factors in wound pathophysiology is of central importance in wound treatment...... methods that directly alter the features of the external wound microenvironment indirectly affect the internal wound microenvironment due to the exchange between the two compartments. In this review, we focus on the effects of temperature, pressure (positive and negative), hydration, gases (oxygen...

  20. Effect of papaya seed extract on microenvironment of cauda epididymis.

    Science.gov (United States)

    Verma, R J; Chinoy, N J

    2001-06-01

    To evaluate the effect of aqueous Carica papaya seed extract on microenvironment of cauda epididymis. Adult male albino rats were intramuscularly administered with 0 (control) or 0.5 mg papaya seed extract/kg body weight for 7 days. Cauda epididymal tubular content was collected by micropuncture technique; epididymal luminal fluid and sperm pellets were separately analyzed. The results revealed that the extract treatment caused significant reduction, as compared with control, in total protein and sialic acid contents in both epididymal fluid and sperm pellet. As compared with control, significantly lowered acid phosphatase activity was recorded in sperm pellet but was higher in epididymal fluid after the treatment. The extract treatment also caused significant reduction in level of inorganic phosphorus in the epididymal fluid. It is concluded that the aqueous papaya seed extract alters cauda epididymal microenvironment.

  1. Optical microassembly platform for constructing reconfigurable microenvironment for biomedical studies

    DEFF Research Database (Denmark)

    Rodrigo, Peter John; Kelemen, Lóránd; Palima, Darwin

    2009-01-01

    Cellular development is highly influenced by the surrounding microenvironment. We propose user-reconfigurable microenvironments and bio-compatible scaffolds as an approach for understanding cellular development processes. We demonstrate a model platform for constructing versatile microenvironment...

  2. Dysembryoplastic neuroepithelial tumors: a model for examining the effects of pathology versus seizures on cognitive dysfunction in epilepsy.

    Science.gov (United States)

    Baxendale, Sallie; Donnachie, Elizabeth; Thompson, Pamela; Sander, Josemir W

    2013-12-01

    Dysembryoplastic neuroepithelial tumors (DNTs) provide a unique model for studying the effects of seizures on cognitive development. Epilepsy and antiepileptic medications are prominent features in the lives and schooling of people who develop seizures in childhood. People with an adult onset share the same underlying brain pathology, but their childhood development is unaffected by seizures. Therefore, DNTs provide a model to examine the specific influence of seizures and their treatment on cognitive development, over and above the effects of the underlying pathology in epilepsy. We examined the neuropsychological characteristics of 56 adults with DNT and medically intractable epilepsy (mean age 32.7 years). Twenty-two adults (39%) had an age of onset of epilepsy before the age of 12 years (childhood-onset group). Scores on tests of intelligence (Verbal IQ and Performance IQ), reading, working memory, verbal learning, verbal recall, visual learning, and expressive and receptive language ability were analyzed. There were no significant localization effects (right vs. left vs. extratemporal) on any of the neuropsychological test scores. In the group as a whole, the neuropsychological test scores were significantly lower than healthy, age-matched controls on measures of Verbal IQ (p reading (p abilities, resulting in patterns of cognitive deficits that remain apparent in adulthood. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  3. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia.

    Science.gov (United States)

    Onorati, Marco; Li, Zhen; Liu, Fuchen; Sousa, André M M; Nakagawa, Naoki; Li, Mingfeng; Dell'Anno, Maria Teresa; Gulden, Forrest O; Pochareddy, Sirisha; Tebbenkamp, Andrew T N; Han, Wenqi; Pletikos, Mihovil; Gao, Tianliuyun; Zhu, Ying; Bichsel, Candace; Varela, Luis; Szigeti-Buck, Klara; Lisgo, Steven; Zhang, Yalan; Testen, Anze; Gao, Xiao-Bing; Mlakar, Jernej; Popovic, Mara; Flamand, Marie; Strittmatter, Stephen M; Kaczmarek, Leonard K; Anton, E S; Horvath, Tamas L; Lindenbach, Brett D; Sestan, Nenad

    2016-09-06

    The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  4. EPHRIN-B1 Mosaicism Drives Cell Segregation in Craniofrontonasal Syndrome hiPSC-Derived Neuroepithelial Cells.

    Science.gov (United States)

    Niethamer, Terren K; Larson, Andrew R; O'Neill, Audrey K; Bershteyn, Marina; Hsiao, Edward C; Klein, Ophir D; Pomerantz, Jason H; Bush, Jeffrey O

    2017-03-14

    Although human induced pluripotent stem cells (hiPSCs) hold great potential for the study of human diseases affecting disparate cell types, they have been underutilized in seeking mechanistic insights into the pathogenesis of congenital craniofacial disorders. Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by mutations in EFNB1 and characterized by craniofacial, skeletal, and neurological anomalies. Heterozygous females are more severely affected than hemizygous males, a phenomenon termed cellular interference that involves mosaicism for EPHRIN-B1 function. Although the mechanistic basis for cellular interference in CFNS has been hypothesized to involve Eph/ephrin-mediated cell segregation, no direct evidence for this has been demonstrated. Here, by generating hiPSCs from CFNS patients, we demonstrate that mosaicism for EPHRIN-B1 expression induced by random X inactivation in heterozygous females results in robust cell segregation in human neuroepithelial cells, thus supplying experimental evidence that Eph/ephrin-mediated cell segregation is relevant to pathogenesis in human CFNS patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. The Role of miRNAs as Key Regulators in the Neoplastic Microenvironment

    Directory of Open Access Journals (Sweden)

    K. K. Wentz-Hunter

    2011-01-01

    Full Text Available The neoplastic microenvironment has been recognized to play a critical role in the development of cancer. Although a large body of evidence has established the importance of the cancer microenvironment, the manners of crosstalk between it and the cancer cells still remains unclear. Emerging mechanisms of communication include microRNAs (miRNAs. miRNAs are small noncoding RNA molecules that are involved in the posttranscriptional regulation of mRNA. Both intracellular and circulating miRNAs are differentially expressed in cancer and some of these alterations have been correlated with clinical patient outcomes. The role of miRNAs in the tumor microenvironment has only recently become a focus of research, however. In this paper, we discuss the influence of miRNAs on the tumor microenvironment as it relates to cancer progression. We conclude that miRNAs are a critical component in understanding invasion and metastasis of cancer cells.

  6. Microenvironment Determinants of Brain Metastasis

    Directory of Open Access Journals (Sweden)

    Zhang Chenyu

    2011-02-01

    Full Text Available Abstract Metastasis accounts for 90% of cancer-related mortality. Brain metastases generally present during the late stages in the natural history of cancer progression. Recent advances in cancer treatment and management have resulted in better control of systemic disease metastatic to organs other than the brain and improved patient survival. However, patients who experience recurrent disease manifest an increasing number of brain metastases, which are usually refractory to therapies. To meet the new challenges of controlling brain metastasis, the research community has been tackling the problem with novel experimental models and research tools, which have led to an improved understanding of brain metastasis. The time-tested "seed-and-soil" hypothesis of metastasis indicates that successful outgrowth of deadly metastatic tumors depends on permissible interactions between the metastatic cancer cells and the site-specific microenvironment in the host organs. Consistently, recent studies indicate that the brain, the major component of the central nervous system, has unique physiological features that can determine the outcome of metastatic tumor growth. The current review summarizes recent discoveries on these tumor-brain interactions, and the potential clinical implications these novel findings could have for the better treatment of patients with brain metastasis.

  7. Targeting the tumor microenvironment for cancer therapy

    National Research Council Canada - National Science Library

    Sounni, Nor Eddine; Noel, Agnès

    With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic...

  8. MRI of metastasis-permissive microenvironments.

    Science.gov (United States)

    Penet, Marie-France; Chen, Zhihang; Bhujwalla, Zaver M

    2011-11-01

    One of the earliest documented observations of the importance of the microenvironment in metastasis was made by Stephen Paget in 1889. More than a century later, the metastatic cascade remains a major cause of mortality from cancer. Cancer meets the criterion of a successful organization that is able to survive by adapting to changing environments. In fact, the tumor microenvironment and stroma are co-opted and shaped by cancer cells to derive a survival advantage. Cohesive strategies integrating advances in molecular biology and chemistry, with noninvasive multimodality imaging, provide new insights into the role of the tumor microenvironment in promoting metastasis from primary tumors as well as insights into environments that attract and permit cancer cells to establish colonies in distant organs. This article provides an overview of molecular and functional imaging characterization of microenvironments that can promote or permit cancer cells to metastasize and the microenvironmental characteristics of distant metastases.

  9. Tumor microenvironment: hypoxia and buffer capacity for immunotherapy.

    Science.gov (United States)

    Liu, Chenghu; Gao, Shangxian; Qu, Zhonghua; Zhang, Lining

    2007-01-01

    In recent years, significant progress has been made in the study of tumor biology and anti-tumor immunotherapy. However, the cellular and molecular mechanisms of tumor progression still remain obscure. As we know, tumor microenvironment that can directly influence tumor development and prognosis has attracted much attention of large number of immunologists. Accumulated evidence has suggested that tumor microenvironment is in a hypoxic condition, under which immune cells may exhibit distinct functions compared to those under normal oxygen tension. The article we propose here will offer a novel point of view for understanding tumor microenvironment in order to instruct clinical immunotherapy. Just like the pH buffer system in human body, interactions of immune cells in tumor microenvironment may also constitute a buffer system, the balance of which is of great importance during immunotherapy for tumors. However, many protocols for tumor immunotherapy in clinic at present have not taken it into account, so the therapeutic outcome is often disappointing. In the present study, we have demonstrated the effect of Corynebacterium parvum, a well known immune stimulator, on malignant melanoma. Cell ingredients in tumor-infiltrating lymphocytes (TIL) and their anti-tumor effect have been altered when dosage of Corynebacterium parvum is changed. So, to obtain better therapeutic purposes, what we should do first is to detect an index to evaluate immune buffer capacity for the patient during tumor immunotherapy, then to choose appropriate drug doses to augment buffer capacity for their immune buffer system. Taken together, the hypothesis proposed here may help understand the pathogenesis of tumor progression and design more effective strategy for clinical immunotherapy for tumors.

  10. The thymus microenvironment in regulating thymocyte differentiation

    OpenAIRE

    Gameiro, Jacy; Nagib, Patrícia; Verinaud, Liana

    2010-01-01

    The thymus plays a crucial role in the development of T lymphocytes by providing an inductive microenvironment in which committed progenitors undergo proliferation, T-cell receptor gene rearrangements and thymocyte differentiate into mature T cells. The thymus microenvironment forms a complex network of interaction that comprises non lymphoid cells (e.g., thymic epithelial cells, TEC), cytokines, chemokines, extracellular matrix elements (ECM), matrix metalloproteinases and other soluble prot...

  11. Targeting the Neural Microenvironment in Prostate Cancer

    Science.gov (United States)

    2017-10-01

    Award Number: W81XWH-14-1-0505 TITLE: Targeting the Neural Microenvironment in Prostate Cancer PRINCIPAL INVESTIGATOR: Michael Ittmann MD PhD...CONTRACT NUMBER Targeting the Neural Microenvironment in Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0505 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...ABSTRACT Prostate cancer (PCa) remains the most common malignancy and the second leading cause of cancer -related death for men in the United States. Recent

  12. Immunological Dysregulation in Multiple Myeloma Microenvironment

    OpenAIRE

    Alessandra Romano; Concetta Conticello; Maide Cavalli; Calogero Vetro; Alessia La Fauci; Nunziatina Laura Parrinello; Francesco Di Raimondo

    2014-01-01

    Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extr...

  13. [Study on sweat gland regeneration induced by microenvironment of three-dimensional bioprinting].

    Science.gov (United States)

    Yao, B; Xie, J F; Huang, S; Fu, X B

    2017-01-20

    Sweat glands are abundant in the body surface and essential for thermoregulation. Sweat glands fail to conduct self-repair in patients with large area of burn and trauma, and the body temperature of patients increases in hot climate, which may cause shock or even death. Now, co-culture system, reprogramming, and tissue engineering have made progresses in inducing sweat gland regeneration, but the inductive efficiency and duration need to be improved. Cellular microenvironment can regulate cell biological behavior, including cell migration and cell differentiation. This article reviews the studies of establishment of microenvironment in vitro by three-dimensional bioprinting technology to induce sweat gland regeneration.

  14. Body

    OpenAIRE

    Riggs, Christina

    2010-01-01

    The human body is both the physical form inhabited by an individual “self” and the medium through which an individual engages with society. Hence the body both shapes and is shaped by an individual’s social roles. In contrast to the cognate fields of archaeology, anthropology, and classics, there has been little explicit discussion or theorization of the body in Egyptology. Some recent works, discussed here, constitute an exception to this trend, but there is much more scope for exploring anc...

  15. Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation.

    Science.gov (United States)

    Iyengar, Neil M; Gucalp, Ayca; Dannenberg, Andrew J; Hudis, Clifford A

    2016-12-10

    Purpose There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. Methods We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. Results Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. Conclusion The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity

  16. Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Guang; Li, Yan; Wang, Xiao-yu [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China); Han, Zhe [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Chuai, Manli [College of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH (United Kingdom); Wang, Li-jing [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Ho Lee, Kenneth Ka [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Geng, Jian-guo, E-mail: jgeng@umich.edu [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 (United States); Yang, Xuesong, E-mail: yang_xuesong@126.com [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China)

    2013-05-01

    Formation of the neural tube is the morphological hallmark for development of the embryonic central nervous system (CNS). Therefore, neural tube development is a crucial step in the neurulation process. Slit/Robo signaling was initially identified as a chemo-repellent that regulated axon growth cone elongation, but its role in controlling neural tube development is currently unknown. To address this issue, we investigated Slit/Robo1 signaling in the development of chick neCollege of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH, UKural tube and transgenic mice over-expressing Slit2. We disrupted Slit/Robo1 signaling by injecting R5 monoclonal antibodies into HH10 neural tubes to block the Robo1 receptor. This inhibited the normal development of the ventral body curvature and caused the spinal cord to curl up into a S-shape. Next, Slit/Robo1 signaling on one half-side of the chick embryo neural tube was disturbed by electroporation in ovo. We found that the morphology of the neural tube was dramatically abnormal after we interfered with Slit/Robo1 signaling. Furthermore, we established that silencing Robo1 inhibited cell proliferation while over-expressing Robo1 enhanced cell proliferation. We also investigated the effects of altering Slit/Robo1 expression on Sonic Hedgehog (Shh) and Pax7 expression in the developing neural tube. We demonstrated that over-expressing Robo1 down-regulated Shh expression in the ventral neural tube and resulted in the production of fewer HNK-1{sup +} migrating neural crest cells (NCCs). In addition, Robo1 over-expression enhanced Pax7 expression in the dorsal neural tube and increased the number of Slug{sup +} pre-migratory NCCs. Conversely, silencing Robo1 expression resulted in an enhanced Shh expression and more HNK-1{sup +} migrating NCCs but reduced Pax7 expression and fewer Slug{sup +} pre-migratory NCCs were observed. In conclusion, we propose that Slit/Robo1 signaling is involved in regulating neural tube

  17. The effect of allometric scaling in coral thermal microenvironments.

    Directory of Open Access Journals (Sweden)

    Robert H Ong

    Full Text Available A long-standing interest in marine science is in the degree to which environmental conditions of flow and irradiance, combined with optical, thermal and morphological characteristics of individual coral colonies, affects their sensitivity of thermal microenvironments and susceptibility to stress-induced bleaching within and/or among colonies. The physiological processes in Scleractinian corals tend to scale allometrically as a result of physical and geometric constraints on body size and shape. There is a direct relationship between scaling to thermal stress, thus, the relationship between allometric scaling and rates of heating and cooling in coral microenvironments is a subject of great interest. The primary aim of this study was to develop an approximation that predicts coral thermal microenvironments as a function of colony morphology (shape and size, light or irradiance, and flow velocity or regime. To do so, we provided intuitive interpretation of their energy budgets for both massive and branching colonies, and then quantified the heat-size exponent (b* and allometric constant (m using logarithmic linear regression. The data demonstrated a positive relationship between thermal rates and changes in irradiance, A/V ratio, and flow, with an interaction where turbulent regime had less influence on overall stress which may serve to ameliorate the effects of temperature rise compared to the laminar regime. These findings indicated that smaller corals have disproportionately higher stress, however they can reach thermal equilibrium quicker. Moreover, excellent agreements between the predicted and simulated microscale temperature values with no significant bias were observed for both the massive and branching colonies, indicating that the numerical approximation should be within the accuracy with which they could be measured. This study may assist in estimating the coral microscale temperature under known conditions of water flow and irradiance

  18. NK cells in the tumor microenvironment

    DEFF Research Database (Denmark)

    Larsen, Stine K; Gao, Yanhua; Basse, Per H

    2014-01-01

    The presence of natural killer (NK) cells in the tumor microenvironment correlates with outcome in a variety of cancers. However, the role of intratumoral NK cells is unclear. Preclinical studies have shown that, while NK cells efficiently kill circulating tumor cells of almost any origin, they s...

  19. Lysophosphatidate Signaling: The Tumor Microenvironment's New Nemesis.

    Science.gov (United States)

    Benesch, Matthew G K; Yang, Zelei; Tang, Xiaoyun; Meng, Guanmin; Brindley, David N

    2017-11-01

    Lysophosphatidate (LPA) is emerging as a potent mediator of cancer progression in the tumor microenvironment. Strategies for targeting LPA signaling have recently entered clinical trials for fibrosis. These therapies have potential to improve the efficacies of existing chemotherapies and radiotherapy by attenuating chronic inflammation, irrespective of diverse mutations within cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Subjective Evaluation of the Microenvironment Generated by a Hospital Bed with Localized Ventilation System

    DEFF Research Database (Denmark)

    Kehayova, Nushka; Bolashikov, Zhecho Dimitrov; Melikov, Arsen Krikor

    2016-01-01

    A novel method for local hospital bed ventilation, called HBIVCU (Hospital Bed with Integrated Ventilation and Cleansing Unit), was studied in a human subject experiment. The goal of this study was to identify human response to the microenvironment generated by a hospital bed with installed HBIVCU...... and to compare with human response to the micro-environment at a hospital bed without local ventilation. 32 participants took part in two experimental conditions - hospital bed with and without installed HBIVCU. Subject’s votes on the bed microenvironment were collected via standardized questionnaires....... The subjects evaluated the perceived air quality in the ventilated bed as better compared to that in the non-ventilated bed. The whole body thermal sensation (WTS) and acceptability votes were decreasing over time for the non-ventilated bed condition. Significant differences in the local thermal sensation LTS...

  1. Bioinspired Hydrogels to Engineer Cancer Microenvironments.

    Science.gov (United States)

    Park, Kyung Min; Lewis, Daniel; Gerecht, Sharon

    2017-06-21

    Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes.

  2. Lysyl Oxidase and the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Tong-Hong Wang

    2016-12-01

    Full Text Available The lysyl oxidase (LOX family of oxidases contains a group of extracellular copper-dependent enzymes that catalyze the cross-linking of collagen and elastin by oxidation, thus maintaining the rigidity and structural stability of the extracellular matrix (ECM. Aberrant expression or activation of LOX alters the cellular microenvironment, leading to many diseases, including atherosclerosis, tissue fibrosis, and cancer. Recently, a number of studies have shown that LOX is overexpressed in most cancers and that it is involved in the regulation of tumor progression and metastasis. In contrast, a few reports have also indicated the tumor-suppressing role of LOX. In this short review, we discuss recent research on the correlations between LOX and cancer. Further, the role of LOX in tumor microenvironment remodeling, tumorigenesis, and metastasis and the underlying mechanisms have also been elucidated.

  3. Lysyl Oxidase and the Tumor Microenvironment.

    Science.gov (United States)

    Wang, Tong-Hong; Hsia, Shih-Min; Shieh, Tzong-Ming

    2016-12-29

    The lysyl oxidase (LOX) family of oxidases contains a group of extracellular copper-dependent enzymes that catalyze the cross-linking of collagen and elastin by oxidation, thus maintaining the rigidity and structural stability of the extracellular matrix (ECM). Aberrant expression or activation of LOX alters the cellular microenvironment, leading to many diseases, including atherosclerosis, tissue fibrosis, and cancer. Recently, a number of studies have shown that LOX is overexpressed in most cancers and that it is involved in the regulation of tumor progression and metastasis. In contrast, a few reports have also indicated the tumor-suppressing role of LOX. In this short review, we discuss recent research on the correlations between LOX and cancer. Further, the role of LOX in tumor microenvironment remodeling, tumorigenesis, and metastasis and the underlying mechanisms have also been elucidated.

  4. Calcite Biohybrids as Microenvironment for Stem Cells

    Directory of Open Access Journals (Sweden)

    Razi Vago

    2012-04-01

    Full Text Available A new type of composite 3D biomaterial that provides extracellular cues that govern the differentiation processes of mesenchymal stem cells (MSCs has been developed. In the present study, we evaluated the chondrogenecity of a biohybrid composed of a calcium carbonate scaffold in its calcite polymorph and hyaluronic acid (HA. The source of the calcite scaffolding is an exoskeleton of a sea barnacle Tetraclita rifotincta (T. rifotincta, Pilsbry (1916. The combination of a calcium carbonate-based bioactive scaffold with a natural polymeric hydrogel is designed to mimic the organic-mineral composite of developing bone by providing a fine-tuned microenvironment. The results indicate that the calcite-HA interface creates a suitable microenvironment for the chondrogenic differentiation of MSCs, and therefore, the biohybrid may provide a tool for tissue-engineered cartilage.

  5. Epigenetic control of the tumor microenvironment

    Science.gov (United States)

    Marks, David L; Olson, Rachel LO; Fernandez-Zapico, Martin E

    2016-01-01

    Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumor-associated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies. We also summarize the effects of epigenetic mechanism-targeted drugs on stromal cells and discuss the consideration of the microenvironment response in attempts to use these drugs for cancer treatment. PMID:27700179

  6. Immunological dysregulation in multiple myeloma microenvironment.

    Science.gov (United States)

    Romano, Alessandra; Conticello, Concetta; Cavalli, Maide; Vetro, Calogero; La Fauci, Alessia; Parrinello, Nunziatina Laura; Di Raimondo, Francesco

    2014-01-01

    Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

  7. Immunological Dysregulation in Multiple Myeloma Microenvironment

    Directory of Open Access Journals (Sweden)

    Alessandra Romano

    2014-01-01

    Full Text Available Multiple Myeloma (MM is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC in bone marrow (BM. Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

  8. Metastasis Suppressors and the Tumor Microenvironment

    Science.gov (United States)

    Cook, Leah M.; Hurst, Douglas R.; Welch, Danny R.

    2011-01-01

    The most lethal and debilitating attribute of cancer cells is their ability to metastasize. Throughout the process of metastasis, tumor cells interact with other tumor cells, host cells and a variety of molecules. Tumor cells are also faced with a number of insults, such as hemodynamic sheer pressure and immune selection. This brief review explores how metastasis suppressor proteins regulate interactions between tumor cells and the microenvironments in which tumor cells find themselves. PMID:21168504

  9. Untapped Therapeutic Targets in the Tumor Microenvironment

    Science.gov (United States)

    2017-08-01

    important role in tumor evolution . We hypothesized that conventional chemotherapy for ovarian cancer will be more effective if the microenvironment...tumor evolution . The presence of cancer cells induces a reaction in the surrounding stromal cells similar to fibrosis after an injury. These reactions...Seminar Series. Johns Hopkins University School of Medicine. Baltimore, MD. November 16, 2016. 12 b. Website(s) or other Internet site(s). N/A

  10. Imaging Prostate Cancer Microenvironment by Collagen Hybridization

    Science.gov (United States)

    2015-10-01

    of using non- cellular solid state compartment as a source for therapeutic targets and for selective imaging of micro-metastasis2-5. In particular...for 1 hr in sodium acetate ( pH 5). After cooling room temperature, the polymer was treated with EDTA (0.05 M) to capture free 111In ions and further...Brooks, P.C. Impact of the non- cellular tumor microenvironment on metastasis: potential therapeutic and imaging opportunities. Journal of Cellular

  11. Analyzing the Tumor Microenvironment by Flow Cytometry.

    Science.gov (United States)

    Young, Yoon Kow; Bolt, Alicia M; Ahn, Ryuhjin; Mann, Koren K

    2016-01-01

    Flow cytometry is an essential tool for studying the tumor microenvironment. It allows us to quickly quantify and identify multiple cell types in a heterogeneous sample. A brief overview of flow cytometry instrumentation and the appropriate considerations and steps in building a good flow cytometry staining panel are discussed. In addition, a lymphoid tissue and solid tumor leukocyte infiltrate flow cytometry staining protocol and an example of flow cytometry data analysis are presented.

  12. Probing the tumor microenvironment: collection and induction

    Science.gov (United States)

    Williams, James K.; Padgen, Michael R.; Wang, Yarong; Entenberg, David; Gertler, Frank; Condeelis, John S.; Castracane, James

    2012-03-01

    The Nano Intravital Device, or NANIVID, is under development as an optically transparent, implantable tool to study the tumor microenvironment. Two etched glass substrates are sealed using a thin polymer membrane to create a reservoir with a single outlet. This reservoir is loaded with a hydrogel blend that contains growth factors or other chemicals to be delivered to the tumor microenvironment. When the device is implanted in the tumor, the hydrogel will swell and release these entrapped molecules, forming a gradient. Validation of the device has been performed in vitro using epidermal growth factor (EGF) and MenaINV, a highly invasive, rat mammary adenocarcinoma cell line. In both 2-D and 3-D environments, cells migrated toward the gradient of EGF released from the device. The chorioallantoic membrane (CAM) of White Leghorn chicken eggs is being utilized to grow xenograft tumors that will be used for ex vivo cell collection. Device optimization is being performed for in vivo use as a tool to collect the invasive cell population. Preliminary cell collection experiments in vivo were performed using a mouse model of breast cancer. As a second application, the device is being explored as a delivery vehicle for chemicals that induce controlled changes in the tumor microenvironment. H2O2 was loaded in the device and generated intracellular reactive oxygen species (ROS) in cells near the device outlet. In the future, other induction targets will be explored, including hypoglycemia and the manipulation of extracellular matrix stiffness.

  13. Therapeutic Strategies Targeting Cariogenic Biofilm Microenvironment.

    Science.gov (United States)

    Liu, Y; Ren, Z; Hwang, G; Koo, H

    2018-02-01

    Cariogenic biofilms are highly structured microbial communities embedded in an extracellular matrix, a multifunctional scaffold that is essential for the existence of the biofilm lifestyle and full expression of virulence. The extracellular matrix provides the physical and biological properties that enhance biofilm adhesion and cohesion, as well as create a diffusion-modulating milieu, protecting the resident microbes and facilitating the formation of localized acidic pH niches. These biochemical properties pose significant challenges for the development of effective antibiofilm therapeutics to control dental caries. Conventional approaches focusing solely on antimicrobial activity or enhancing remineralization may not achieve maximal efficacy within the complex biofilm microenvironment. Recent approaches disrupting the biofilm microbial community and the microenvironment have emerged, including specific targeting of cariogenic pathogens, modulation of biofilm pH, and synergistic combination of bacterial killing and matrix degradation. Furthermore, new "smart" nanotechnologies that trigger drug release or activation in response to acidic pH are being developed that could enhance the efficacy of current and prospective chemical modalities. Therapeutic strategies that can locally disrupt the pathogenic niche by targeting the biofilm structure and its microenvironment to eliminate the embedded microorganism and facilitate the action of remineralizing agents may lead to enhanced and precise anticaries approaches.

  14. Effects of laser immunotherapy on tumor microenvironment

    Science.gov (United States)

    Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.

    2014-02-01

    The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.

  15. Targeting the tumour microenvironment in ovarian cancer.

    Science.gov (United States)

    Hansen, Jean M; Coleman, Robert L; Sood, Anil K

    2016-03-01

    The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. The effect of commuting microenvironment on commuter exposures to vehicular emission in Hong Kong

    Science.gov (United States)

    Chan, L. Y.; Chan, C. Y.; Qin, Y.

    Vehicular exhaust emission has gradually become the major air pollution source in modern cities and traffic related exposure is found to contribute significantly to total human exposure level. A comprehensive survey was conducted from November 1995 to July 1996 in Hong Kong to assess the effect of traffic-induced air pollution inside different commuting microenvironments on commuter exposure. Microenvironmental monitoring is performed for six major public commuting modes (bus, light bus, MTR, railway, tram, ferry), plus private car and roadside pavement. Traffic-related pollutants, CO, NO x, THC and O 3 were selected as the target pollutants. The results indicate that commuter exposure is highly influenced by the choice of commuting microenvironment. In general, the exposure level in decreasing order of measured pollutant level for respective commuting microenvironments are: private car, the group consisting light bus, bus, tram and pavement, MTR and train, and finally ferry. In private car, the CO level is several times higher than that in the other microenvironments with a trip averaged of 10.1 ppm and a maximum of 24.9 ppm. Factors such as the body position of the vehicle, intake point of the ventilation system, fuel used, ventilation, transport mode, road and driving conditions were used in the analysis. Inter-microenvironment, intra-microenvironment and temporal variation of CO concentrations were used as the major indicator. The low body position and low intake point of the ventilation system of the private car are believed to be the cause of higher intake of exhaust of other vehicles and thus result in high pollution level in this microenvironment. Compared with other metropolis around the world and the Hong Kong Air Quality Objectives (HKAQO), exposure levels of commuter to traffic-related air pollution in Hong Kong are relatively low for most pollutants measured. Only several cases of exceedence of HKAQO by NO 2 were recorded. The strong prevailing wind

  17. The role of the microenvironment in tumor immune surveillance

    OpenAIRE

    Oluwadara, Oluwadayo; Giacomelli, Luca; Brant, Xenia; Christensen, Russell; Avezova, Raisa; Kossan, George; Chiappelli, Francesco

    2011-01-01

    The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O'Shea & Paul, 2010 [4]). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.

  18. The role of the microenvironment in tumor immune surveillance.

    Science.gov (United States)

    Oluwadara, Oluwadayo; Giacomelli, Luca; Brant, Xenia; Christensen, Russell; Avezova, Raisa; Kossan, George; Chiappelli, Francesco

    2011-01-06

    The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O'Shea & Paul, 2010 [4]). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.

  19. The influence of the microenvironment on the malignant phenotype

    Science.gov (United States)

    Park, C. C.; Bissell, M. J.; Barcellos-Hoff, M. H.

    2000-01-01

    Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells, adjacent normal cells such as stroma and endothelium, and their microenvironments. The current dominant paradigm wherein multiple genetic lesions provide both the impetus for, and the Achilles heel of, cancer might be inadequate to understand cancer as a disease process. In the following brief review, we will use selected examples to illustrate the influence of the microenvironment in the evolution of the malignant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions might be derived from focusing on microenvironment and tumor cells interactions.

  20. T-cell exhaustion in the tumor microenvironment

    National Research Council Canada - National Science Library

    Jiang, Y; Li, Y; Zhu, B

    2015-01-01

    .... The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination...

  1. Cancer Cell Colonisation in the Bone Microenvironment

    Directory of Open Access Journals (Sweden)

    Casina Kan

    2016-10-01

    Full Text Available Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow.

  2. Interaction microenvironment - Pantoea agglomerans limits maize yield

    Directory of Open Access Journals (Sweden)

    Daniel Ruíz Juárez

    2018-01-01

    Full Text Available Pantoea agglomerans has been reported as the cause of chlorotic streaks on maize leaves in the Central High Valleys of México (CVHM, but there are no current data of how the infection of this new pathogen in Mexico affects production and yield of the crop. To understand the development of the disease in the crop, two experiments with a split-plot design and three replications were established during spring-summer 2010 in different microenvironments: Ayapango and Temamatla. Three cultivars of maize (a tri-linear HS2 hybrid, the single-cross hybrid Triunfo and the native Cacahuacintle were evaluated with three P. agglomerans isolates. In the three maize cultivars, chlorotic streaks appeared on new leaves; at the ripening stage, the symptoms were less perceptible. The average incidence of plants with chlorotic streaks was higher in the town of Temamatla than in Ayapango, and in both microenvironments, the average degree of severity was less than 40%. Isolate A was the most virulent (P < 0.0001 on the three cultivars evaluated. These results will provide the basis for effective management of the disease under environmental conditions similar to those evaluated in this research.

  3. Bone marrow microenvironment in Waldenstrom's Macroglobulinemia.

    Science.gov (United States)

    Jalali, Shahrzad; Ansell, Stephen M

    2016-06-01

    Waldenstrom Macroglobulinemia (WM) is a low-grade B-cell lymphoma defined firstly by infiltration of lymphoplasmacytic cells into the bone marrow (BM), the milieu where the cells acquire signals that promote malignant growth and proliferation. A second characteristic associated with WM is the increased synthesis of monoclonal immunoglobulin M (IgM) by lymphoplasmacytic cells, which is secreted in the serum and often results in hyperviscosity. Advanced genomic tools have improved our understanding of the genetic events that contribute to malignant transformation in WM, but the role of BM microenvironment is also emerging as having an essential role in WM disease progression. Therefore, delineation of malignant WM cell growth in the context of its microenvironment would benefit the design of more efficient therapeutic strategies. Here, we highlight available data regarding the interaction of the WM cells with the cellular and non-cellular compartments of the BM and discuss how BM provides a permissive environment for WM cell growth and proliferation. Copyright © 2016. Published by Elsevier Ltd.

  4. Exploiting the tumor microenvironment for theranostic imaging.

    Science.gov (United States)

    Stasinopoulos, Ioannis; Penet, Marie-France; Chen, Zhihang; Kakkad, Samata; Glunde, Kristine; Bhujwalla, Zaver M

    2011-07-01

    The integration of chemistry and molecular biology with imaging is providing some of the most exciting opportunities in the treatment of cancer. The field of theranostic imaging, where diagnosis is combined with therapy, is particularly suitable for a disease as complex as cancer, especially now that genomic and proteomic profiling can provide an extensive 'fingerprint' of each tumor. Using this information, theranostic agents can be shaped for personalized treatment to target specific compartments, such as the tumor microenvironment (TME), whilst minimizing damage to normal tissue. These theranostic agents can also be used to target multiple pathways or networks by incorporating multiple small interfering RNAs (siRNAs) within a single agent. A decade ago genetic alterations were the primary focus in cancer research. Now it is apparent that the tumor physiological microenvironment, interactions between cancer cells and stromal cells, such as endothelial cells, fibroblasts and macrophages, the extracellular matrix (ECM), and a host of secreted factors and cytokines, influence progression to metastatic disease, aggressiveness and the response of the disease to treatment. In this review, we outline some of the characteristics of the TME, describe the theranostic agents currently available to target the TME and discuss the unique opportunities the TME provides for the design of novel theranostic agents for cancer therapy. Copyright © 2011 John Wiley & Sons, Ltd.

  5. (Micro)managing the mechanical microenvironment.

    Science.gov (United States)

    Moraes, Christopher; Sun, Yu; Simmons, Craig A

    2011-10-01

    Mechanical forces are critical components of the cellular microenvironment and play a pivotal role in driving cellular processes in vivo. Dissecting cellular responses to mechanical forces is challenging, as even "simple" mechanical stimulation in vitro can cause multiple interdependent changes in the cellular microenvironment. These stimuli include solid deformation, fluid flows, altered physical and chemical surface features, and a complex transfer of loads between the various interacting components of a biological culture system. The active mechanical and biochemical responses of cells to these stimuli in generating internal forces, reorganizing cellular structures, and initiating intracellular signals that specify cell fate and remodel the surrounding environment further complicates cellular response to mechanical forces. Moreover, cells present a non-linear response to combinations of mechanical forces, materials, chemicals, surface features, matrix properties and other effectors. Microtechnology-based approaches to these challenges can yield key insights into the mechanical nature of cellular behaviour, by decoupling stimulation parameters; enabling multimodal control over combinations of stimuli; and increasing experimental throughput to systematically probe cellular response. In this critical review, we briefly discuss the complexities inherent in the mechanical stimulation of cells; survey and critically assess the applications of present microtechnologies in the field of experimental mechanobiology; and explore opportunities and possibilities to use these tools to obtain a deeper understanding of mechanical interactions between cells and their environment. This journal is © The Royal Society of Chemistry 2011

  6. Reticle storage in microenvironments with extreme clean dry air

    Science.gov (United States)

    Gettel, Astrid; Glüer, Detlev; Honold, Alfred

    2012-11-01

    Haze formation on the patterned metal surface of reticles is a known problem for IC manufacturers that can impact device yield and increase operational costs due to the need for more frequent cleaning of the reticles. Storage of reticles in an ultraclean environment can reduce haze formation and reduce operational costs. We examined the contamination levels of a new type of reticle stocker that stores reticles in microenvironments which are continuously purged with extreme clean dry air (XCDA). Each microenvironment consists of twelve vertically stacked reticle storage slots which can be opened at any slot. The design of the microenvironment includes an XCDA supply that provides a homogeneous horizontal flow of XCDA between the reticles. Figure 1. Reduction of contamination levels inside the storage microenvironment as a function of XCDA flow rate. As shown in Fig. 1, continuous XCDA purge reduces the contaminant levels inside the microenvironment. The amount of reduction depends on the XCDA purge flow rate and the chemical species. Volatile organic substances can be reduced by more than two orders of magnitude. Humidity is reduced less because the plastic material of the storage microenvironment incorporates water in its matrix and can release moisture to the extremely dry atmosphere. Chemical filters applied to mini- or microenvironments typically reduce the contaminant levels only by 95-99% and do not reduce the humidity. To pick and place reticles, the reticle storage microenvironment must be opened. The transient contaminant levels inside the empty microenvironment show an increase at the moment when the microenvironment is opened. Under the given conditions, the microenvironment returns to equilibrium levels with a time constant of 105 seconds (see Fig. 2). Similar dynamic response was measured for IPA and acetone. Figure 2. Transient humidity when the storage microenvironment was opened for reticle handling. The impact of handling on reticles stored inside

  7. Manipulating the Microvasculature and Its Microenvironment

    Science.gov (United States)

    Krishnan, Laxminarayanan; Chang, Carlos C.; Nunes, Sara S; Williams, Stuart K.; Weiss, Jeffrey A.; Hoying, James B.

    2014-01-01

    The microvasculature is a dynamic cellular system necessary for tissue health and function. Therapeutic strategies that target the microvasculature are expanding and evolving, including those promoting angiogenesis and microvascular expansion. When considering how to manipulate angiogenesis, either as part of a tissue construction approach or a therapy to improve tissue blood flow, it is important to know the microenvironmental factors that regulate and direct neovessel sprouting and growth. Much is known concerning both diffusible and matrix-bound angiogenic factors, which stimulate and guide angiogenic activity. How the other aspects of the extravascular microenvironment, including tissue biomechanics and structure, influence new vessel formation is less well known. Recent research, however, is providing new insights into these mechanisms and demonstrating that the extent and character of angiogenesis (and the resulting new microcirculation) is significantly affected. These observations and the resulting implications with respect to tissue construction and microvascular therapy are addressed. PMID:24580565

  8. Diverse macrophages polarization in tumor microenvironment.

    Science.gov (United States)

    Rhee, Inmoo

    2016-11-01

    Macrophages are traditional innate immune cells that play critical roles in the clearance of pathogens and the maintenance of tissue homeostasis. Accumulating evidence proves that macrophages affect cancer initiation and malignancy. Macrophages can be categorized into two extreme subsets, classically activated (M1) and alternatively activated (M2) macrophages based on their distinct functional abilities in response to microenvironmental stimuli. In a tumor microenvironment, tumor associated macrophages (TAMs) are considered to be of the polarized M2 phenotype that enhances tumor progression and represent a poor prognosis. Furthermore, TAMs enhance tumor angiogenesis, growth, metastasis, and immunosuppression by secreting a series of cytokines, chemokines, and proteases. The regulation of macrophage polarization is considered to be a potential future therapy for cancer management.

  9. Alkalization of tumor microenvironment for cancer treatment

    Science.gov (United States)

    Lozhkomoev, A. S.

    2017-09-01

    The paper is devoted to describing how boehmite, magnesium hydroxide and calcium hydroxide nanoparticles in the form of nanoplates with a size of 20-200 nm having cytotoxic properties to tumor cells were synthesized. It is shown that calcium hydroxide has the highest cytotoxicity, while boehmite has the lowest one. The characterization of the synthesized nanostructures demonstrated that the major antitumor factors probably are the acid-base surface properties. It is established that calcium hydroxide raises the pH of the cell culture medium up to 12.8, magnesium hydroxide—up to 10.8, boehmite—up to 8.6. At the same time, synthesized nanoplates are less toxic to the normal cell lines. The approach presented can be used for synthesis of materials that are able to change tumor cells microenvironment acidity in the defined range for anticancer therapy, and also potentiating standard chemotherapy drugs effect due to extracellular acidosis decreasing.

  10. Of Microenvironments and Mammary Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    LaBarge, Mark A; Petersen, Ole W; Bissell, Mina J

    2007-06-01

    In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.

  11. Human response to an individually controlled microenvironment

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor; Knudsen, G.L.

    2007-01-01

    The response of 48 subjects to an individually controlled microenvironment was studied at room air temperatures of 20 degrees C, 22 degrees C, and 26 degrees C An individually controlled system (ICS) comprising personalized ventilation, an under-desk air terminal device supplying cool air, a chair...... with convectively heated backrest, an under-desk radiant heating panel, and a floor-heating panel were used. The temperature of the air supplied from the personalized ventilation and the under-desk device was 20 degrees C The subjects were provided with control of the flow rate and direction of the personalized air...... at a room temperature of 22 degrees C without ICS. Thus, ICS will increase the number of satisfied occupants when applied in practice. The design and control of the ICS, as well as the background air distribution in a room, should be carefully considered in order to obtain the maximum number of occupants...

  12. Individual daytime noise exposure in different microenvironments.

    Science.gov (United States)

    Kraus, Ute; Breitner, Susanne; Hampel, Regina; Wolf, Kathrin; Cyrys, Josef; Geruschkat, Uta; Gu, Jianwei; Radon, Katja; Peters, Annette; Schneider, Alexandra

    2015-07-01

    Numerous studies showed that chronic noise exposure modeled through noise mapping is associated with adverse health effects. However, knowledge about real individual noise exposure, emitted by several sources, is limited. To explain the variation in individual daytime noise exposure regarding different microenvironments, activities and individual characteristics. In a repeated measures study in Augsburg, Germany (March 2007-December 2008), 109 individuals participated in 305 individual noise measurements with a mean duration of 5.5h. Whereabouts and activities were recorded in a diary. One-minute averages of A-weighted equivalent continuous sound pressure levels (Leq) were determined. We used mixed additive models to elucidate the variation of Leq by diary-based information, baseline characteristics and time-invariant variables like long-term noise exposure. Overall noise levels were highly variable (median: 64 dB(A); range: 37-105 dB(A)). Highest noise levels were measured in traffic during bicycling (69 dB(A); 49-97 dB(A)) and lowest while resting at home (54 dB(A); 37-94 dB(A)). Nearly all diary-based information as well as physical activity, sex and age-group had significant influences on individual noise. In an additional analysis restricted to times spent at the residences, long-term noise exposure did not improve the model fit. Individual exposures to day-time noise were moderate to high and showed high variations in different microenvironments except when being in traffic. Individual noise levels were greatly determined by personal activities but also seemed to depend on environmental noise levels. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Exosomes in tumor microenvironment: novel transporters and biomarkers.

    Science.gov (United States)

    Wang, Zhen; Chen, Jun-Qiang; Liu, Jin-Lu; Tian, Lei

    2016-10-19

    Tumor microenvironment (TME) plays an integral part in the biology of cancer, participating in tumor initiation, progression, and response to therapy. Exosome is an important part of TME. Exosomes are small vesicles formed in vesicular bodies with a diameter of 30-100 nm and a classic "cup" or "dish" morphology. They can contain microRNAs, mRNAs, DNA fragments and proteins, which are shuttled from a donor cell to recipient cells. Exosomes secreted from tumor cells are called tumor-derived (TD) exosomes. There is emerging evidence that TD exosomes can construct a fertile environment to support tumor proliferation, angiogenesis, invasion and premetastatic niche preparation. TD exosomes also may facilitate tumor growth and metastasis by inhibiting immune surveillance and by increasing chemoresistance via removal of chemotherapeutic drugs. Therefore, TD-exosomes might be potential targets for therapeutic interventions via their modification or removal. For example, exosomes can serve as specific delivery vehicles to tumors of drugs, small molecules, or agents of prevention and gene therapy. Furthermore, the biomarkers detected in exosomes of biological fluids imply a potential for exosomes in the early detection and diagnosis, prediction of therapeutic efficacy, and determining prognosis of cancer. Although exosomes may serve as cancer biomarkers and aid in the treatment of cancer, we have a long way to go before we can further enhance the anti-tumor therapy of exosomes and develop exosome-based cancer diagnostic and therapeutic strategies.

  14. Neuroepithelial transforming protein 1 short interfering RNA-mediated gene silencing with microbubble and ultrasound exposure inhibits the proliferation of hepatic carcinoma cells in vitro.

    Science.gov (United States)

    Han, Xue; Cheng, Wen; Jing, Hui; Zhang, Jiu-Wei; Tang, Li-Li

    2012-06-01

    Short interfering RNA (siRNA) has been used to knock down the expression of targeted genes in a process known as RNA interference. However, the key to RNA interference is the efficient intracellular delivery of the siRNA. In this study, we sought to enhance the efficiency of transduction and find a novel therapy for hepatic carcinoma. Three types of neuroepithelial transforming protein 1 (NET-1) siRNAs (labeled fluorescent) were designed and transduced into HepG2 cells. Then the most effective one in silencing NET-1 was determined. The HepG2 cells were divided into 5 groups: untreated control; delivery of siRNA; delivery of siRNA using Lipofectamine 2000 (Invitrogen, Carlsbad, CA; group L); delivery of siRNA using ultrasound exposure and microbubbles (group US); and delivery of siRNA using Lipofectamine, ultrasound exposure, and microbubbles (group LUS). The efficiency of siRNA transfer was determined by detection of luciferase activity on microscopy; NET-1 expression was assayed by reverse transcription-polymerase chain reaction and western blotting; and proliferation investigations of the HepG2 cells were performed. RESULTS- The transfection efficiency of microbubbles combined with ultrasound exposure was nearly equal to Lipofectamine-mediated transfection (P = .609). More importantly, the combination of Lipofectamine, microbubbles, and ultrasound exposure effectively reduced NET-1 expression compared with the other groups (P < .01). Furthermore, the proliferation of cells in groups L, US, and LUS was visibly inhibited between 24 and 72 hours. The use of a microbubble contrast agent combined with ultrasound exposure could be a potent physical method for increasing gene delivery efficiency. This technique is a promising nonviral approach that can be used in liver cancer.

  15. Innate lymphoid cells and their stromal microenvironments.

    Science.gov (United States)

    Kellermayer, Zoltán; Vojkovics, Dóra; Balogh, Péter

    2017-09-01

    In addition to the interaction between antigen presenting cells, T and B lymphocytes, recent studies have revealed important roles for a diverse set of auxiliary cells that profoundly influence the induction and regulation of immune responses against pathogens. Of these the stromal cells composed of various non-hematopoietic constituents are crucial for the creation and maintenance of specialized semi-static three-dimensional lymphoid tissue microenvironment, whereas the more recently described innate lymphoid cells are generated by the diversification of committed lymphoid precursor cells independently from clonally rearranged antigen receptor genes. Recent findings have revealed important contributions by innate lymphoid cells in inflammation and protection against pathogens in a tissue-specific manner. Importantly, lymphoid stromal cells also influence the onset of immune responses in tissue-specific fashion, raising the possibility of tissue-specific stromal - innate lymphoid cell collaboration. In this review we summarize the main features and interactions between these two cells types, with particular emphasis on ILC type 3 cells and their microenvironmental partners. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  16. Tumor and the Microenvironment: A Chance to Reframe the Paradigm of Carcinogenesis?

    Directory of Open Access Journals (Sweden)

    Mariano Bizzarri

    2014-01-01

    Full Text Available The somatic mutation theory of carcinogenesis has eventually accumulated an impressive body of shortfalls and paradoxes, as admittedly claimed by its own supporters given that the cell-based approach can hardly explain the emergence of tissue-based processes, like cancer. However, experimental data and alternatives theories developed during the last decades may actually provide a new framework on which cancer research should be reframed. Such issue may be fulfilled embracing new theoretical perspectives, taking the cells-microenvironment interplay as the privileged level of observation and assuming radically different premises as well as new methodological frameworks. Within that perspective, the tumor microenvironment cannot be merely considered akin to new “factor” to be added to an already long list of “signaling factors”; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach. That endeavour entails three fundamental aspects: general biological premises, the level of observation (i.e., the systems to which we are looking for, and the principles of biological organization that would help in integrating and understanding experimental data.

  17. Dry Eye Management: Targeting the Ocular Surface Microenvironment

    Science.gov (United States)

    Zhang, Xiaobo; Jeyalatha M, Vimalin; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo

    2017-01-01

    Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment. PMID:28661456

  18. Microenvironment Tracker (MicroTrac) Model helps track air quality

    Science.gov (United States)

    MicroTrac is a model that uses global positioning system (GPS) data to estimate time of day and duration that people spend in different microenvironments (e.g., indoors and outdoors at home, work, school).

  19. Microenvironment-Centred Dynamics in Aggressive B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Matilde Cacciatore

    2012-01-01

    Full Text Available Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.

  20. Breast cancer stem cells, cytokine networks, and the tumor microenvironment

    National Research Council Canada - National Science Library

    Korkaya, Hasan; Liu, Suling; Wicha, Max S

    2011-01-01

    .... These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment - including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune...

  1. Impact of the ovarian microenvironment on serous cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0182 TITLE: Impact of the ovarian microenvironment on serous cancer PRINCIPAL INVESTIGATOR: Joanna E. Burdette...Impact of the ovarian microenvironment on serous cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0182 5c. PROGRAM ELEMENT NUMBER 6...for intervention that would block serous cancer while still confined to the fallopian tubes. Using a series of normal, modified, and tumorigenic tubal

  2. Targeting the Prometastatic Microenvironment of the Involuting mammary gland

    Science.gov (United States)

    2016-09-01

    AWARD NUMBER: W81XWH-13-1-0290 TITLE: Targeting the Prometastatic Microenvironment of the Involuting Mammary Gland PRINCIPAL INVESTIGATOR...2016 4. TITLE AND SUBTITLE Targeting the Prometastatic Microenvironment of the Involuting mammary gland 5a. CONTRACT NUMBER Mammary Gland 5b. GRANT...complete) Task 3) Determine the pathological significance of gain and loss of LTBP1 in genetically engineered mouse models. (75% complete) Ø

  3. Identification and distribution of neuronal nitric oxide synthase and neurochemical markers in the neuroepithelial cells of the gill and the skin in the giant mudskipper, Periophthalmodon schlosseri.

    Science.gov (United States)

    Zaccone, Giacomo; Lauriano, Eugenia Rita; Kuciel, Michał; Capillo, Gioele; Pergolizzi, Simona; Alesci, Alessio; Ishimatsu, Atsushi; Ip, Yuen Kwong; Icardo, Jose M

    2017-08-05

    Mudskippers are amphibious fishes living in mudflats and mangroves. These fishes hold air in their large buccopharyngeal-opercular cavities where respiratory gas exchange takes place via the gills and higher vascularized epithelium lining the cavities and also the skin epidermis. Although aerial ventilation response to changes in ambient gas concentration has been studied in mudskippers, the localization and distribution of respiratory chemoreceptors, their neurochemical coding and function as well as physiological evidence for the gill or skin as site for O2 and CO2 sensing are currently not known. In the present study we assessed the distribution of serotonin, acetylcholine, catecholamines and nitric oxide in the neuroepithelial cells (NECs) of the mudskipper gill and skin epithelium using immunohistochemistry and confocal microscopy. Colocalization studies showed that 5-HT is coexpressed with nNOS, Na+/K+-ATPase, TH and VAChT; nNOS is coexpressed with Na+/K+-ATPase and TH in the skin. In the gill 5-HT is coexpressed with nNOS and VAhHT and nNOS is coexpressed with Na+/K+-ATPase and TH. Acetylcholine is also expressed in chain and proximal neurons projecting to the efferent filament artery and branchial smooth muscle. The serotonergic cells c labeled with VAChT, nNOS and TH, thus indicating the presence of NEC populations and the possibility that these neurotransmitters (other than serotonin) may act as primary transmitters in the hypoxic reflex in fish gills. Immunolabeling with TH antibodies revealed that NECs in the gill and the skin are innervated by catecholaminergic nerves, thus suggesting that these cells are involved in a central control of branchial functions through their relationships with the sympathetic branchial nervous system. The Na+/K+-ATPase in mitochondria-rich cells (MRCs), which are most concentrated in the gill lamellar epithelium, is colabeled with nNOS and associated with TH nerve terminals. TH-immunopositive fine varicosities were also

  4. The immune microenvironment in cutaneous leishmaniasis.

    Science.gov (United States)

    Jabbour, M N; Issa, G; Charafeddine, K; Simaan, Y; Karam, M; Khalifeh, H; Habib, R; Khalifeh, I

    2015-06-01

    duration did not correlate with Ridley pattern. The significant decrease in CD1a expression is postulated by two mechanisms; either via direct CD1a receptor uptake by leishmania amastigotes and/or negative feedback inhibition of CD1a Langerhans cells by double-negative CD3 T-regulatory cells. Modulation of the immune microenvironment in cutaneous leishmaniasis represents a potential therapeutic and prophylactic target. © 2014 European Academy of Dermatology and Venereology.

  5. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Directory of Open Access Journals (Sweden)

    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  6. One microenvironment does not fit all: heterogeneity beyond cancer cells.

    Science.gov (United States)

    Kim, Ik Sun; Zhang, Xiang H-F

    2016-12-01

    Human cancers exhibit formidable molecular heterogeneity, to a large extent accounting for the incomplete and transitory efficacy of current anti-cancer therapies. However, neoplastic cells alone do not manifest the disease, but conscript a battery of non-tumor cells to enable and sustain hallmark capabilities of cancer. Escaping immunosurveillance is one of such capabilities. Tumors evolve immunosuppressive microenvironment to subvert anti-tumor immunity. In this review, we will focus on tumor-associated myeloid cells, which constitute an essential part of the immune microenvironment and reciprocally interact with cancer cells to establish malignancy toward metastasis. The diversity and plasticity of these cells constitute another layer of heterogeneity, beyond the heterogeneity of cancer cells themselves. We envision that immune microenvironment co-evolves with the genetic heterogeneity of tumor. Addressing the question of how genetically distinct tumors shape and are shaped by unique immune microenvironment will provide an attractive rationale to develop novel immunotherapeutic modalities. Here, we discuss the complex nature of tumor microenvironment, with an emphasis on the cellular and functional heterogeneity among tumor-associated myeloid cells as well as immune environment heterogeneity in the context of a full spectrum of human breast cancers.

  7. Out on a limb: Thermal microenvironments in the tropical forest canopy and their relevance to ants.

    Science.gov (United States)

    Stark, Alyssa Y; Adams, Benjamin J; Fredley, Jennifer L; Yanoviak, Stephen P

    2017-10-01

    Small, cursorial ectotherms like ants often are immersed in the superheated air layers that develop millimeters above exposed, insolated surfaces (i.e., the thermal boundary layer). We quantified the thermal microenvironments around tree branches in the tropical rainforest canopy, and explored the effects of substrate color on the internal body temperature and species composition of arboreal ants. Branch temperatures during the day (09:00-16:00) were hottest (often > 50°C) and most variable on the upper surface, while the lowest and least variable temperatures occurred on the underside. Temperatures on black substrates declined with increasing distance above the surface in both the field and the laboratory. By contrast, a micro-scale temperature inversion occurred above white substrates. Wind events (ca. 2ms -1 ) eliminated these patterns. Internal temperatures of bodies of Cephalotes atratus workers experimentally heated in the laboratory were 6°C warmer on white vs. black substrates, and 6°C cooler than ambient in windy conditions. The composition of ant species foraging at baits differed between black-painted and unpainted tree branches, with a tendency for smaller ants to avoid the significantly hotter black surfaces. Collectively, these outcomes show that ants traversing canopy branches experience very heterogeneous thermal microenvironments that are partly influenced in predictable ways by branch surface coloration and breezy conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. The Tumor Microenvironment and Strategies to Improve Drug Distribution

    Directory of Open Access Journals (Sweden)

    Jasdeep K Saggar

    2013-06-01

    Full Text Available The microenvironment within tumors is composed of a heterogeneous mixture of cells with varying levels of nutrients and oxygen. Differences in oxygen content result in survival or compensatory mechanisms within tumors that may favor a more malignant or lethal phenotype. Cells that are rapidly proliferating are richly nourished and preferentially located close to blood vessels. Chemotherapy can target and kill cells that are adjacent to the vasculature, while cells that reside farther away are often not exposed to adequate amounts of drug and may survive and repopulate following treatment. The characteristics of the tumor microenvironment can be manipulated in order to design more effective therapies. In this review, we describe important features of the tumor microenvironment and discuss strategies whereby drug distribution and activity may be improved.

  9. Immunosuppression associated with chronic inflammation in the tumor microenvironment

    Science.gov (United States)

    Wang, Dingzhi; DuBois, Raymond N.

    2015-01-01

    Chronic inflammation contributes to cancer development via multiple mechanisms. One potential mechanism is that chronic inflammation can generate an immunosuppressive microenvironment that allows advantages for tumor formation and progression. The immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is characterized by accumulation of proinflammatory mediators, infiltration of immune suppressor cells and activation of immune checkpoint pathways in effector T cells. In this review, we highlight recent advances in our understanding of how immunosuppression contributes to cancer and how proinflammatory mediators induce the immunosuppressive microenvironment via induction of immunosuppressive cells and activation of immune checkpoint pathways. PMID:26354776

  10. Impact of the Ovarian Microenvironment on Serous Cancer

    Science.gov (United States)

    2015-08-01

    AWARD NUMBER: W81XWH-14-1-0182 TITLE: Impact of the Ovarian Microenvironment on Serous Cancer PRINCIPAL INVESTIGATOR: Burdette, Joanna E... Impact of the Ovarian Microenvironment on Serous Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0182 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...results were verified to show repression of CTGF similar to the qPCR. The results are shown in Figure 9. The volcano plot in Figure 9A shows the most

  11. Osteoporosis, a Result of an “Aged” Bone Microenvironment

    OpenAIRE

    Yu, Bo; Wang, Cun-Yu

    2016-01-01

    Osteoporosis is an age-related progressive bone disease. Recent advances in epigenetics, cell biology, osteoimmunology, and genetic epidemiology have unraveled new mechanisms and players underlying the pathology of osteoporosis, supporting a model of age-related dysregulation and crosstalk in the bone microenvironment.

  12. Exosomic microRNAs in the tumor microenvironment

    Directory of Open Access Journals (Sweden)

    Paolo eNeviani

    2015-07-01

    Full Text Available Dissecting the cross talk between tumor cells and tumor microenvironment is quickly becoming the new frontier in cancer research. It is now widely accepted that cancer cells can exert a profound influence over their surroundings, by changing the microenvironment from a normal to a tumor-supportive state that allows for sustained tumor-growth, invasion and drug-resistance. Extracellular vesicles, especially exosomes, are recognized as a new category of intercellular communicator and they are emerging as of primary importance in controlling the interplay between the tumor and its environment. Exosomes derived from cancer cells or from cells of the tumor microenvironment allow for the horizontal transfer of information by virtue of their cargo, made of functional proteins and nucleic acids that are specifically sorted and loaded in exosomes during their biogenesis. In this review we will discuss the current knowledge regarding the role invested by microRNAs, a family of short non-coding RNAs frequently deregulated in malignancies and present in exosomes, in shaping the microenvironment in a cancer-dependent manner.

  13. Effects of ground insulation and greenhouse microenvironment on ...

    African Journals Online (AJOL)

    A study was conducted at Egerton University, Njoro, Kenya to establish the potential of plastic digester to produce biogas under natural and greenhouse microenvironment. The specific objectives were to evaluate the effects of greenhouse and ground insulation on the rate and quality of biogas generation. A greenhouse ...

  14. Assessing multiparametric drug response in tissue engineered tumor microenvironment models.

    Science.gov (United States)

    Harris, Alexandra R; Yuan, Jessica X; Munson, Jennifer M

    2017-12-16

    The tumor microenvironment is important in promoting treatment resistance of tumor cells via multiple mechanisms. However, studying this interaction often proves difficult. In vivo animal models are costly, time-consuming, and often fail to adequately predict human response to treatment. Conversely, testing drug response on human tumor cells in vitro in 2D cell culture excludes the important contribution of stromal cells and biophysical forces seen in the in vivo tumor microenvironment. Here, we present tissue-engineered models of both human brain and breast tumor microenvironments incorporating key stromal cell populations for assessing multiple mechanisms of therapeutic response using flow cytometry. We show our physiologically-relevant systems used to interrogate a variety of parameters associated with chemotherapeutic efficacy, including cell death, proliferation, drug uptake, and invasion of cancer and stromal cell populations. The use of flow cytometry allows for single cell, quantitative, and fast assessments of multiple outcomes affecting anti-tumor therapy failure. Our system can be modified to add and remove cellular components with ease, thereby enabling the study of individual cellular contributions in the tumor microenvironment. Together, our models and analysis methods illustrate the importance of developing fast, cost-effective, and reproducible methods to model complex human systems in a physiologically-relevant manner that may prove useful for drug screening efforts in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Microenvironments and microscale productivity of cyanobacterial desert crusts

    Science.gov (United States)

    Garcia-Pichel, F.; Belnap, Jayne

    1996-01-01

    We used microsensors to characterize physicochemical microenvironments and photosynthesis occurring immediately after water saturation in two desert soil crusts from southeastern Utah, which were formed by the cyanobacteria Microcoleus vaginatus Gomont, Nostoc spp., and Scytonema sp. The light fields within the crusts presented steep vertical gradients in magnitude and spectral composition. Near-surface light-trapping zones were formed due to the scattering nature of the sand particles, but strong light attenuation resulted in euphotic zones only ca. 1 mm deep, which were progressively enriched in longer wavelengths with depth. Rates of gross photosynthesis (3.4a??9.4 mmol O2A?ma??2A?ha??1) and dark respiration (0.81a??3.1 mmol Oa??2A?ma??2A?ha??1) occurring within 1 to several mm from the surface were high enough to drive the formation of marked oxygen microenvironments that ranged from oxygen supersaturation to anoxia. The photosynthetic activity also resulted in localized pH values in excess of 10, 2a??3 units above the soil pH. Differences in metabolic parameters and community structure between two types of crusts were consistent with a successional pattern, which could be partially explained on the basis of the microenvironments. We discuss the significance of high metabolic rates and the formation of microenvironments for the ecology of desert crusts, as well as the advantages and limitations of microsensor-based methods for crust investigation.

  16. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    Science.gov (United States)

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate tha...

  17. Operation of the computer model for microenvironment atomic oxygen exposure

    Science.gov (United States)

    Bourassa, R. J.; Gillis, J. R.; Gruenbaum, P. E.

    1995-01-01

    A computer model for microenvironment atomic oxygen exposure has been developed to extend atomic oxygen modeling capability to include shadowing and reflections. The model uses average exposure conditions established by the direct exposure model and extends the application of these conditions to treat surfaces of arbitrary shape and orientation.

  18. Screening the Cellular Microenvironment: A Role for Microfluidics

    Science.gov (United States)

    Warrick, Jay W.; Murphy, William L.; Beebe, David J.

    2010-01-01

    The cellular microenvironment is an increasingly discussed topic in cell biology as it has been implicated in the progression of cancer and the maintenance of stem cells. The microenvironment of a cell is an organized combination of extracellular matrix (ECM), cells, and interstitial fluid that influence cellular phenotype through physical, mechanical, and biochemical mechanisms. Screening can be used to map combinations of cells and microenvironments to phenotypic outcomes in a way that can help develop more predictive in vitro models and to better understand phenotypic mechanisms from a systems biology perspective. This paper examines microenvironmental screening in terms of outcomes and benefits, key elements of the screening process, challenges for implementation, and a possible role for microfluidics as the screening platform. To assess microfluidics for use in microenvironmental screening, examples and categories of micro-scale and microfluidic technology are highlighted. Microfluidic technology shows promise for simultaneous control of multiple parameters of the microenvironment and can provide a base for scaling advanced cell-based experiments into automated high-throughput formats. PMID:20190880

  19. Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets

    NARCIS (Netherlands)

    W. van Ewijk (Willem); G. Hollander; C. Terhorst; B. Wang (Baoping)

    2000-01-01

    textabstractT-cell development is under the tight control of thymic microenvironments. Conversely, the integrity of thymic microenvironments depends on the physical presence of developing thymocytes, a phenomenon designated as 'thymic crosstalk'. We now show, using

  20. Implications of the tumor immune microenvironment for staging and therapeutics.

    Science.gov (United States)

    Taube, Janis M; Galon, Jérôme; Sholl, Lynette M; Rodig, Scott J; Cottrell, Tricia R; Giraldo, Nicolas A; Baras, Alexander S; Patel, Sanjay S; Anders, Robert A; Rimm, David L; Cimino-Mathews, Ashley

    2017-12-01

    Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an 'Immunoscore', which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies

  1. Innate and Adaptive Immune Cell Metabolism in Tumor Microenvironment.

    Science.gov (United States)

    Wu, Duojiao

    2017-01-01

    During an immune response, leukocytes undergo major changes in growth and function that are tightly coupled to dynamic shifts in metabolic processes. Immunometabolism is an emerging field that investigates the interplay between immunological and metabolic processes. The immune system has a key role to play in controlling cancer initiation and progression. Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. In tumor microenvironment, immune cells collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus prompting tumorigenesis and resistance to treatments. Here, we summarize the latest insights into the metabolic reprogramming of immune cells in tumor microenvironment and their potential roles in tumor progression and metastasis. Manipulating metabolic remodeling and immune responses may provide an exciting new option for cancer immunotherapy.

  2. A study for radiation-related tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Son, Young Sook; Hong, Seok Il; Kim, Young Soon; Jin Yong Jae; Lee, Tae Hee; Chung, Eun Kyung; Yi, Jae Yeun; Park, Myung Jin; Kim, Yun Young; Kang, Sin Keun

    1999-04-01

    In this study, we attempted to elucidate the mechanism involved in radiation-induced modification and changes of biological factors and physicochemical factors of tumor microenvironment and develop techniques and agents for the modification of tumor microenvironment which is favorable for efficient radio-cancer therapy based on our basic study. We established in vitro tumor invasion and angiogenesis model, elucidated the importance of MMPs activation and the MMPs/TIMPs complex in the invasive transition of tumor. Furthermore we showed the signaling pathway for MMPs induction through EGF receptor and TGF beta 1 stimulated E-M transition. We also established primary culture of human endothelial cells and tubule forming condition which is utilized for the detection of novel angiogenic factors. We also identified hypoxia induced signaling pathway and showed that GBE improved blood perfusion which may increase the effectiveness of radio-cancer therapy.

  3. Metabolomics Analyses of Cancer Cells in Controlled Microenvironments.

    Science.gov (United States)

    Gravel, Simon-Pierre; Avizonis, Daina; St-Pierre, Julie

    2016-01-01

    The tumor microenvironment is a complex and heterogeneous milieu in which cancer cells undergo metabolic reprogramming to fuel their growth. Cancer cell lines grown in vitro using traditional culture methods represent key experimental models to gain a mechanistic understanding of tumor biology. This protocol describes the use of gas chromatography-mass spectrometry (GC-MS) to assess metabolic changes in cancer cells grown under varied levels of oxygen and nutrients that may better mimic the tumor microenvironment. Intracellular metabolite changes, metabolite uptake and release, as well as stable isotope ((13)C) tracer analyses are done in a single experimental setup to provide an integrated understanding of metabolic adaptation. Overall, this chapter describes some essential tools and methods to perform comprehensive metabolomics analyses.

  4. Engineering three-dimensional cell mechanical microenvironment with hydrogels.

    Science.gov (United States)

    Huang, Guoyou; Wang, Lin; Wang, Shuqi; Han, Yulong; Wu, Jinhui; Zhang, Qiancheng; Xu, Feng; Lu, Tian Jian

    2012-12-01

    Cell mechanical microenvironment (CMM) significantly affects cell behaviors such as spreading, migration, proliferation and differentiation. However, most studies on cell response to mechanical stimulation are based on two-dimensional (2D) planar substrates, which cannot mimic native three-dimensional (3D) CMM. Accumulating evidence has shown that there is a significant difference in cell behavior in 2D and 3D microenvironments. Among the materials used for engineering 3D CMM, hydrogels have gained increasing attention due to their tunable properties (e.g. chemical and mechanical properties). In this paper, we provide an overview of recent advances in engineering hydrogel-based 3D CMM. Effects of mechanical cues (e.g. hydrogel stiffness and externally induced stress/strain in hydrogels) on cell behaviors are described. A variety of approaches to load mechanical stimuli in 3D hydrogel-based constructs are also discussed.

  5. Engineering mechanical microenvironment of macrophage and its biomedical applications.

    Science.gov (United States)

    Li, Jing; Li, Yuhui; Gao, Bin; Qin, Chuanguang; He, Yining; Xu, Feng; Yang, Hui; Lin, Min

    2018-01-15

    Macrophages are the most plastic cells in the hematopoietic system and can be widely found in almost all tissues. Recently studies have shown that mechanical cues (e.g., matrix stiffness and stress/strain) can significantly affect macrophage behaviors. Although existing reviews on the physical and mechanical cues that regulate the macrophage's phenotype are available, engineering mechanical microenvironment of macrophages in vitro as well as a comprehensive overview and prospects for their biomedical applications (e.g., tissue engineering and immunotherapy) has yet to be summarized. Thus, this review provides an overview on the existing methods for engineering mechanical microenvironment of macrophages in vitro and then a section on their biomedical applications and further perspectives are presented.

  6. The perivascular niche microenvironment in brain tumor progression

    Science.gov (United States)

    Charles, Nikki

    2010-01-01

    Glioblastoma, the most frequent and aggressive malignant brain tumor, has a very poor prognosis of approximately 1-year. The associated aggressive phenotype and therapeutic resistance of glioblastoma is postulated to be due to putative brain tumor stem-like cells (BTSC). The best hope for improved therapy lies in the ability to understand the molecular biology that controls BTSC behavior. The tumor vascular microenvironment of brain tumors has emerged as important regulators of BTSC behavior. Emerging data have identified the vascular microenvironment as home to a multitude of cell types engaged in various signaling that work collectively to foster a supportive environment for BTSCs. Characterization of the signaling pathways and intercellular communication between resident cell types in the microvascular niche of brain tumors is critical to the identification of potential BTSC-specific targets for therapy. PMID:20714216

  7. Tumor microenvironment: The culprit for ovarian cancer metastasis?

    Science.gov (United States)

    Luo, Zhongyue; Wang, Qiu; Lau, Wayne Bond; Lau, Bonnie; Xu, Lian; Zhao, Linjie; Yang, Huiliang; Feng, Min; Xuan, Yu; Yang, Yanfei; Lei, Lingzi; Wang, Chenlu; Yi, Tao; Zhao, Xia; Wei, Yuquan; Zhou, Shengtao

    2016-07-28

    Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently, with poor prognosis. However, the molecular mechanisms underlying ovarian cancer metastasis still remain unelucidated. The tumor microenvironment, consisting of stromal cells (including fibroblasts, macrophages, regulatory T cells, myeloid-derived suppressor cells, endothelial cells, pericytes and platelets), the extracellular matrix component (EMC) (including inflammatory cytokines, chemokines, matrix metalloproteinases, integrins, and other secreted molecules) and exosomes (small extracellular vesicles loaded with molecules), establishes an autocrine-paracrine communication circuit that reinforces invasion and cancer cell metastasis via reciprocal signaling. Recent evidences have unraveled the significant contribution of tumor microenvironment to ovarian cancer metastasis. In this review, we provide a comprehensive landscape of the reciprocity between tumor stroma and ovarian cancer cells upon metastasis, aiming to offer novel clues on the development of novel diagnostic biomarkers and therapeutic targets for ovarian cancer in future clinical practice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Extracellular matrix inspired surface functionalization with heparin, fibronectin and VEGF provides an anticoagulant and endothelialization supporting microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xue [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China); Liu, Tao [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China); Jiangsu Provincial Key Laboratory for Interventional Medical Devices, Huaiyin Institute of Technology, Huai’an (China); Chen, Yuan [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China); Zhang, Kun [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China); School of Life Science, Zhengzhou University, Zhengzhou (China); Maitz, Manfred F. [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China); Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, Hohe Str. 06, 01069 Dresden (Germany); Pan, Changjiang [Jiangsu Provincial Key Laboratory for Interventional Medical Devices, Huaiyin Institute of Technology, Huai’an (China); Chen, Junying, E-mail: chenjy@263.net [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China); Huang, Nan [Key Laboratory of Advanced Technology for Materials of Chinese Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu (China)

    2014-11-30

    Highlights: • Surface modification with fibronectin, heparin and VEGF could selectively anticoagulant and promote endothelialization. • The bioactivity of biomolecules was more efficiently maintained via specific intermolecular interaction. • Poly-l-lysine interlayer was more feasible and the degradation product had no harm to human body. - Abstract: The biocompatibility of currently used coronary artery stent is still far from perfect, which closely related to insufficient endothelialization and thrombus formation. In this study, heparin, fibronectin and VEGF were immobilized on Ti surface to construct a multifunctional microenvironment with favorable properties to inhibit thrombosis formation and promote endothelialization simultaneously. The microenvironment on Ti surface was characterized in detail and demonstrated that the Hep/Fn/VEGF biofunctional coating was constructed successfully on Ti surface. The influence of surface properties such as chemical composition, roughness, hydrophilicity, and binding density of biomolecules on the performances of hemocompatibility and cytocompatibility was evaluated and discussed. Modified surface significantly enhanced the AT III binding density and prolonged the clotting time. In vitro platelet adhesion and activation assays further proved that the modified surface presented favorable anti-coagulant property. In addition, the proliferation of endothelial progenitor cells (EPCs) and endothelial cells (ECs) on the Hep/Fn/VEGF biofunctional coating was significantly promoted. In conclusion, the Hep/Fn/VEGF biofunctional coating was successfully constructed with desirable anticoagulant and endothelialization supporting properties. This work may provide a promising approach for biofunctional surface modification of coronary artery stent to acquire a desired multifunctional microenvironment.

  9. Reprogramming the Metastatic Microenvironment to Combat Disease Recurrence

    Science.gov (United States)

    2016-10-01

    dominant immunologic response7,10. Instead many patients have significant numbers of tumor-infiltrating innate immune cells including macrophages and...using existing breast cancer patient samples to create a biomarker panel that combines disseminated tumor cell (DTC) classification and “ immune ...protects tumor cells from the cytotoxic effects of chemotherapy4. This protective microenvironment may also create an immune privileged site that prevents

  10. Impact of the Ovarian Microenvironment on Serous Cancer

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0182 TITLE: Impact of the Ovarian Microenvironment on Serous Cancer PRINCIPAL INVESTIGATOR: Joanna Burdette...FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2016 2. REPORT TYPE Annual 3. DATES COVERED 1Aug2015 - 31Jul2016 4. TITLE AND SUBTITLE Impact of...indirectly. Future research will use fast- protein liquid chromatography (FPLC) to narrow down the list of proteins potentially stimulated migration

  11. Immune microenvironments in solid tumors: new targets for therapy

    OpenAIRE

    Shiao, Stephen L.; Ganesan, A. Preethi; Rugo, Hope S; Coussens, Lisa M.

    2011-01-01

    In this timely review, Coussens and colleagues delve into the current landscape of tumor inflammation. They survey the current literature on cancer-associated immune microenvironments and assess the effects of various types of immune cells—from both the adaptive and immune arms—on tumor growth. This review further discusses the immune-based mechanisms that regulate the response to conventional cytotoxic therapy and evaluates combinational strategies for cancer therapy that combine cytotoxins ...

  12. Tumor Microenvironment Inflammation and Obesity in Advanced Prostate Cancer

    Science.gov (United States)

    2015-09-30

    of prostate cancer in the cancer prevention study II nutrition cohort. Cancer Epidemiol Biomarkers Prev 161(1):63–69 3. Freedland S, Banez L, Sun L...mass index, weight change, and risk of prostate cancer in the cancer prevention study II nutrition cohort. Cancer Epidemiol Biomarkers Prev 161(1):63...AWARD NUMBER: W81XWH-14-1-0064 TITLE: Tumor Microenvironment Inflammation and Obesity in Advanced Prostate Cancer PRINCIPAL INVESTIGATOR

  13. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis

    Science.gov (United States)

    Iozzo, Renato V; Sanderson, Ralph D

    2011-01-01

    Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecans and glypicans, can also directly affect cancer growth by modulating key signalling pathways. The bioactivity of these proteoglycans is further modulated by several classes of enzymes within the tumour microenvironment: (i) sheddases that cleave transmembrane or cell-associated syndecans and glypicans, (ii) various proteinases that cleave the protein core of pericellular proteoglycans and (iii) heparanases and endosulfatases which modify the structure and bioactivity of various heparan sulphate proteoglycans and their bound growth factors. In contrast, some of the small leucine-rich proteoglycans, such as decorin and lumican, act as tumour repressors by physically antagonizing receptor tyrosine kinases including the epidermal growth factor and the Met receptors or integrin receptors thereby evoking anti-survival and pro-apoptotic pathways. In this review we will critically assess the expanding repertoire of molecular interactions attributed to various proteoglycans and will discuss novel proteoglycan functions modulating cancer progression, invasion and metastasis and how these factors regulate the tumour microenvironment. PMID:21155971

  14. Designing the stem cell microenvironment for guided connective tissue regeneration.

    Science.gov (United States)

    Bogdanowicz, Danielle R; Lu, Helen H

    2017-12-01

    Adult mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine because of their ability to self-renew and their capacity for multilineage differentiation and tissue regeneration. For connective tissues, such as ligaments or tendons, MSCs are vital to the modulation of the inflammatory response following acute injury while also interacting with resident fibroblasts to promote cell proliferation and matrix synthesis. To date, MSC injection for connective tissue repair has yielded mixed results in vivo, likely due to a lack of appropriate environmental cues to effectively control MSC response and promote tissue healing instead of scar formation. In healthy tissues, stem cells reside within a complex microenvironment comprising cellular, structural, and signaling cues that collectively maintain stemness and modulate tissue homeostasis. Changes to the microenvironment following injury regulate stem cell differentiation, trophic signaling, and tissue healing. Here, we focus on models of the stem cell microenvironment that are used to elucidate the mechanisms of stem cell regulation and inspire functional approaches to tissue regeneration. Recent studies in this frontier area are highlighted, focusing on how microenvironmental cues modulate MSC response following connective tissue injury and, more importantly, how this unique cell environment can be programmed for stem cell-guided tissue regeneration. © 2017 New York Academy of Sciences.

  15. Obesity, metabolism and the microenvironment: Links to cancer

    Directory of Open Access Journals (Sweden)

    Sneha Sundaram

    2013-01-01

    Full Text Available Historically, cancer research has focused on identifying mutations or amplification of genes within the tumor, which informed the development of targeted therapies against affected pathways. This work often considers tumor cells in isolation; however, it is becoming increasingly apparent that the microenvironment surrounding tumor cells strongly influences tumor onset and progression. This is the so-called "seed and soil" hypothesis wherein the seed (cancer cell is fed and molded by the metabolites, growth factors, modifications of the extracellular matrix or angiogenic factors provided by the soil (or stroma. Currently, 65% of the US population is obese or overweight; similarly staggering figures are reported in US children and globally. Obesity mediates and can exacerbate, both normal and tumor microenvironment dysfunction. Many obesity-associated endocrine, metabolic and inflammatory mediators are suspected to play a role in oncogenesis by modifying systemic nutrient metabolism and the nutrient substrates available locally in the stroma. It is vitally important to understand the biological processes linking obesity and cancer to develop better intervention strategies aimed at curbing the carcinogenic events associated with obesity. In this review, obesity-driven changes in both the normal and tumor microenvironment, alterations in metabolism, and release of signaling molecules such as endocrine, growth, and inflammatory mediators will be highlighted. In addition, we will discuss the effects of the timing of obesity onset or particular "windows of susceptibility," with a focus on breast cancer etiology.

  16. Orthodontic treatment mediates dental pulp microenvironment via IL17A.

    Science.gov (United States)

    Yu, Wenjing; Zhang, Yueling; Jiang, Chunmiao; He, Wei; Yi, Yating; Wang, Jun

    2016-06-01

    Orthodontic treatment induces dental tissue remodeling; however, dental pulp stem cell (DPSC)-mediated pulp micro-environmental alteration is still largely uncharacterized. In the present study, we identified elevated interleukin-17A (IL17A) in the dental pulp, which induced the osteogenesis of DPSCs after orthodontic force loading. Tooth movement animal models were established in Sprague-Dawley rats, and samples were harvested at 1, 4, 7, 14, and 21 days after orthodontic treatment loading. DPSC self-renewal and differentiation at different time points were examined, as well as the alteration of the microenvironment of dental pulp tissue by histological analysis and the systemic serum IL17A expression level by an ELISA assay. In vitro recombinant IL17A treatment was used to confirm the effect of IL17A on the enhancement of DPSC self-renewal and differentiation. Orthodontic treatment altered the dental pulp microenvironment by activation of the pro-inflammatory cytokine IL17A in vivo. Orthodontic loading significantly promoted the self-renewal and differentiation of DPSCs. Inflammation and elevated IL17A secretion occurred in the dental pulp during orthodontic tooth movement. Moreover, in vitro recombinant IL17A treatment mimicked the enhancement of the self-renewal and differentiation of DPSCs. Orthodontic treatment enhanced the differentiation and self-renewal of DPSCs, mediated by orthodontic-induced inflammation and subsequent elevation of IL17A level in the dental pulp microenvironment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments.

    Science.gov (United States)

    Cipitria, Amaia; Salmeron-Sanchez, Manuel

    2017-08-01

    Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report provides a critical overview of key studies that incorporate growth factor (GF) signalling and mechanotransduction into the design of advanced microenvironments. Materials systems have been developed for surface-bound presentation of GFs, either covalently tethered or sequestered through physico-chemical affinity to the matrix, as an alternative to soluble GFs. Furthermore, some materials contain both GF and integrin binding regions and thereby enable synergistic signalling between the two. Mechanotransduction refers to the ability of the cells to sense physical properties of the ECM and to transduce them into biochemical signals. Various aspects of the physics of the ECM, i.e. stiffness, geometry and ligand spacing, as well as time-dependent properties, such as matrix stiffening, degradability, viscoelasticity, surface mobility as well as spatial patterns and gradients of physical cues are discussed. To conclude, various examples illustrate the potential for cooperative signalling of growth factors and the physical properties of the microenvironment for potential applications in regenerative medicine, cancer research and drug testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Biophysics and dynamics of natural and engineered stem cell microenvironments.

    Science.gov (United States)

    Keung, Albert J; Healy, Kevin E; Kumar, Sanjay; Schaffer, David V

    2010-01-01

    Stem cells are defined by their ability to self-renew and to differentiate into one or more mature lineages, and they reside within natural niches in many types of adult and embryonic tissues that present them with complex signals to regulate these two hallmark properties. The diverse nature of these in vivo microenvironments raises important questions about the microenvironmental cues regulating stem cell plasticity, and the stem cell field has built a strong foundation of knowledge on the biochemical identities and regulatory effects of the soluble, cellular, and extracellular matrix factors surrounding stem cells through the isolation and culture of stem cells in vitro within microenvironments that, in effect, emulate the properties of the natural niche. Recent work, however, has expanded the field's perspective to include biophysical and dynamic characteristics of the microenvironment. These include biomechanical characteristics such as elastic modulus, shear force, and cyclic strain; architectural properties such as geometry, topography, and dimensionality; and dynamic structures and ligand profiles. We will review how these microenvironmental characteristics have been shown to regulate stem cell fate and discuss future research directions that may help expand our current understanding of stem cell biology and aid its application to regenerative medicine.

  19. Custom Design of the Cardiac Microenvironment With Biomaterials

    Science.gov (United States)

    Davis, Michael E.; Hsieh, Patrick C.H.; Grodzinsky, Alan J.; Lee, Richard T.

    2009-01-01

    Many strategies for repairing injured myocardium are under active investigation, with some early encouraging results. These strategies include cell therapies, despite little evidence of long-term survival of exogenous cells, and gene or protein therapies, often with incomplete control of locally-delivered dose of the factor. We propose that, ultimately, successful repair and regeneration strategies will require quantitative control of the myocardial microenvironment. This precision control can be engineered through designed biomaterials that provide quantitative adhesion, growth, or migration signals. Quantitative timed release of factors can be regulated by chemical design to direct cellular differentiation pathways such as angiogenesis and vascular maturation. Smart biomaterials respond to the local environment, such as protease activity or mechanical forces, with controlled release or activation. Most of these new biomaterials provide much greater flexibility for regenerating tissues ex vivo, but emerging technologies like self-assembling nanofibers can now establish intramyocardial cellular microenvironments by injection. This may allow percutaneous cardiac regeneration and repair approaches, or injectable-tissue engineering. Finally, materials can be made to multifunction by providing sequential signals with custom design of differential release kinetics for individual factors. Thus, new rationally-designed biomaterials no longer simply coexist with tissues, but can provide precision bioactive control of the microenvironment that may be required for cardiac regeneration and repair. PMID:16002755

  20. Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance

    Directory of Open Access Journals (Sweden)

    Jennifer Pasquier

    2013-01-01

    Full Text Available Despite recent progresses in cancer therapy and increased knowledge in cancer biology, ovarian cancer remains a challenging condition. Among the latest concepts developed in cancer biology, cancer stem cells and the role of microenvironment in tumor progression seem to be related. Indeed, cancer stem cells have been described in several solid tumors including ovarian cancers. These particular cells have the ability to self-renew and reconstitute a heterogeneous tumor. They are characterized by specific surface markers and display resistance to therapeutic regimens. During development, specific molecular cues from the tumor microenvironment can play a role in maintaining and expanding stemness of cancer cells. The tumor stroma contains several compartments: cellular component, cytokine network, and extracellular matrix. These different compartments interact to form a permissive niche for the cancer stem cells. Understanding the molecular cues underlying this crosstalk will allow the design of new therapeutic regimens targeting the niche. In this paper, we will discuss the mechanisms implicated in the interaction between ovarian cancer stem cells and their microenvironment.

  1. Chemical and physical microenvironments at the Viking landing sites

    Science.gov (United States)

    Clark, B. C.

    1979-01-01

    Physical and chemical considerations permit the division of the near-surface regolith on Mars into at least six zones of distinct microenvironments. The zones are euphotic, duricrust/peds, tempofrost, permafrost, endolithic, and interfacial/transitional. Microenvironments vary significantly in temperature extremes, mean temperature, salt content, relative pressure of water vapor, UV and visible light irradiance, and exposure to ionizing radiation events (100 Mrad) and oxidative molecular species. From what is known of the chemistry of the atmosphere and regolith fines (soil), limits upon the aqueous chemistry of soil pastes may be estimated. Heat of wetting could reach 45 cal/g dry soil; initial pH is indeterminate between 1 and 10; ionic strength and salinity are predicted to be extremely high; freezing point depression is inadequate to provide quantities of liquid water except in special cases. The prospects for biotic survival are grim by terrestrial standards, but the extremes of biological resiliency are inaccessible to evaluation. Second-generation in situ experiments which will better define Martian microenvironments are clearly possible. Antarctic dry valleys are approximations to Martian conditions, but deviate significantly by at least half-a-dozen criteria.

  2. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney.

    Science.gov (United States)

    Stemmer, Kerstin; Perez-Tilve, Diego; Ananthakrishnan, Gayathri; Bort, Anja; Seeley, Randy J; Tschöp, Matthias H; Dietrich, Daniel R; Pfluger, Paul T

    2012-09-01

    Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO) promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens) or partially resistant (DIOres) to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.

  3. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney

    Directory of Open Access Journals (Sweden)

    Kerstin Stemmer

    2012-09-01

    Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens or partially resistant (DIOres to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1, interleukin (IL-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3 and mammalian target of rapamycin (mTOR phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.

  4. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2013-12-01

    Full Text Available Introduction: The dysregulation of pH by cancerous cells of solid tumors is able to create a unique milieu that is in favor of progression, invasion and metastasis as well as chemo-/immuno-resistance traits of solid tumors. Bioelements involved in pH dysregulation provide new set of oncotargets, inhibition of which may result in better clinical outcome. Methods: To study the impacts of pH dysregulation, we investigated the tumor development and progression in relation with Warburg effect, glycolysis and formation of aberrant tumor microenvironment. Results: The upregulation of glucose transporter GLUT-1 and several enzymes involve in glycolysis exacerbates this phenomenon. The accumulation of lactic acids in cancer cells provokes upregulation of several transport machineries (MCT-1, NHE-1, CA IX and H+ pump V-ATPase resulting in reinforced efflux of proton into extracellular fluid. This deviant event makes pH to be settled at 7.4 and 6.6 respectively in cancer cells cytoplasm and extracellular fluid within the tumor microenvironment, which in return triggers secretion of lysosomal components (various enzymes in acidic milieu with pH 5 into cytoplasm. All these anomalous phenomena make tumor microenvironment (TME to be exposed to cocktail of various enzymes with acidic pH, upon which extracellular matrix (ECM can be remodeled and even deformed, resulting in emergence of a complex viscose TME with high interstitial fluid pressure. Conclusion: It seems that pH dysregulation is able to remodel various physiologic functions and make solid tumors to become much more invasive and metastatic. It also can cause undesired resistance to chemotherapy and immunotherapy. Hence, cancer therapy needs to be reinforced using specific inhibitors of bioelements involved in pH dysregulation of TME in solid tumors.

  5. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy.

    Science.gov (United States)

    Barar, Jaleh; Omidi, Yadollah

    2013-01-01

    The dysregulation of pH by cancerous cells of solid tumors is able to create a unique milieu that is in favor of progression, invasion and metastasis as well as chemo-/immuno-resistance traits of solid tumors. Bioelements involved in pH dysregulation provide new set of oncotargets, inhibition of which may result in better clinical outcome. To study the impacts of pH dysregulation, we investigated the tumor development and progression in relation with Warburg effect, glycolysis and formation of aberrant tumor microenvironment. The upregulation of glucose transporter GLUT-1 and several enzymes involve in glycolysis exacerbates this phenomenon. The accumulation of lactic acids in cancer cells provokes upregulation of several transport machineries (MCT-1, NHE-1, CA IX and H(+) pump V-ATPase) resulting in reinforced efflux of proton into extracellular fluid. This deviant event makes pH to be settled at 7.4 and 6.6 respectively in cancer cells cytoplasm and extracellular fluid within the tumor microenvironment, which in return triggers secretion of lysosomal components (various enzymes in acidic milieu with pH 5) into cytoplasm. All these anomalous phenomena make tumor microenvironment (TME) to be exposed to cocktail of various enzymes with acidic pH, upon which extracellular matrix (ECM) can be remodeled and even deformed, resulting in emergence of a complex viscose TME with high interstitial fluid pressure. It seems that pH dysregulation is able to remodel various physiologic functions and make solid tumors to become much more invasive and metastatic. It also can cause undesired resistance to chemotherapy and immunotherapy. Hence, cancer therapy needs to be reinforced using specific inhibitors of bioelements involved in pH dysregulation of TME in solid tumors.

  6. Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

    Science.gov (United States)

    Nakagawa, Saki; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Takahashi, Yayoi; Rai, Yoshiaki; Sagara, Yasuaki; Ohi, Yasuyo; Hirakawa, Hisashi; Tamaki, Kentaro; Ishida, Takanori; Watanabe, Mika; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2016-01-01

    Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.

  7. Engineered nanomedicine for myeloma and bone microenvironment targeting.

    Science.gov (United States)

    Swami, Archana; Reagan, Michaela R; Basto, Pamela; Mishima, Yuji; Kamaly, Nazila; Glavey, Siobhan; Zhang, Sufeng; Moschetta, Michele; Seevaratnam, Dushanth; Zhang, Yong; Liu, Jinhe; Memarzadeh, Masoumeh; Wu, Jun; Manier, Salomon; Shi, Jinjun; Bertrand, Nicolas; Lu, Zhi Ning; Nagano, Kenichi; Baron, Roland; Sacco, Antonio; Roccaro, Aldo M; Farokhzad, Omid C; Ghobrial, Irene M

    2014-07-15

    Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(D,L-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.

  8. Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment

    Science.gov (United States)

    Costa, Fabricio F; Seftor, Elisabeth A; Bischof, Jared M; Kirschmann, Dawn A; Strizzi, Luigi; Arndt, Kelly; de Fatima Bonaldo, Maria; Soares, Marcelo B; Hendrix, Mary JC

    2010-01-01

    We have previously shown that the microenvironment of human embryonic stem cells (hESCs) is able to change and reprogram aggressive cancer cells to a less aggressive state. Some mechanisms implicated in the phenotypic changes observed after this exposure are mainly associated with the Nodal signaling pathway, which plays a key role in tumor cell plasticity. However, several other molecular mechanisms might be related directly and/or indirectly to these changes, including microRNA (miRNA) regulation and DNA methylation. Aim: To further explore the epigenetic mechanisms potentially underlying the phenotypic changes that occur after exposing metastatic melanoma cells to a hESC microenvironment. Materials & Methods: A total of 365 miRNAs were screened using the TaqMan® Low Density Arrays. We also evaluated whether DNA methylation could be one of the factors regulating the expression of the inhibitor of Nodal, Lefty, in hESCs (where it is highly expressed) vs melanoma cells (where it is not expressed). Results: Using these experimental approaches, we identified miRNAs that are up- and down-regulated in melanoma cells exposed to a hESC microenvironment, such as miR-302a and miR-27b, respectively. We also demonstrate that Notch4 is one of the targets of miR-302a, which is upstream of Nodal. Additionally, one of the mechanisms that might explain the absence of the inhibitor of Nodal, Lefty, in cancer cells is silencing by DNA methylation, which provides new insights into the unregulated expression of Nodal in melanoma. Conclusion: These findings suggest that epigenetic changes such as DNA methylation and regulation by microRNAs might play a significant role in tumor cell plasticity and the metastatic phenotype. PMID:20495621

  9. Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Eunice Yuen-Ting Lau

    2017-01-01

    Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.

  10. Low Dose IR Creates an Oncogenic Microenvironment by Inducing Premature

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Zhi-Min [Harvard School of Public Health

    2013-04-28

    Introduction Much of the work addressing ionizing radiation-induced cellular response has been carried out mainly with the traditional cell culture technique involving only one cell type, how cellular response to IR is influenced by the tissue microenvironment remains elusive. By use of a three-dimensional (3D) co-culture system to model critical interactions of different cell types with their neighbors and with their environment, we recently showed that low-dose IR-induced extracellular signaling via the tissue environment affects profoundly cellular responses. This proposal aims at determining the response of mammary epithelial cells in a tissue-like setting.

  11. Combined Effects of Pericytes in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Aline Lopes Ribeiro

    2015-01-01

    Full Text Available Pericytes are multipotent perivascular cells whose involvement in vasculature development is well established. Evidences in the literature also suggest that pericytes display immune properties and that these cells may serve as an in vivo reservoir of stem cells, contributing to the regeneration of diverse tissues. Pericytes are also capable of tumor homing and are important cellular components of the tumor microenvironment (TME. In this review, we highlight the contribution of pericytes to some classical hallmarks of cancer, namely, tumor angiogenesis, growth, metastasis, and evasion of immune destruction, and discuss how collectively these hallmarks could be tackled by therapies targeting pericytes, providing a rationale for cancer drugs aiming at the TME.

  12. Impact of Microenvironment and Stem-Like Plasticity in Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Raggi, Chiara; Invernizzi, Pietro; Andersen, Jesper Bøje

    2014-01-01

    Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) represent a major challenge in the assessment of effective targeted therapies. Molecular and cellular mechanisms underlying diversity of CCA growth patterns remain a key issue and a clinical concern...... or tumor microenvironment (TME) likely promotes initiation and progression of this malignancy contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA....

  13. T-cell exhaustion in the tumor microenvironment

    Science.gov (United States)

    Jiang, Y; Li, Y; Zhu, B

    2015-01-01

    T-cell exhaustion was originally identified during chronic infection in mice, and was subsequently observed in humans with cancer. The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination. Restoring exhausted T cells represents an inspiring strategy for cancer treatment, which has yielded promising results and become a significant breakthrough in the cancer immunotherapy. In this review, we overview the updated understanding on the exhausted T cells in cancer and their potential regulatory mechanisms and discuss current therapeutic interventions targeting exhausted T cells in clinical trials. PMID:26086965

  14. Mammographic evidence of microenvironment changes in tumorous breasts.

    Science.gov (United States)

    Marin, Zach; Batchelder, Kendra A; Toner, Brian C; Guimond, Lyne; Gerasimova-Chechkina, Evgeniya; Harrow, Amy R; Arneodo, Alain; Khalil, Andre

    2017-04-01

    The microenvironment of breast tumors plays a critical role in tumorigenesis. As long as the structural integrity of the microenvironment is upheld, the tumor is suppressed. If tissue structure is lost through disruptions in the normal cell cycle, the microenvironment may act as a tumor promoter. Therefore, the properties that distinguish between healthy and tumorous tissues may not be solely in the tumor characteristics but rather in surrounding non-tumor tissue. The goal of this paper was to show preliminary evidence that tissue disruption and loss of homeostasis in breast tissue microenvironment and breast bilateral asymmetry can be quantitatively and objectively assessed from mammography via a localized, wavelet-based analysis of the whole breast. A wavelet-based multifractal formalism called the 2D Wavelet Transform Modulus Maxima (WTMM) method was used to quantitate density fluctuations from mammographic breast tissue via the Hurst exponent (H). Each entire mammogram was cut in hundreds of 360 × 360 pixel subregions in a gridding scheme of overlapping sliding windows, with each window boundary separated by 32 pixels. The 2D WTMM method was applied to each subregion individually. A data mining approach was set up to determine which metrics best discriminated between normal vs. cancer cases. These same metrics were then used, without modification, to discriminate between normal vs. benign and benign vs. cancer cases. The density fluctuations in healthy mammographic breast tissue are either monofractal anti-correlated (H 1/2) for dense tissue. However, tissue regions with H~1/2, as well as left vs. right breast asymetries, were found preferably in tumorous (benign or cancer) breasts vs. normal breasts, as quantified via a combination metric yielding a P-value ~ 0.0006. No metric considered showed significant differences between cancer vs. benign breasts. Since mammographic tissue regions associated with uncorrelated (H~1/2) density fluctuations were

  15. Nanocomposite injectable gels capable of self-replenishing regenerative extracellular microenvironments for in vivo tissue engineering.

    Science.gov (United States)

    Nagahama, Koji; Oyama, Naho; Ono, Kimika; Hotta, Atsushi; Kawauchi, Keiko; Nishikata, Takahito

    2018-01-30

    regenerative extracellular microenvironment within the gels in the body, demonstrating the potential utility of the nanocomposite injectable gels for in vivo tissue engineering.

  16. Inflammatory Alterations of the Extracellular Matrix in the Tumor Microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Iijima, Junko [Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan); Konno, Kenjiro [Department of Animal Medical Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan); Itano, Naoki, E-mail: itanon@cc.kyoto-su.ac.jp [Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan)

    2011-08-09

    Complex interactions between cancer cells and host stromal cells result in the formation of the “tumor microenvironment”, where inflammatory alterations involve the infiltration of tumor-associated fibroblasts and inflammatory leukocytes that contribute to the acquisition of malignant characteristics, such as increased cancer cell proliferation, invasiveness, metastasis, angiogenesis, and avoidance of adaptive immunity. The microenvironment of a solid tumor is comprised not only of cellular compartments, but also of bioactive substances, including cytokines, growth factors, and extracellular matrix (ECM). ECM can act as a scaffold for cell migration, a reservoir for cytokines and growth factors, and a signal through receptor binding. During inflammation, ECM components and their degraded fragments act directly and indirectly as inflammatory stimuli in certain cases and regulate the functions of inflammatory and immune cells. One such ECM component, hyaluronan, has recently been implicated to modulate innate immune cell function through pattern recognition toll-like receptors and accelerate the recruitment and activation of tumor-associated macrophages in inflamed cancers. Here, we will summarize the molecular mechanism linking inflammation with ECM remodeling in the tumor microenvironment, with a particular emphasis on the role of hyaluronan in controlling the inflammatory response.

  17. Emergence of therapy resistance in multiple myeloma in heterogeneous microenvironment

    Science.gov (United States)

    Wu, Amy; Zhang, Qiucen; Lambert, Guillaume; Khin, Zayar; Silva, Ariosto; Gatenby, Robert; Kim, Hyungsung; Pourmand, Nader; Austin, Robert; Sturm, James

    2014-03-01

    Cancer chemotherapy resistance is always a problem that is not clear considering spatial heterogeneity in the tumor microenvironment. We culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region in a microfluidic device which mimics the tumor microenvironment with a chemotherapy drug gradient and microhabitats. Resistance of the multiple myeloma cells to doxorubicin emerged within two weeks. For the resistant cells evolved from the devices, the doxorubicin concentration that inhibits 50% of the controlled population increased by 16-fold than the parental cells. Whole transcriptome sequencing revealed that 39% of newly acquired mutational hotspots (the genes with more than 3 non-synonymous point mutation) of the resistant cells are involved in apoptosis and DNA repair. On the other hand, 40% of the non-mutated genes that are abnormally regulated in the resistant cells, are involved in metabolism, biosynthesis, and biomolecular transport. Among them, metabolic drug efflux pumps and oxidative stress scavengers are up-regulated to reduce the cytotoxicity of doxorubicin and further result in the resistance. The roles of the spatial drug gradients and microhabitats in rapid emergence of cancer resistance will be discussed. The project described was supported by the National Science Foundation and the National Cancer Institute.

  18. Oxidative and Nitrosative Stress in the Metastatic Microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Ortega, Ángel L. [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 15 Av. Blasco Ibañez, 46010 Valencia (Spain); Mena, Salvador [Green Molecular S.L., Pol. Ind. La Coma-Parc Cientific, 46190 Paterna, Valencia (Spain); Estrela, José M., E-mail: jose.m.estrela@uv.es [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 15 Av. Blasco Ibañez, 46010 Valencia (Spain)

    2010-03-26

    Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Additional factors, such as the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and endothelial cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids and reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H{sub 2}O{sub 2} are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue can still be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps; from the primary tumor until colonization of a distant organ; metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles.

  19. Particle-bound polycyclic aromatic hydrocarbon concentrations in transportation microenvironments

    Science.gov (United States)

    Houston, Douglas; Wu, Jun; Yang, Dongwoo; Jaimes, Guillermo

    2013-06-01

    This study is one of the first case studies to characterize the exposure of urban residents to traffic-related air pollution across locations and transportation microenvironments during everyday activities. Twenty-four adult residents of Boyle Heights, a neighborhood near downtown Los Angeles, carried a portable air pollution monitor and a Global Positioning Systems (GPS) tracking device for a total of 96 days. We found significant spatial and temporal variation in the particle-bound polycyclic aromatic hydrocarbon (pPAH) concentrations in transportation microenvironments. Average pPAH concentrations were higher while walking outdoors (190 ng m-3) compared to traveling in private passenger vehicles (138-155 ng m-3) or traveling in public transportation (61-124 ng m-3). Although travel comprised 5% of participant days, it was associated with 27% of overall daily pPAH exposure. Regression models explained 40-55% of the variation in daily average pPAH concentrations, and 40-44% of the variation in 1-min interval concentrations. Important factors included time spent traveling, travel speed, meteorological and nearby land use factors, time of day, and proximity to roadways. Although future research is needed to develop stronger predictive models, our study demonstrates portable tracking devices can provide a more complete, diurnal characterization of air pollution exposures for urban populations.

  20. Stromal cells in tumor microenvironment and breast cancer.

    Science.gov (United States)

    Mao, Yan; Keller, Evan T; Garfield, David H; Shen, Kunwei; Wang, Jianhua

    2013-06-01

    Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

  1. Stroma Cells in Tumor Microenvironment and Breast Cancer

    Science.gov (United States)

    Mao, Yan; Keller, Evan T.; Garfield, David H.; Shen, Kunwei; Wang, Jianhua

    2015-01-01

    Cancer is a systemic disease, encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic resistances. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistances. This review summarizes the current understanding of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. The effects of other stromal components such as endothelial cells, macrophages and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to sort patients into a specific and confirmed subtype for personalized treatment. PMID:23114846

  2. Lymphatic vessels regulate immune microenvironments in human and murine melanoma.

    Science.gov (United States)

    Lund, Amanda W; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S; Broggi, Maria A; Spranger, Stefani; Gajewski, Thomas F; Alitalo, Kari; Eikesdal, Hans P; Wiig, Helge; Swartz, Melody A

    2016-09-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.

  3. Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma.

    Science.gov (United States)

    Han, Ke-Qi; He, Xue-Qun; Ma, Meng-Yu; Guo, Xiao-Dong; Zhang, Xue-Min; Chen, Jie; Han, Hui; Zhang, Wei-Wei; Zhu, Quan-Gang; Nian, Hua; Ma, Li-Jun

    2015-04-28

    To study the inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma (HCC) in nude mice. CBRH-7919 HCC cells were injected into the subcutaneous region of nude mice. Beginning two weeks after the challenge, tumor growth was measured every week for six weeks. The stromal microenvironment and inflammatory cell infiltration was assessed by immunohistochemistry in paired tumor and adjacent peritumoral samples, and macrophage phenotype was assessed using double-stain immunohistochemistry incorporating expression of an intracellular enzyme. A chemokine PCR array, comprised of 98 genes, was used to screen differential gene expressions, which were validated by Western blotting. Additionally, expression of identified chemokines was knocked-down by RNA interference, and the effect on tumor growth was assessed. Inflammatory cell infiltrates are a key feature of adjacent peritumoral tissues with increased macrophage, neutrophil, and T cell (specifically helper and activated subsets) infiltration. Macrophages within adjacent peritumoral tissues express inducible nitric oxide synthase, suggestive of a proinflammatory phenotype. Fifty-one genes were identified in tumor tissues during the progression period, including 50 that were overexpressed (including CXCL1, CXCL2 and CXCL3) and three that were underexpressed (CXCR1, Ifg and Actb). RNA interference of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice and inhibited expression of CXCL2, CXCL3 and interleukin-1β protein. These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.

  4. Revisiting ovarian cancer microenvironment: a friend or a foe?

    Science.gov (United States)

    Zhang, Boyi; Chen, Fei; Xu, Qixia; Han, Liu; Xu, Jiaqian; Gao, Libin; Sun, Xiaochen; Li, Yiwen; Li, Yan; Qian, Min; Sun, Yu

    2017-09-19

    Development of ovarian cancer involves the co-evolution of neoplastic cells together with the adjacent microenvironment. Steps of malignant progression including primary tumor outgrowth, therapeutic resistance, and distant metastasis are not determined solely by genetic alterations in ovarian cancer cells, but considerably shaped by the fitness advantage conferred by benign components in the ovarian stroma. As the dynamic cancer topography varies drastically during disease progression, heterologous cell types within the tumor microenvironment (TME) can actively determine the pathological track of ovarian cancer. Resembling many other solid tumor types, ovarian malignancy is nurtured by a TME whose dark side may have been overlooked, rather than overestimated. Further, harnessing breakthrough and targeting cures in human ovarian cancer requires insightful understanding of the merits and drawbacks of current treatment modalities, which mainly target transformed cells. Thus, designing novel and precise strategies that both eliminate cancer cells and manipulate the TME is increasingly recognized as a rational avenue to improve therapeutic outcome and prevent disease deterioration of ovarian cancer patients.

  5. The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

    Directory of Open Access Journals (Sweden)

    Dimakatso Alice Senthebane

    2017-07-01

    Full Text Available Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially ‘omics’ technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously ‘unsupportive’ microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely

  6. Targets in the microenvironment of rectal cancer : A focus on angiogenic growth factors and chemokines

    NARCIS (Netherlands)

    Tamas, Karin Rita

    2015-01-01

    Cancer cells interact with each other, and with cells of the tumor microenvironment. This coincides with the production of numerous soluble factors which can stimulate cancer cell growth and migration. In addition the tumor microenvironment can facilitate cancer cells to escape the effect of

  7. Inflammation and Tumor Microenvironment in Lymph Node Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Xuesong; Takekoshi, Tomonori; Sullivan, Ashley; Hwang, Sam T., E-mail: sthwang@mcw.edu [Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States)

    2011-03-01

    In nearly all human cancers, the presence of lymph node (LN) metastasis increases clinical staging and portends worse prognosis (compared to patients without LN metastasis). Herein, principally reviewing experimental and clinical data related to malignant melanoma, we discuss diverse factors that are mechanistically involved in LN metastasis. We highlight recent data that link tumor microenvironment, including inflammation (at the cellular and cytokine levels) and tumor-induced lymphangiogenesis, with nodal metastasis. Many of the newly identified genes that appear to influence LN metastasis facilitate general motility, chemotactic, or invasive properties that also increase the ability of cancer cells to disseminate and survive at distant organ sites. These new biomarkers will help predict clinical outcome and point to novel future therapies in metastatic melanoma as well as other cancers.

  8. Cancer-stroma evolutionary dynamics in stress-gradient microenvironment

    Science.gov (United States)

    Wu, Amy; Lambert, Guillaume; Austin, Robert; Sturm, James; Khin, Zayar; Silva, Ariosto

    2012-02-01

    In order to study the evolution of drug resistance in cancer, it is important to mimic the tumor microenvironment, in which cells are exposed to not uniform concentrations but rather gradients of drugs, nutrients, and other factors Compared to traditional in-vitro methods, microfluidic structure enables better control of the temporal and spatial profile of gradients. Here we demonstrate a microfluidic Doxorubicin gradient environment with heterogeneous landscape, and culture multiple myeloma (8226-S, expressing RFP) and bone marrow stroma (HS-5, expressing GFP) cell lines together. The myeloma cells are not directly motile, but they are able to migrate via the adhesion to motile stroma cells. The indirect motility mechanism of the myeloma cells is crucial for the adaptation to stress environment. Finally, we will report the co-culture dynamics under the stress of doxorubicin gradients, observing for cellular migrations and growth

  9. Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments.

    Science.gov (United States)

    Miller, Anne; Nagy, Csörsz; Knapp, Bernhard; Laengle, Johannes; Ponweiser, Elisabeth; Groeger, Marion; Starkl, Philipp; Bergmann, Michael; Wagner, Oswald; Haschemi, Arvand

    2017-11-07

    Over the past years, plenty of evidence has emerged illustrating how metabolism supports many aspects of cellular function and how metabolic reprogramming can drive cell differentiation and fate. Here, we present a method to assess the metabolic configuration of single cells within their native tissue microenvironment via the visualization and quantification of multiple enzymatic activities measured at saturating substrate conditions combined with subsequent cell type identification. After careful validation of the approach and to demonstrate its potential, we assessed the intracellular metabolic configuration of different human immune cell populations in healthy and tumor colon tissue. Additionally, we analyzed the intercellular metabolic relationship between cancer cells and cancer-associated fibroblasts in a breast cancer tissue array. This study demonstrates that the determination of metabolic configurations in single cells could be a powerful complementary tool for every researcher interested to study metabolic networks in situ. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. More than the genes, the tumor microenvironment in neuroblastoma

    Science.gov (United States)

    Borriello, Lucia; Seeger, Robert C.; Asgharzadeh, Shahab; DeClerck, Yves A.

    2017-01-01

    Neuroblastoma is the second most common solid tumor in children. Since the seminal discovery of the role of amplification of the MYCN oncogene in the pathogenesis of neuroblastoma in the 1980s, much focus has been on the contribution of genetic alterations in the progression of this cancer. However it is now clear that not only genetic events play a role but that the tumor microenvironment (TME) substantially contributes to the biology of neuroblastoma. In this article, we present a comprehensive review of the literature on the contribution of the TME to the ten hallmarks of cancer in neuroblastoma and discuss the mechanisms of communication between neuroblastoma cells and the TME that underlie the influence of the TME on neuroblastoma progression. We end our review by discussing how the knowledge acquired over the last two decades in this field is now leading to new clinical trials targeting the TME. PMID:26597947

  11. Fabrication of highly modulable fibrous 3D extracellular microenvironments

    KAUST Repository

    Zhang, Xixiang

    2017-06-13

    Three-dimensional (3D) in vitro scaffolds that mimic the irregular fibrous structures of in vivo extracellular matrix (ECM) are critical for many important biological applications. However, structural properties modulation of fibrous 3D scaffolds remains a challenge. Here, we report the first highly modulable 3D fibrous scaffolds self-assembled by high-aspect-ratio (HAR) microfibers. The scaffolds structural properties can be easily tailored to incorporate various physical cues, including geometry, stiffness, heterogeneity and nanotopography. Moreover, the fibrous scaffolds are readily and accurately patterned on desired locations of the substrate. Cell culture exhibits that our scaffolds can elicit strong bidirectional cell-material interactions. Furthermore, a functional disparity between the two-dimensional substrate and our 3D scaffolds is identified by cell spreading and proliferation data. These results prove the potential of the proposed scaffold as a biomimetic extracellular microenvironment for cell study.

  12. Tumor Cells and Micro-environment in Brain Metastases

    Directory of Open Access Journals (Sweden)

    Wen ZHONG

    2016-09-01

    Full Text Available Improvements in survival and quality of life of patients with lung cancer had been achieved due to the progression of early diagnosis and precision medicine at recent years, however, until now, treatments targeted at lesions in central nervous system are far from satisfying, thus threatening livelihood of patients involved. After all, in the issue of prophylaxis and therapeutics of brain metastases, it is crucial to learn about the biological behavior of tumor cells in brain metastases and its mechanism underlying, and the hypothesis ”seed and soil”, that is, tumor cells would generate series of adaptive changes to fit in the new environment, is liable to help explain this process well. In this assay, we reviewed documents concerning tumor cells, brain micro-environments and their interactions in brain metastases, aiming to provide novel insight into the treatments of brain metastases.

  13. Targeting tumor microenvironment: crossing tumor interstitial fluid by multifunctional nanomedicines.

    Science.gov (United States)

    Omidi, Yadollah; Barar, Jaleh

    2014-01-01

    The genesis of cancer appears to be a complex matter, which is not simply based upon few genetic abnormalities/alteration. In fact, irregular microvasculature and aberrant interstitium of solid tumors impose significant pathophysiologic barrier functions against cancer treatment modalities, hence novel strategies should holistically target bioelements of tumor microenvironment (TME). In this study, we provide some overview and insights on TME and important strategies used to control the impacts of such pathophysiologic barriers. We reviewed all relevant literature for the impacts of tumor interstitium and microvasculature within the TME as well as the significance of the implemented strategies. While tumorigenesis initiation seems to be in close relation with an emergence of hypoxia and alterations in epigenetic/genetic materials, large panoplies of molecular events emerge as intricate networks during oncogenesis to form unique lenient TME in favor of tumor progression. Within such irregular interstitium, immune system displays defective surveillance functionalities against malignant cells. Solid tumors show multifacial traits with coadaptation and self-regulation potentials, which bestow profound resistance against the currently used conventional chemotherapy and immunotherapy agents that target solely one face of the disease. The cancerous cells attain unique abilities to form its permissive microenvironment, wherein (a) extracellular pH is dysregulated towards acidification, (b) extracellular matrix (ECM) is deformed, (c) stromal cells are cooperative with cancer cells, (d) immune system mechanisms are defective, (e) non-integrated irregular microvasculature with pores (120-1200 nm) are formed, and (h) interstitial fluid pressure is high. All these phenomena are against cancer treatment modalities. As a result, to control such abnormal pathophysiologic traits, novel cancer therapy strategies need to be devised using multifunctional nanomedicines and theranostics.

  14. Social networks help to infer causality in the tumor microenvironment.

    Science.gov (United States)

    Crespo, Isaac; Doucey, Marie-Agnès; Xenarios, Ioannis

    2016-03-15

    Networks have become a popular way to conceptualize a system of interacting elements, such as electronic circuits, social communication, metabolism or gene regulation. Network inference, analysis, and modeling techniques have been developed in different areas of science and technology, such as computer science, mathematics, physics, and biology, with an active interdisciplinary exchange of concepts and approaches. However, some concepts seem to belong to a specific field without a clear transferability to other domains. At the same time, it is increasingly recognized that within some biological systems--such as the tumor microenvironment--where different types of resident and infiltrating cells interact to carry out their functions, the complexity of the system demands a theoretical framework, such as statistical inference, graph analysis and dynamical models, in order to asses and study the information derived from high-throughput experimental technologies. In this article we propose to adopt and adapt the concepts of influence and investment from the world of social network analysis to biological problems, and in particular to apply this approach to infer causality in the tumor microenvironment. We showed that constructing a bidirectional network of influence between cell and cell communication molecules allowed us to determine the direction of inferred regulations at the expression level and correctly recapitulate cause-effect relationships described in literature. This work constitutes an example of a transfer of knowledge and concepts from the world of social network analysis to biomedical research, in particular to infer network causality in biological networks. This causality elucidation is essential to model the homeostatic response of biological systems to internal and external factors, such as environmental conditions, pathogens or treatments.

  15. Concentrations of mobile source air pollutants in urban microenvironments.

    Science.gov (United States)

    Fujita, Eric M; Campbell, David E; Arnott, W Patrick; Johnson, Ted; Ollison, Will

    2014-07-01

    Human exposures to criteria and hazardous air pollutants (HAPs) in urban areas vary greatly due to temporal-spatial variations in emissions, changing meteorology, varying proximity to sources, as well as due to building, vehicle, and other environmental characteristics that influence the amounts of ambient pollutants that penetrate or infiltrate into these microenvironments. Consequently, the exposure estimates derived from central-site ambient measurements are uncertain and tend to underestimate actual exposures. The Exposure Classification Project (ECP) was conducted to measure pollutant concentrations for common urban microenvironments (MEs) for use in evaluating the results of regulatory human exposure models. Nearly 500 sets of measurements were made in three Los Angeles County communities during fall 2008, winter 2009, and summer 2009. MEs included in-vehicle, near-road, outdoor and indoor locations accessible to the general public. Contemporaneous 1- to 15-min average personal breathing zone concentrations of carbon monoxide (CO), carbon dioxide (CO2), volatile organic compounds (VOCs), nitric oxide (NO), nitrogen oxides (NO(x)), particulate matter (diesel trucks, was unrelated to ambient measurements at nearby monitors. Comparisons of ME concentrations estimated using the median ME/ambient ratio versus regression slopes and intercepts indicate that the regression approach may be more accurate for on-road MEs. Ranges in the ME/ambient ratios among ME categories were generally greater than differences among the three communities for the same ME category, suggesting that the ME proximity factors may be more broadly applicable to urban MEs. Implications: Estimates of population exposure to air pollutants extrapolated from ambient measurements at ambient fixed site monitors or exposure surrogates are prone to uncertainty. This study measured concentrations of mobile source air toxics (MSAT) and related criteria pollutants within in-vehicle, outdoor near

  16. Modulation of innate immunity in the tumor microenvironment.

    Science.gov (United States)

    Gonzalez-Gugel, Elena; Saxena, Mansi; Bhardwaj, Nina

    2016-10-01

    A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses. We have investigated innate immune cells (dendritic cells, NK cells) in the tumor microenvironment (TME) in order to devise effective targeted anticancer immune therapies. We find that matrix metalloproteinase-2 (MMP-2), secreted from melanoma cells and stromal cells, cleaves IFNAR1 and stimulates TLR-2 on dendritic cells (DC) within the TME. Both these events independently culminate in programing the DCs to promote pro-tumorigenic TH2 T cell differentiation. In addition, we have shown that NK cells become functionally exhausted in melanoma patients. We identified the expression of Tim-3 as one of the factors responsible for NK cell exhaustion and showed that anti-Tim3 antibodies partially reversed this exhaustion. We have initiated local intervention strategies such as intra-tumoral administration of DC activating Poly-ICLC and compared the efficacy of different TLR agonists and melanoma antigens for use as combination tumor vaccine in clinical trials. Such approaches will provide a unique insight into tumor biology and will facilitate in development of highly effective and cell type-specific immune therapies.

  17. Epstein-Bar Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma

    DEFF Research Database (Denmark)

    Kamper, Peter; Bendix, Knud; Hamilton-Dutoit, Stephen Jacques

    2012-01-01

    Epstein-Bar Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma......Epstein-Bar Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma...

  18. Epstein-Bar Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma

    DEFF Research Database (Denmark)

    Kamper, Peter; Bendix, Knud; Honoré, Bent

    Epstein-Bar Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma......Epstein-Bar Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma...

  19. Assessment of DNA damage as an index of genetic toxicity in welding microenvironments among iron-based industries.

    Science.gov (United States)

    Singh, Zorawar; Chadha, Pooja

    2016-10-01

    Welding is used extensively in different industries. Welders are always at a risk of exposure to a number of gases and metal-containing fumes in their respective microenvironments in which they work. Welding fumes consist of a wide range of complex metal oxide particles which can deposit in different parts of their bodies causing serious health problems. In the present study, 35 welders (age: 33.80 ± 1.04 years) from two iron-based industries have been assessed for DNA damage in peripheral blood lymphocytes using single-cell gel electrophoresis. An equal number of subjects (N = 35; age: 30.40 ± 1.51 years) matched to exposed subjects with respect to sex, age, socioeconomic status, smoking, and alcoholic habits were taken as controls. The results revealed that the damaged cell frequency (DCF) and mean comet tail length (CTL) in welders were significantly higher as compared to the controls (DCF: 69.74 ± 1.68 vs. 31.14 ± 1.67 and CTL: 29.21 ± 1.48 vs. 1.47 ± 0.08; p < 0.05). The effect of confounding factors such as age, duration of exposure, smoking, and drinking habits was also studied. Blood lead levels also showed a positive correlation with duration of exposure and CTL, and the overall results indicated an increased genetic damage as an index of genotoxicity in workers occupationally engaged in welding microenvironments. © The Author(s) 2015.

  20. Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy

    Directory of Open Access Journals (Sweden)

    Catarina Roma-Rodrigues

    2017-01-01

    Full Text Available Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes’ release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs make them suitable vehicles to pursuit this goal. AuNPs’ properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs’ role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

  1. Concise Review: An (Im)Penetrable Shield: How the Tumor Microenvironment Protects Cancer Stem Cells.

    Science.gov (United States)

    Relation, Theresa; Dominici, Massimo; Horwitz, Edwin M

    2017-05-01

    Cancer stem cells (CSCs) are defined by their unlimited self-renewal ability and their capacity to initiate and maintain malignancy, traits that are not found in most cells that comprise the tumor. Although current cancer treatments successfully reduce tumor burden, the tumor will likely recur unless CSCs are effectively eradicated. This challenge is made greater by the protective impact of the tumor microenvironment (TME), consisting of infiltrating immune cells, endothelial cells, extracellular matrix, and signaling molecules. The TME acts as a therapeutic barrier through immunosuppressive, and thereby tumor-promoting, actions. These factors, outside of the cancer cell lineage, work in concert to shelter CSCs from both the body's intrinsic anticancer immunity and pharmaceutical interventions to maintain cancer growth. Emerging therapies aimed at the TME offer a promising new tool in breaking through this shield to target the CSCs, yet definitive treatments remain unrealized. In this review, we summarize the mechanisms by which CSCs are protected by the TME and current efforts to overcome these barriers. Stem Cells 2017;35:1123-1130. © 2017 AlphaMed Press.

  2. Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy.

    Science.gov (United States)

    Roma-Rodrigues, Catarina; Raposo, Luís R; Cabral, Rita; Paradinha, Fabiana; Baptista, Pedro V; Fernandes, Alexandra R

    2017-01-14

    Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes' release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs' properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs' role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

  3. Exosome in Tumour Microenvironment: Overview of the Crosstalk between Normal and Cancer Cells

    Directory of Open Access Journals (Sweden)

    Catarina Roma-Rodrigues

    2014-01-01

    Full Text Available Cancer development is a multistep process in which exosomes play important roles. Exosomes are small vesicles formed in vesicular bodies in the endosomal network. The major role of exosomes seems to be the transport of bioactive molecules between cells. Depending on the cell of origin, exosomes are implicated in the regulation of several cellular events, with phenotypic consequences in recipient cells. Cancer derived exosomes (CCEs are important players in the formation of the tumour microenvironment by (i enabling the escape of tumour cells to immunological system and help initiating the inflammatory response; (ii acting in the differentiation of fibroblasts and mesenchymal cells into myofibroblasts; (iii triggering the angiogenic process; and (iv enhancing the metastatic evolution of the tumour by promoting epithelial to mesenchymal transformation of tumour cells and by preparing the tumour niche in the new anatomical location. Since the finding that exosomes content resembles that of the cell of origin, they may be regarded as suitable biomarkers for cancer diagnosis, allowing for diagnosis and prognosis via a minimal invasive procedure. Exosome involvement in cancer may open new avenues regarding therapeutics, such as vectors for targeted drug delivery.

  4. Tumor microenvironment: driving forces and potential therapeutic targets for breast cancer metastasis.

    Science.gov (United States)

    Xie, Hong-Yan; Shao, Zhi-Min; Li, Da-Qiang

    2017-03-29

    Distant metastasis to specific target organs is responsible for over 90% of breast cancer-related deaths, but the underlying molecular mechanism is unclear. Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ-specific metastasis of this lethal disease. Here, we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis; we also discuss potential therapeutic intervention strategies aimed at targeting components of the tumor microenvironment.

  5. Microenvironment Elements Involved in the Development of Pancreatic Cancer Tumor

    Directory of Open Access Journals (Sweden)

    Katarzyna Gardian

    2012-01-01

    Full Text Available Introduction. In spite of intensive research during many years, pancreatic adenocarcinoma remains one of the deadliest cancers. The surgical intervention remains main possibility of treatment because chemotherapy and radiotherapy has a minimal impact on long-term survival. We are still looking for the weak points of this devastating disease. Materials and Methods. Pancreatic tumor tissue samples were collected from 36 patients. Immunohistochemistry staining was used to evaluate expression of growth factors and immune infiltrates. Activity of MMP2 and MMP9 was assessed by gelatin zymography on 7.5% SDS-PAGE gel with 0.1% gelatin. Results. All growth factors were strongly expressed in pancreatic tumor tissue. We found that level of expression of c-Met receptor was higher for G3 tumors than for G2 tumors. Also we found that active MMP2 was present at all stages of tumor while active MMP9 just at more advanced tumors. Abundant immune cells infiltration was distinctive for tumor tissue, especially macrophages were infiltrating tumor tissue. We found that amount of macrophages was associated with lymph nodes metastases. Conclusion. In our research we demonstrated that among many factors influencing tumor microenvironment c-Met receptor, infiltrating macrophages and MMP2 have significant influence on development and invasion of pancreatic cancer.

  6. Source characterization of BTEX in indoor microenvironments in Hong Kong

    Science.gov (United States)

    Guo, H.; Lee, S. C.; Li, W. M.; Cao, J. J.

    Levels of benzene, toluene, ethylbenzene and the xylenes (BTEX) in different indoor microenvironments such as offices, homes, schools, shopping malls and restaurants were investigated in Hong Kong. Different indoor environments including six offices, six homes, six air-conditioned classrooms, six shopping malls and four restaurants were selected in Hong Kong for indoor and outdoor BTEX measurement. This study is aimed to determine qualitatively or semi-quantitatively sources of BTEX. Source identification is possible by determining the indoor/outdoor ( I/ O) concentration ratio. An I/ O ratio>1 was considered as an indicator for indoor sources. For BTEX in different indoor environments except for schools, some of the pollutants were dominated by outdoor sources while others mainly originated from indoor sources. In schools, however, the BTEX predominantly originated from outdoor sources. The potential sources of BTEX in indoor environments were also identified by using principal component analysis and nonparametric Kruskal-Wallis test. The number of variables was reduced to two and one new factors for indoor and outdoor data, respectively. These factors were related to certain source characteristics. It is shown that the type of land use, the use of printers, the traffic condition, the cooking style, the type of gas stove, smoking and internal decoration strongly influence the indoor concentrations of BTEX ( p<0.05). Significant difference of BTEX concentrations in the five types of indoor environments were also observed ( p<0.05).

  7. GPS-based Microenvironment Tracker (MicroTrac) Model to ...

    Science.gov (United States)

    A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure to do so can add uncertainty and bias to risk estimates. In this study, a classification model, called MicroTrac, was developed to estimate time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from global positioning system (GPS) data and geocoded building boundaries. Based on a panel study, MicroTrac estimates were compared to 24 h diary data from 7 participants on workdays and 2 participants on nonworkdays, with corresponding GPS data and building boundaries of home, school, and work. MicroTrac correctly classified the ME for 99.5% of the daily time spent by the participants. The capability of MicroTrac could help to reduce the time-location uncertainty in air pollution exposure models and exposure metrics for individuals in health studies. The National Exposure Research Laboratory’s (NERL’s) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA’s mission to protect human health and the environment. HEASD’s research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA’s strategic plan. More specifically, our division conducts research to characterize

  8. The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Jiamin Zhou

    2014-01-01

    Full Text Available Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.

  9. Designing degradable hydrogels for orthogonal control of cell microenvironments

    Science.gov (United States)

    Kharkar, Prathamesh M.

    2013-01-01

    Degradable and cell-compatible hydrogels can be designed to mimic the physical and biochemical characteristics of native extracellular matrices and provide tunability of degradation rates and related properties under physiological conditions. Hence, such hydrogels are finding widespread application in many bioengineering fields, including controlled bioactive molecule delivery, cell encapsulation for controlled three-dimensional culture, and tissue engineering. Cellular processes, such as adhesion, proliferation, spreading, migration, and differentiation, can be controlled within degradable, cell-compatible hydrogels with temporal tuning of biochemical or biophysical cues, such as growth factor presentation or hydrogel stiffness. However, thoughtful selection of hydrogel base materials, formation chemistries, and degradable moieties is necessary to achieve the appropriate level of property control and desired cellular response. In this review, hydrogel design considerations and materials for hydrogel preparation, ranging from natural polymers to synthetic polymers, are overviewed. Recent advances in chemical and physical methods to crosslink hydrogels are highlighted, as well as recent developments in controlling hydrogel degradation rates and modes of degradation. Special attention is given to spatial or temporal presentation of various biochemical and biophysical cues to modulate cell response in static (i.e., non-degradable) or dynamic (i.e., degradable) microenvironments. This review provides insight into the design of new cell-compatible, degradable hydrogels to understand and modulate cellular processes for various biomedical applications. PMID:23609001

  10. Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap.

    Science.gov (United States)

    Morton, J Jason; Bird, Gregory; Refaeli, Yosef; Jimeno, Antonio

    2016-11-01

    Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap. Humanized mice (HM) allow researchers to examine xenograft growth in the context of a human immune system and resultant tumor microenvironment, and recent studies have highlighted the increased similarities in attendant tumor structure, metastasis, and signaling to those features in cancer patients. This setting also facilitates the examination of investigational cancer therapies, including new immunotherapies. This review discusses recent advancements in the generation and application of HM models, their promise in cancer research, and their potential in generating clinically relevant treatments. This review also focuses on current efforts to improve HM models by engineering mouse strains expressing human cytokines or HLA proteins and implanting human bone, liver, and thymus tissue to facilitate immune cell maturation and trafficking. Finally, we discuss how these improvements may help direct future HM model cancer studies. Cancer Res; 76(21); 6153-8. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. Influence of the neural microenvironment on prostate cancer.

    Science.gov (United States)

    Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J; Ayala, Gustavo

    2018-02-01

    Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

  12. PTEN action in leukaemia dictated by the tissue microenvironment.

    Science.gov (United States)

    Miething, Cornelius; Scuoppo, Claudio; Bosbach, Benedikt; Appelmann, Iris; Nakitandwe, Joy; Ma, Jing; Wu, Gang; Lintault, Laura; Auer, Martina; Premsrirut, Prem K; Teruya-Feldstein, Julie; Hicks, James; Benveniste, Helene; Speicher, Michael R; Downing, James R; Lowe, Scott W

    2014-06-19

    PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.

  13. PTEN action in leukemia dictated by the tissue microenvironment

    Science.gov (United States)

    Miething, Cornelius; Scuoppo, Claudio; Bosbach, Benedikt; Appelmann, Iris; Nakitandwe, Joy; Ma, Jing; Wu, Gang; Lintault, Laura; Auer, Martina; Premsrirut, Prem K.; Teruya-Feldstein, Julie; Hicks, James; Benveniste, Helene; Speicher, Michael R.; Downing, James R.; Lowe, Scott W.

    2014-01-01

    PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing1–3. PTEN dephosphorylates phosphatidylinositol 3,4,5-triphosphate (PIP3), thereby opposing the activity of class I phosphatidylinositol 3-kinases (PI3Ks) that mediate growth and survival factors signaling through PI3K effectors such as AKT and mTOR2. To determine whether continued PTEN inactivation is required to maintain malignancy, we generated an RNAi-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal PTEN knockdown in the hematopoietic compartment produced highly disseminated T-cell leukemia (T-ALL). Surprisingly, reactivation of PTEN mainly reduced T-ALL dissemination but had little effect on tumor load in hematopoietic organs. Leukemia infiltration into the intestine was dependent on CCR9 G-protein coupled receptor (GPCR) signaling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, GPCRs may play an unanticipated role in driving tumor growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumor maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype. PMID:24805236

  14. Exosomal tetraspanins mediate cancer metastasis by altering host microenvironment.

    Science.gov (United States)

    Lu, Jun; Li, Jun; Liu, Shuo; Wang, Teng; Ianni, Alessandro; Bober, Eva; Braun, Thomas; Xiang, Rong; Yue, Shijing

    2017-09-22

    The metastases of malignant tumors develop through a cascade of events. The establishment of a pre-metastatic micro-environment is initiated by communication between tumors and host. Exosomes come into focus as the most potent intercellular communicators playing a pivotal role in this process. Cancer cells release exosomes into the extracellular environment prior to metastasis. Tetraspanin is a type of 4 times transmembrane proteins. It may be involved in cell motility, adhesion, morphogenesis, as well as cell and vesicular membrane fusion. The exosomal tetraspanin network is a molecular scaffold connecting various proteins for signaling transduction. The complex of tetraspanin-integrin determines the recruiting cancer exosomes to pre-metastatic sites. Tetraspanin is a key element for the target cell selection of exosomes uptake that may lead to the reprogramming of target cells. Reprogrammed target cells assist pre-metastatic niche formation. Previous reviews have described the biogenesis, secretion and intercellular interaction of exosomes in various tumors. However, there is a lack of reviews on the topic of exosomal tetraspanin in the context of cancer. In this review, we will describe the main characteristics of exosomal tetraspanin in cancer cells. We will also discuss how the cancer exosomal tetraspanin alters extracellular environment and regulates cancer metastasis.

  15. Influential parameters on particle exposure of pedestrians in urban microenvironments

    Science.gov (United States)

    Buonanno, G.; Fuoco, F. C.; Stabile, L.

    2011-03-01

    Exposure to particle concentrations in urban areas was evaluated in several studies since airborne particles are considered to bring about adverse health effects. Transportation modes and urban microenvironments account for the highest contributions to the overall daily particle exposure concentration. In the present study an evaluation of the influential parameters affecting particle exposure of pedestrian in urban areas is reported. Street geometry, traffic mode, wind speed and direction effects were analyzed through an experimental campaign performed in different streets of an Italian town. To this purpose a high-resolution time measurement apparatus was used in order to capture the dynamic of the freshly emitted particles. Number, surface area and mass concentrations and distributions were measured continuously along both the sides of street canyons and avenue canyons during 10-minutes walking routes. The combined effect of street geometry and wind direction may contribute strongly to dilute the fresh particles emitted by vehicles. In particular, street canyons are characterized by lower ventilation phenomena which lead to similar concentration values on both the side of the street. Higher wind speed was found to decrease concentrations in the canyon. Traffic mode also seems to influence exposure concentrations. In particular, submicrometer particle mass concentration was higher as the traffic is more congested; otherwise, coarse fraction dominates mass exposure concentration along street characterized by a more fluent traffic, showing a typical resuspension modality.

  16. Theranostic Probes for Targeting Tumor Microenvironment: An Overview.

    Science.gov (United States)

    Sikkandhar, Musafar Gani; Nedumaran, Anu Maashaa; Ravichandar, Roopa; Singh, Satnam; Santhakumar, Induja; Goh, Zheng Cong; Mishra, Sachin; Archunan, Govindaraju; Gulyás, Balázs; Padmanabhan, Parasuraman

    2017-05-11

    Long gone is the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues, and immune cells in their environment, which is now known as the tumor microenvironment (TME). It has been found that the interactions between tumors and their surrounds promote tumor growth, invasion, and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design, and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME such as tumor vasculature, ECM, stromal cells, and the lymphatic system. This review explores how these significant factors in the TME, supply tumors with the required growth factors and signaling molecules to proliferate, invade, and metastasize. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis, and anticancer drug delivery systems. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT)).

  17. Theranostic Probes for Targeting Tumor Microenvironment: An Overview

    Science.gov (United States)

    Sikkandhar, Musafar Gani; Nedumaran, Anu Maashaa; Ravichandar, Roopa; Singh, Satnam; Santhakumar, Induja; Goh, Zheng Cong; Mishra, Sachin; Archunan, Govindaraju; Gulyás, Balázs; Padmanabhan, Parasuraman

    2017-01-01

    Long gone is the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues, and immune cells in their environment, which is now known as the tumor microenvironment (TME). It has been found that the interactions between tumors and their surrounds promote tumor growth, invasion, and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design, and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME such as tumor vasculature, ECM, stromal cells, and the lymphatic system. This review explores how these significant factors in the TME, supply tumors with the required growth factors and signaling molecules to proliferate, invade, and metastasize. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis, and anticancer drug delivery systems. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT)). PMID:28492519

  18. Targeting tumor microenvironment: crossing tumor interstitial fluid by multifunctional nanomedicines

    Directory of Open Access Journals (Sweden)

    Yadollah Omidi

    2014-06-01

    Results: We reviewed all relevant literature for the impacts of tumor interstitium and microvasculature within the TME as well as the significance of the implemented strategies. Results: While tumorigenesis initiation seems to be in close relation with an emergence of hypoxia and alterations in epigenetic/genetic materials, large panoplies of molecular events emerge as intricate networks during oncogenesis to form unique lenient TME in favor of tumor progression. Within such irregular interstitium, immune system displays defective surveillance functionalities against malignant cells. Solid tumors show multifacial traits with coadaptation and self-regulation potentials, which bestow profound resistance against the currently used conventional chemotherapy and immunotherapy agents that target solely one face of the disease. Conclusion: The cancerous cells attain unique abilities to form its permissive microenvironment, wherein (a extracellular pH is dysregulated towards acidification, (b extracellular matrix (ECM is deformed, (c stromal cells are cooperative with cancer cells, (d immune system mechanisms are defective, (e non-integrated irregular microvasculature with pores (120-1200 nm are formed, and (h interstitial fluid pressure is high. All these phenomena are against cancer treatment modalities. As a result, to control such abnormal pathophysiologic traits, novel cancer therapy strategies need to be devised using multifunctional nanomedicines and theranostics.

  19. Exposure visualisation of ultrafine particle counts in a transport microenvironment

    Science.gov (United States)

    Kaur, S.; Clark, R. D. R.; Walsh, P. T.; Arnold, S. J.; Colvile, R. N.; Nieuwenhuijsen, M. J.

    An increasing number of studies indicate that short-term peak exposures, such as those seen in the transport microenvironment, pose particular health threats. Short-term exposure can only be sufficiently characterised using portable, fast-response monitoring instrumentation with detailed summaries of individual activity. In this paper, we present an exposure visualisation system that addresses this issue—it allows the simultaneous presentation of mobile video imagery synchronised with measured real-time ultrafine particle count exposure of an individual. The combined data can be examined in detail for the contribution of the surrounding environment and the individual's activities to their peak and overall exposure. The exposure visualisation system is demonstrated and evaluated around the DAPPLE study site in Central London using different modes of transport (walking, cycling, bus, car and taxi). The video images, synchronised with the exposure profile, highlight the extent to which ultrafine particle exposure is associated with traffic density and proximity to pollutant source. The extremely rapid decline in concentration with increasing distance away from the pollutant source, such as from the main street to the backstreets, is clearly evident. The visualisation technique allows these data to be presented to both technical audiences and laypersons thus making it an effective environmental risk communication tool. Some exposure peaks however are not obviously associated with any event recorded on video—in these cases it will be necessary to use advanced dispersion modelling techniques to investigate meteorological conditions and other variables influencing in-street conditions to identify their possible causes.

  20. Natural Compounds Regulate Glycolysis in Hypoxic Tumor Microenvironment

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    Jian-Li Gao

    2015-01-01

    Full Text Available In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect. Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1 is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.

  1. CAF cellular glycolysis: linking cancer cells with the microenvironment.

    Science.gov (United States)

    Roy, Amrita; Bera, Soumen

    2016-07-01

    Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.

  2. Peritoneal inflammation – A microenvironment for Epithelial Ovarian Cancer (EOC

    Directory of Open Access Journals (Sweden)

    Liu Jinsong

    2004-06-01

    Full Text Available Abstract Epithelial ovarian cancer (EOC is a significant cause of cancer related morbidity and mortality in women. Preferential involvement of peritoneal structures contributes to the overall poor outcome in EOC patients. Advances in biotechnology, such as cDNA microarray, are a product of the Human Genome Project and are beginning to provide fresh opportunities to understand the biology of EOC. In particular, it is now possible to examine in depth, at the molecular level, the complex relationship between the tumor itself and its surrounding microenvironment. This review focuses on the anatomy, physiology, and current immunobiologic research of peritoneal structures, and addresses certain potentially useful animal models. Changes in both the inflammatory and non-inflammatory cell compartments, as well as alterations to the extracellular matrix, appear to be signal events that contribute to the remodeling effects of the peritoneal stroma and surface epithelial cells on tumor growth and spread. These alterations may involve a number of proteins, including cytokines, chemokines, growth factors, either membrane or non-membrane bound, and integrins. Interactions between these molecules and molecular structures within the extracellular matrix, such as collagens and the proteoglycans, may contribute to a peritoneal mesothelial surface and stromal environment that is conducive to tumor cell proliferation and invasion. These alterations need to be examined and defined as possible prosnosticators and as therapeutic or diagnostic targets.

  3. Model of spacecraft atomic oxygen and solar exposure microenvironments

    Science.gov (United States)

    Bourassa, R. J.; Pippin, H. G.

    1993-01-01

    Computer models of environmental conditions in Earth orbit are needed for the following reasons: (1) derivation of material performance parameters from orbital test data, (2) evaluation of spacecraft hardware designs, (3) prediction of material service life, and (4) scheduling spacecraft maintenance. To meet these needs, Boeing has developed programs for modeling atomic oxygen (AO) and solar radiation exposures. The model allows determination of AO and solar ultraviolet (UV) radiation exposures for spacecraft surfaces (1) in arbitrary orientations with respect to the direction of spacecraft motion, (2) overall ranges of solar conditions, and (3) for any mission duration. The models have been successfully applied to prediction of experiment environments on the Long Duration Exposure Facility (LDEF) and for analysis of selected hardware designs for deployment on other spacecraft. The work on these models has been reported at previous LDEF conferences. Since publication of these reports, a revision has been made to the AO calculation for LDEF, and further work has been done on the microenvironments model for solar exposure.

  4. Chronic inflammation drives glioma growth: cellular and molecular factors responsible for an immunosuppressive microenvironment

    Directory of Open Access Journals (Sweden)

    Joseph P Antonios

    2014-09-01

    Full Text Available This review examines glioma disease initiation, promotion, and progression with a focus on the cell types present within the tumor mass and the molecules responsible for the immunosuppressive microenvironment that are present at each step of the disease. The cell types and molecules present also correlate with the grade of malignancy. An overall "type 2" chronic inflammatory microenvironment develops that facilitates glioma promotion and contributes to the neo-vascularization characteristic of gliomas. An immunosuppressive microenvironment shields the tumor mass from clearance by the patient's own immune system. Here, we provide suggestions to deal with a chronically-inflamed tumor microenvironment and provide recommendations to help optimize adjuvant immune- and gene therapies currently offered to glioma patients.

  5. Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination

    Directory of Open Access Journals (Sweden)

    Fabian Benencia

    2012-01-01

    Full Text Available Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC- based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment.

  6. Spatiotemporal dynamics of the biological interface between cancer and the microenvironment: a fractal anomalous diffusion model with microenvironment plasticity

    Directory of Open Access Journals (Sweden)

    Tsai Feng-Chou

    2012-08-01

    Full Text Available Abstract Background The invasion-metastasis cascade of cancer involves a process of parallel progression. A biological interface (module in which cells is linked with ECM (extracellular matrix by CAMs (cell adhesion molecules has been proposed as a tool for tracing cancer spatiotemporal dynamics. Methods A mathematical model was established to simulate cancer cell migration. Human uterine leiomyoma specimens, in vitro cell migration assay, quantitative real-time PCR, western blotting, dynamic viscosity, and an in vivo C57BL6 mouse model were used to verify the predictive findings of our model. Results The return to origin probability (RTOP and its related CAM expression ratio in tumors, so-called "tumor self-seeding", gradually decreased with increased tumor size, and approached the 3D Pólya random walk constant (0.340537 in a periodic structure. The biphasic pattern of cancer cell migration revealed that cancer cells initially grew together and subsequently began spreading. A higher viscosity of fillers applied to the cancer surface was associated with a significantly greater inhibitory effect on cancer migration, in accordance with the Stokes-Einstein equation. Conclusion The positional probability and cell-CAM-ECM interface (module in the fractal framework helped us decipher cancer spatiotemporal dynamics; in addition we modeled the methods of cancer control by manipulating the microenvironment plasticity or inhibiting the CAM expression to the Pólya random walk, Pólya constant.

  7. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

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    Bo Jiang

    2017-03-01

    Full Text Available Metabolic abnormalities is a hallmark of cancer. About 100 years ago, Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells. Recently more and more novel opinions about cancer metabolism supplement to this hypothesis, consist of glucose uptake, lactic acid generation and secretion, acidification of the microenvironment and cancer immune evasion. Here we briefly review metabolic pathways generating lactate, and discuss the function of higher lactic acid in cancer microenvironments.

  8. The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development

    Science.gov (United States)

    2015-09-01

    AWARD NUMBER: W81XWH-12-1-0271 TITLE: The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development PRINCIPAL...31Aug 2015 4. TITLE AND SUBTITLE The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development 5a. CONTRACT NUMBER...initiate prostate cancer (PCa), promote PCa progression, and facilitate the development of mixed osteoblastic/osteolytic bone lesions . However, the

  9. Cell microenvironment engineering and monitoring for tissue engineering and regenerative medicine: the recent advances.

    Science.gov (United States)

    Barthes, Julien; Özçelik, Hayriye; Hindié, Mathilde; Ndreu-Halili, Albana; Hasan, Anwarul; Vrana, Nihal Engin

    2014-01-01

    In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells' behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future.

  10. Cell Microenvironment Engineering and Monitoring for Tissue Engineering and Regenerative Medicine: The Recent Advances

    Directory of Open Access Journals (Sweden)

    Julien Barthes

    2014-01-01

    Full Text Available In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells’ behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future.

  11. Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment.

    Science.gov (United States)

    Huang, Guoyou; Li, Fei; Zhao, Xin; Ma, Yufei; Li, Yuhui; Lin, Min; Jin, Guorui; Lu, Tian Jian; Genin, Guy M; Xu, Feng

    2017-10-25

    The cell microenvironment has emerged as a key determinant of cell behavior and function in development, physiology, and pathophysiology. The extracellular matrix (ECM) within the cell microenvironment serves not only as a structural foundation for cells but also as a source of three-dimensional (3D) biochemical and biophysical cues that trigger and regulate cell behaviors. Increasing evidence suggests that the 3D character of the microenvironment is required for development of many critical cell responses observed in vivo, fueling a surge in the development of functional and biomimetic materials for engineering the 3D cell microenvironment. Progress in the design of such materials has improved control of cell behaviors in 3D and advanced the fields of tissue regeneration, in vitro tissue models, large-scale cell differentiation, immunotherapy, and gene therapy. However, the field is still in its infancy, and discoveries about the nature of cell-microenvironment interactions continue to overturn much early progress in the field. Key challenges continue to be dissecting the roles of chemistry, structure, mechanics, and electrophysiology in the cell microenvironment, and understanding and harnessing the roles of periodicity and drift in these factors. This review encapsulates where recent advances appear to leave the ever-shifting state of the art, and it highlights areas in which substantial potential and uncertainty remain.

  12. Effects of tumor microenvironments on targeted delivery of glycol chitosan nanoparticles.

    Science.gov (United States)

    Yhee, Ji Young; Jeon, Sangmin; Yoon, Hong Yeol; Shim, Man Kyu; Ko, Hyewon; Min, Jiwoong; Na, Jin Hee; Chang, Hyeyoun; Han, Hyounkoo; Kim, Jong-Ho; Suh, Minah; Lee, Hyukjin; Park, Jae Hyung; Kim, Kwangmeyung; Kwon, Ick Chan

    2017-12-10

    In cancer theranostics, the main strategy of nanoparticle-based targeted delivery system has been understood by enhanced permeability and retention (EPR) effect of macromolecules. Studies on diverse nanoparticles provide a better understanding of different EPR effects depending on their structure, physicochemical properties, and chemical modifications. Recently the tumor microenvironment has been considered as another important factor for determining tumor-targeted delivery of nanoparticles, but the correlation between EPR effects and tumor microenvironment has not yet been fully elucidated. Herein, ectopic subcutaneous tumor models presenting different tumor microenvironments were established by inoculation of SCC7, U87, HT29, PC3, and A549 cancer cell lines into athymic nude mice, respectively. In the five different types of tumor-bearing mice, tumor-targeted delivery of self-assembled glycol chitosan nanoparticles (CNPs) were comparatively evaluated to identify the correlation between the tumor microenvironments and targeted delivery of CNPs. As a result, neovascularization and extents of intratumoral extracellular matrix (ECM) were both important in determining the tumor targeted delivery of CNPs. The EPR effect was maximized in the tumors which include large extent of angiogenic blood vessels and low intratumoral ECM content. This comprehensive study provides substantial evidence that the EPR effects based tumor-targeted delivery of nanoparticles can be different depending on the tumor microenvironment in individual tumors. To overcome current limitations in clinical nanomedicine, the tumor microenvironment of the patients and EPR effects in clinical tumors should also be carefully studied. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. The Unique Molecular and Cellular Microenvironment of Ovarian Cancer

    Science.gov (United States)

    Worzfeld, Thomas; Pogge von Strandmann, Elke; Huber, Magdalena; Adhikary, Till; Wagner, Uwe; Reinartz, Silke; Müller, Rolf

    2017-01-01

    The reciprocal interplay of cancer cells and host cells is an indispensable prerequisite for tumor growth and progression. Cells of both the innate and adaptive immune system, in particular tumor-associated macrophages (TAMs) and T cells, as well as cancer-associated fibroblasts enter into a malicious liaison with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Ovarian cancer, the most lethal of all gynecological malignancies, is characterized by a unique TME that enables specific and efficient metastatic routes, impairs immune surveillance, and mediates therapy resistance. A characteristic feature of the ovarian cancer TME is the role of resident host cells, in particular activated mesothelial cells, which line the peritoneal cavity in huge numbers, as well as adipocytes of the omentum, the preferred site of metastatic lesions. Another crucial factor is the peritoneal fluid, which enables the transcoelomic spread of tumor cells to other pelvic and peritoneal organs, and occurs at more advanced stages as a malignancy-associated effusion. This ascites is rich in tumor-promoting soluble factors, extracellular vesicles and detached cancer cells as well as large numbers of T cells, TAMs, and other host cells, which cooperate with resident host cells to support tumor progression and immune evasion. In this review, we summarize and discuss our current knowledge of the cellular and molecular interactions that govern this interplay with a focus on signaling networks formed by cytokines, lipids, and extracellular vesicles; the pathophysiologial roles of TAMs and T cells; the mechanism of transcoelomic metastasis; and the cell type selective processing of signals from the TME. PMID:28275576

  14. WE-E-BRE-12: Tumor Microenvironment Dynamics Following Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Campos, D; Niles, D; Adamson, E; Torres, A; Kissick, M; Eliceiri, K; Kimple, R [University of Wisconsin, Madison, WI (United States)

    2014-06-15

    Purpose: This work aims to understand the radiation-induced interplay between tumor oxygenation and metabolic activity. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Using patient-derived xenografts of head and neck cancer we assessed tumor oxygenation via fiber-optic probe monitored hemoglobin saturation and Blood Oxygen Level Dependent (BOLD) MRI. Measurements were taken before and after a 10 Gy dose of radiation. Changes in metabolic activity were measured via Fluorescence Lifetime IMaging (FLIM) with the appropriate controls following a 10 Gy dose of radiation. FLIM can non-invasively monitor changes in fluorescence in response to the microenvironment including being able to detect free and bound states of the intrinsically fluorescent metabolite NADH (Nicotinamide Adenine Dinucleotide). With this information FLIM can accurately quantify the metabolic state of cells that have been radiated. To model the observed changes, a two-compartment, source-sink simulation relating hemoglobin saturation and metabolic activity was performed using MATLAB. Results: Hemoglobin saturation as measured by interstitial probe and BOLD-MRI decreased by 30% within 15 minutes following radiation. FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways. Simulation of radiation-induced alterations in tumor oxygenation demonstrated that these changes can be the result of changes in either vasculature or metabolic activity. Conclusion: Radiation induces significant changes in hemoglobin saturation and metabolic activity. These alterations occur on time scales approximately the duration of common radiation treatments. Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response.

  15. Engineered microenvironments for synergistic VEGF - Integrin signalling during vascularization.

    Science.gov (United States)

    Moulisová, Vladimíra; Gonzalez-García, Cristina; Cantini, Marco; Rodrigo-Navarro, Aleixandre; Weaver, Jessica; Costell, Mercedes; Sabater I Serra, Roser; Dalby, Matthew J; García, Andrés J; Salmerón-Sánchez, Manuel

    2017-05-01

    We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling. Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. Importantly, the growth factor binding (FNIII12-14) and integrin binding (FNIII9-10) regions are simultaneously available on FN fibrils assembled on PEA. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. MR-Visible Lipids and the Tumor Microenvironment

    Science.gov (United States)

    Delikatny, E. James; Chawla, Sanjeev; Leung, Daniel-Joseph; Poptani, Harish

    2013-01-01

    MR-visible lipids or mobile lipids are defined as lipids that are observable using proton magnetic resonance spectroscopy in cells and in tissues. These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in intracellular neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment. This review will discuss factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types such as immune cells and fibroblasts. We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions and in response to activating stimuli or apoptotic cell death induced by anticancer drugs. This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo and radiotherapy, and to human tumors where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis. Conducive conditions for mobile lipid formation in the tumor microenvironment will be discussed including low pH, oxygen availability and the presence of inflammatory cells. It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response. Mobile lipids stored as neutral lipid droplets may play a role in detoxification of the cell or act as an alternate energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments. The role of MR-visible lipids in cancer diagnosis and assessment of treatment response both in animal models of cancer as well as human brain tumors will also be discussed. Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be used as a potential biomarker for assessing treatment response in cancer. PMID:21538631

  17. Quantitative histology analysis of the ovarian tumour microenvironment.

    Science.gov (United States)

    Lan, Chunyan; Heindl, Andreas; Huang, Xin; Xi, Shaoyan; Banerjee, Susana; Liu, Jihong; Yuan, Yinyin

    2015-11-17

    Concerted efforts in genomic studies examining RNA transcription and DNA methylation patterns have revealed profound insights in prognostic ovarian cancer subtypes. On the other hand, abundant histology slides have been generated to date, yet their uses remain very limited and largely qualitative. Our goal is to develop automated histology analysis as an alternative subtyping technology for ovarian cancer that is cost-efficient and does not rely on DNA quality. We developed an automated system for scoring primary tumour sections of 91 late-stage ovarian cancer to identify single cells. We demonstrated high accuracy of our system based on expert pathologists' scores (cancer = 97.1%, stromal = 89.1%) as well as compared to immunohistochemistry scoring (correlation = 0.87). The percentage of stromal cells in all cells is significantly associated with poor overall survival after controlling for clinical parameters including debulking status and age (multivariate analysis p = 0.0021, HR = 2.54, CI = 1.40-4.60) and progression-free survival (multivariate analysis p = 0.022, HR = 1.75, CI = 1.09-2.82). We demonstrate how automated image analysis enables objective quantification of microenvironmental composition of ovarian tumours. Our analysis reveals a strong effect of the tumour microenvironment on ovarian cancer progression and highlights the potential of therapeutic interventions that target the stromal compartment or cancer-stroma signalling in the stroma-high, late-stage ovarian cancer subset.

  18. Quercetin Decreases Insulin Resistance in a Polycystic Ovary Syndrome Rat Model by Improving Inflammatory Microenvironment.

    Science.gov (United States)

    Wang, Zhenzhi; Zhai, Dongxia; Zhang, Danying; Bai, Lingling; Yao, Ruipin; Yu, Jin; Cheng, Wen; Yu, Chaoqin

    2017-05-01

    Insulin resistance (IR) is a clinical feature of polycystic ovary syndrome (PCOS). Quercetin, derived from Chinese medicinal herbs such as hawthorn, has been proven practical in the management of IR in diabetes. However, whether quercetin could decrease IR in PCOS is unknown. This study aims to observe the therapeutic effect of quercetin on IR in a PCOS rat model and explore the underlying mechanism. An IR PCOS rat model was established by subcutaneous injection with dehydroepiandrosterone. The body weight, estrous cycle, and ovary morphology of the quercetin-treated rats were observed. Serum inflammatory cytokines were analyzed using enzyme-linked immunosorbent assay. In ovarian tissues, the expression of key genes involved in the inflammatory signaling pathway was detected through Western blot, real-time polymerase chain reaction, or immunohistochemistry. The nuclear translocation of nuclear factor κB (NF-κB) was also observed by immunofluorescence. The estrous cycle recovery rate of the insulin-resistant PCOS model after quercetin treatment was 58.33%. Quercetin significantly reduced the levels of blood insulin, interleukin 1β, IL-6, and tumor necrosis factor α. Quercetin also significantly decreased the granulosa cell nuclear translocation of NF-κB in the insulin-resistant PCOS rat model. The treatment inhibited the expression of inflammation-related genes, including the nicotinamide adenine dinucleotide phosphate oxidase subunit p22phox, oxidized low-density lipoprotein, and Toll-like receptor 4, in ovarian tissue. Quercetin improved IR and demonstrated a favorable therapeutic effect on the PCOS rats. The underlying mechanism of quercetin potentially involves the inhibition of the Toll-like receptor/NF-κB signaling pathway and the improvement in the inflammatory microenvironment of the ovarian tissue of the PCOS rat model.

  19. A Network Model to Explore the Effect of the Micro-environment on Endothelial Cell Behavior during Angiogenesis

    Directory of Open Access Journals (Sweden)

    Nathan Weinstein

    2017-11-01

    Full Text Available Angiogenesis is an important adaptation mechanism of the blood vessels to the changing requirements of the body during development, aging, and wound healing. Angiogenesis allows existing blood vessels to form new connections or to reabsorb existing ones. Blood vessels are composed of a layer of endothelial cells (ECs covered by one or more layers of mural cells (smooth muscle cells or pericytes. We constructed a computational Boolean model of the molecular regulatory network involved in the control of angiogenesis. Our model includes the ANG/TIE, HIF, AMPK/mTOR, VEGF, IGF, FGF, PLCγ/Calcium, PI3K/AKT, NO, NOTCH, and WNT signaling pathways, as well as the mechanosensory components of the cytoskeleton. The dynamical behavior of our model recovers the patterns of molecular activation observed in Phalanx, Tip, and Stalk ECs. Furthermore, our model is able to describe the modulation of EC behavior due to extracellular micro-environments, as well as the effect due to loss- and gain-of-function mutations. These properties make our model a suitable platform for the understanding of the molecular mechanisms underlying some pathologies. For example, it is possible to follow the changes in the activation patterns caused by mutations that promote Tip EC behavior and inhibit Phalanx EC behavior, that lead to the conditions associated with retinal vascular disorders and tumor vascularization. Moreover, the model describes how mutations that promote Phalanx EC behavior are associated with the development of arteriovenous and venous malformations. These results suggest that the network model that we propose has the potential to be used in the study of how the modulation of the EC extracellular micro-environment may improve the outcome of vascular disease treatments.

  20. Assembly of hydrogel units for 3D microenvironment in a poly(dimethylsiloxane) channel

    Science.gov (United States)

    Cho, Chang Hyun; Kwon, Seyong; Park, Je-Kyun

    2017-12-01

    Construction of three-dimensional (3D) microenvironment become an important issue in recent biological studies due to their biological relevance compared to conventional two-dimensional (2D) microenvironment. Various fabrication techniques have been employed to construct a 3D microenvironment, however, it is difficult to fully satisfy the biological and mechanical properties required for the 3D cell culture system, such as heterogeneous tissue structures generated from the functional differences or diseases. We propose here an assembly method for facile construction of 3D microenvironment in a poly(dimethylsiloxane) (PDMS) channel using hydrogel units. The high-aspect-ratio of hydrogel units was achieved by fabricating these units using a 2D mold. With this approach, 3D heterogeneous hydrogel units were produced and assembled in a PDMS channel by structural hookup. In vivo-like 3D heterogeneous microenvironment in a precisely controllable fluidic system was also demonstrated using a controlled assembly of different types of hydrogel units, which was difficult to obtain from previous methods. By regulating the flow condition, the mechanical stability of the assembled hydrogel units was verified by the flow-induced deformation of hydrogel units. In addition, in vivo-like cell culture environment was demonstrated using an assembly of cell-coated hydrogel units in the fluidic channel. Based on these features, our method expects to provide a beneficial tool for the 3D cell culture module and biomimetic engineering.

  1. Tertiary lymphoid tissue in the tumor microenvironment: from its occurrence to immunotherapeutic implications.

    Science.gov (United States)

    Di Caro, Giuseppe; Castino, Giovanni Francesco; Bergomas, Francesca; Cortese, Nina; Chiriva-Internati, Maurizio; Grizzi, Fabio; Mantovani, Alberto; Marchesi, Federica

    2015-03-01

    Recruitment of immune and inflammatory cells in the microenvironment of solid tumors is highly heterogeneous and follows patterns, varying according to the organ of origin and stage of disease, with critical roles in the process of cancer onset and progression. While adaptive cells are endowed with anti-tumor activities, inflammatory components of the immune infiltrate orchestrate an immunosuppressive microenvironment that reveals ambivalent functions of the immune contexture in the tumor milieu. The balance between opposing pro-tumoral and anti-tumoral immune pathways, which occur concomitantly in the tumor microenvironment, and the regulatory networks of these phenomena have been the target of several immunotherapeutic strategies. While the scarcity of adaptive immune effectors in tumors correlates with dismal prognosis, the pathways of activation of tumor-specific lymphocytes are yet to be fully elucidated. Recently, the occurrence of tertiary lymphoid tissue was revealed to be critical in mediating the dynamics of T cell recruitment and local activation of immune cells in the tumor microenvironment. Thus, tertiary lymphoid tissue assessment and targeting emerge as a promising approach for the design of novel prognostic immune signatures and immunotherapeutic strategies. The immunological behavior of tertiary lymphoid tissue, its occurrence in the tumor immune microenvironment and its clinical relevance are discussed here.

  2. Body Image

    Science.gov (United States)

    ... Blog About Us Contact Us Text size | Print | Body Image Developing a positive body image and a healthy mental attitude is crucial ... Read on for tips to have a healthy body image. Â Topics About body image When you ...

  3. Body Hair

    Science.gov (United States)

    ... www.girlshealth.gov/ Home Body Puberty Body hair Body hair Even before you get your first period , you ... spreads up in a V shape over time. Body hair is normal, and some people think it looks ...

  4. Breast cancer by proxy: Can the microenvironment be both the cause and consequence?

    Energy Technology Data Exchange (ETDEWEB)

    Ronnov-Jessen, Lone; Bissell, Mina J

    2008-11-16

    Breast cancer is one of the most clear-cut examples of a solid tumor in which systemic cues play a decisive part in its development. The breast tissue is constantly subjected to changes in hormone levels and modifications in the microenvironment. This scenario is even more striking during tumor development because of the dramatic loss or aberration of basement membrane (BM) and myoepithelial cells and the gain of peritumoral myofibroblasts. We suggest that the microenvironment, defined here as all components of the mammary gland other than luminal and/or tumor epithelial cells, might be instrumental in maintaining organ integrity and in promoting, and at times even initiating, breast cancer development. As such, the tumor microenvironment and its constituents, alone or in combination, might serve as promising targets for therapy.

  5. Contribution of various microenvironments to the daily personal exposure to ultrafine particles

    DEFF Research Database (Denmark)

    Bekö, Gabriel; Kjeldsen, Birthe Uldahl; Olsen, Yulia

    2015-01-01

    occurring in various microenvironments (residence, during active and passive transport, other indoor and outdoor environments) to the total daily exposure. On average, the fractional contribution of each microenvironment to the daily integrated personal exposure roughly corresponded to the fractions...... of the day the subjects spent in each microenvironment. The home environment accounted for 50% of the daily personal exposure. Indoor environments other than home or vehicles contributed with similar to 40%. The highest median UFP concentration was obtained during passive transport (vehicles). However, being...... in transit or outdoors contributed 5% or less to the daily exposure. Additionally, the subjects recorded in a diary the periods when they were at home. With this approach, 66% of the total daily exposure was attributable to the home environment. The subjects spent 28% more time at home according to the diary...

  6. [Design of an anesthesia and micro-environment information management system in mobile operating room].

    Science.gov (United States)

    Wang, Xianwen; Liu, Zhiguo; Zhang, Wenchang; Wu, Qingfu; Tan, Shulin

    2013-08-01

    We have designed a mobile operating room information management system. The system is composed of a client and a server. A client, consisting of a PC, medical equipments, PLC and sensors, provides the acquisition and processing of anesthesia and micro-environment data. A server is a powerful computer that stores the data of the system. The client gathers the medical device data by using the C/S mode, and analyzes the obtained HL7 messages through the class library call. The client collects the micro-environment information with PLC, and finishes the data reading with the OPC technology. Experiment results showed that the designed system could manage the patient anesthesia and micro-environment information well, and improve the efficiency of the doctors' works and the digital level of the mobile operating room.

  7. Microsensor measurements of the external and internal microenvironment of Fucus vesiculosus

    DEFF Research Database (Denmark)

    Spilling, Kristian; Titelman, Josefin; Greve, Tina M.

    2010-01-01

    We investigated the O2, pH, and irradiance microenvironment in and around the tissue of the brown alga Fucus vesiculosus L. using microsensors. Microsensors are ideal tools for gaining new insights into what limits and controls macroalgal activity and growth at very fine spatial (<100 µm) and tem......We investigated the O2, pH, and irradiance microenvironment in and around the tissue of the brown alga Fucus vesiculosus L. using microsensors. Microsensors are ideal tools for gaining new insights into what limits and controls macroalgal activity and growth at very fine spatial (...) and temporal (seconds) scales. This first microsensor investigation of a fucoid macroalga revealed differences in the microenvironment and metabolic activities at the level of different cell layers and thallus structures. F. vesiculosus responded quickly to rapid shifts in irradiance resulting in a highly...

  8. Regulation of mesenchymal stem cell 3D microenvironment: From macro to microfluidic bioreactors.

    Science.gov (United States)

    Sart, Sébastien; Agathos, Spiros N; Li, Yan; Ma, Teng

    2016-01-01

    Human mesenchymal stem cells (hMSCs) have emerged as an important cell type in cell therapy and tissue engineering. In these applications, maintaining the therapeutic properties of hMSCs requires tight control of the culture environments and the structural cell organizations. Bioreactor systems are essential tools to achieve these goals in the clinical-scale expansion and tissue engineering applications. This review summarizes how different bioreactors provide cues to regulate the structure and the chemico-mechanical microenvironment of hMSCs with a focus on 3D organization. In addition to conventional bioreactors, recent advances in microfluidic bioreactors as a novel approach to better control the hMSC microenvironment are also discussed. These advancements highlight the key role of bioreactor systems in preserving hMSC's functional properties by providing dynamic and temporal regulation of in vitro cellular microenvironment. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Fine particulate matter and carbon monoxide exposure concentrations in urban street transport microenvironments

    Science.gov (United States)

    Kaur, S.; Nieuwenhuijsen, M. J.; Colvile, R. N.

    Personal exposure studies are crucial alongside microenvironment and ambient studies in order to get a better understanding of the health risks posed by fine particulate matter and carbon monoxide in the urban transport microenvironment and for making informed decisions to manage and reduce the health risks. Studies specifically assessing the PM 2.5, ultrafine particle count and carbon monoxide personal exposure concentrations of adults in an urban transport microenvironment have steadily increased in number over the last decade. However, no recent collective summary is available, particularly one which also considers ultrafine particles; therefore, we present a review of the personal exposure concentration studies for the above named pollutants on different modes of surface transportation (walking, cycling, bus, car and taxi) in the urban transport microenvironment. Comparisons between personal exposure measurements and concentrations recorded at fixed monitoring sites are considered in addition to the factors influencing personal exposure in the transport microenvironment. In general, the exposure studies examined revealed pedestrians and cyclists to experience lower fine particulate matter and CO exposure concentrations in comparison to those inside vehicles—the vehicle shell provided no protection to the passengers. Proximity to the pollutant sources had a significant impact on exposure concentration levels experienced, consequently individuals should be encouraged to use back street routes. Fixed monitoring stations were found to be relatively poor predictors of CO and PM 2.5 exposure concentration levels experienced by individuals in the urban transport microenvironment. Although the mode of transport, traffic and meteorology parameters were commonly identified as significant factors influencing exposure concentrations to the different pollutants under examination, a large amount of the exposure concentration variation in the exposure studies remained

  10. Tumor Microenvironment Metabolism: A New Checkpoint for Anti-Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Nicole E. Scharping

    2016-12-01

    Full Text Available When a T cell infiltrates a tumor, it is subjected to a variety of immunosuppressive and regulatory signals in the microenvironment. However, it is becoming increasingly clear that due to the proliferative and energetically-deregulated nature of tumor cells, T cells also operate at a metabolic disadvantage. The nutrient dearth of the tumor microenvironment (TME creates “metabolic checkpoints” upon infiltrating T cells, impacting their ability to survive, proliferate and function effectively. In this review, we summarize the basics of tumor cell and T cell metabolism and discuss recent advances elucidating the individual metabolic checkpoints exerted on T cells that drive their dysfunction in the TME.

  11. It takes a tissue to make a tumor: epigenetics, cancer and the microenvironment

    Science.gov (United States)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    How do normal tissues limit the development of cancer? This review discusses the evidence that normal cells effectively restrict malignant behavior, and that such tissue forces must be subjugated to establish a tumor. The action of ionizing radiation will be specifically discussed regarding the disruption of the microenvironment that promotes the transition from preneoplastic to neoplastic growth. Unlike the highly unpredictable nature of genetic mutations, the response of normal cells to radiation damage follows an epigenetic program similar to wound healing and other damage responses. Our hypothesis is that the persistent disruption of the microenvironment in irradiated tissue compromises its ability to suppress carcinogenesis.

  12. Rapid dissolution of ZnO nanocrystals in acidic cancer microenvironment leading to preferential apoptosis

    Science.gov (United States)

    Sasidharan, Abhilash; Chandran, Parwathy; Menon, Deepthy; Raman, Sreerekha; Nair, Shantikumar; Koyakutty, Manzoor

    2011-09-01

    The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ~150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ~5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival.The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ~150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in

  13. It takes a tissue to make a tumor: Epigenetics, cancer and the microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Barcellos-Hoff, Mary Helen

    2001-01-19

    How do normal tissues limit the development of cancer? This review discusses the evidence that normal cells effectively restrict malignant behavior, and that such tissue forces must be subjugated to establish a tumor. The action of ionizing radiation will be specifically discussed regarding the disruption of the microenvironment that promotes the transition from preneoplastic to neoplastic growth. Unlike the highly unpredictable nature of genetic mutations, the response of normal cells to radiation damage follows an epigenetic program similar to wound healing and other damage responses. Our hypothesis is that the persistent disruption of the microenvironment in irradiated tissue compromises its ability to suppress carcinogenesis.

  14. Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound

    Directory of Open Access Journals (Sweden)

    Chun-Han Lin

    2017-10-01

    Full Text Available Tumor microenvironments are a driver of resistance to anti-cancer drugs. Dissecting cell-microenvironment interactions into tractable units of study presents a challenge. Here, we assess the impact of hundreds of tumor-inspired microenvironments, in parallel, on lapatinib responses in four cancer cell lines. Combinations of ECM and soluble factors were printed on stiffness-tunable substrata to generate a collection of controlled microenvironments in which to explore cell-based functional responses. Proliferation, HER2 protein expression and phosphorylation, and morphology were measured in single cells. Using dimension reduction and linear modeling, the effects of microenvironment constituents were identified and then validated empirically. Each of the cell lines exhibits unique microenvironment-response patterns. Fibronectin, type IV collagen, and matrix rigidity are significant regulators of lapatinib resistance in HER2-amplified breast cancer cells. Small-molecule inhibitors were identified that could attenuate microenvironment-imposed resistance. Thus, we demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments to improve the efficacy of anti-cancer therapeutics.

  15. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments

    Science.gov (United States)

    Albritton, Jacob L.

    2017-01-01

    ABSTRACT Even with many advances in treatment over the past decades, cancer still remains a leading cause of death worldwide. Despite the recognized relationship between metastasis and increased mortality rate, surprisingly little is known about the exact mechanism of metastatic progression. Currently available in vitro models cannot replicate the three-dimensionality and heterogeneity of the tumor microenvironment sufficiently to recapitulate many of the known characteristics of tumors in vivo. Our understanding of metastatic progression would thus be boosted by the development of in vitro models that could more completely capture the salient features of cancer biology. Bioengineering groups have been working for over two decades to create in vitro microenvironments for application in regenerative medicine and tissue engineering. Over this time, advances in 3D printing technology and biomaterials research have jointly led to the creation of 3D bioprinting, which has improved our ability to develop in vitro models with complexity approaching that of the in vivo tumor microenvironment. In this Review, we give an overview of 3D bioprinting methods developed for tissue engineering, which can be directly applied to constructing in vitro models of heterogeneous tumor microenvironments. We discuss considerations and limitations associated with 3D printing and highlight how these advances could be harnessed to better model metastasis and potentially guide the development of anti-cancer strategies. PMID:28067628

  16. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments

    Directory of Open Access Journals (Sweden)

    Jacob L. Albritton

    2017-01-01

    Full Text Available Even with many advances in treatment over the past decades, cancer still remains a leading cause of death worldwide. Despite the recognized relationship between metastasis and increased mortality rate, surprisingly little is known about the exact mechanism of metastatic progression. Currently available in vitro models cannot replicate the three-dimensionality and heterogeneity of the tumor microenvironment sufficiently to recapitulate many of the known characteristics of tumors in vivo. Our understanding of metastatic progression would thus be boosted by the development of in vitro models that could more completely capture the salient features of cancer biology. Bioengineering groups have been working for over two decades to create in vitro microenvironments for application in regenerative medicine and tissue engineering. Over this time, advances in 3D printing technology and biomaterials research have jointly led to the creation of 3D bioprinting, which has improved our ability to develop in vitro models with complexity approaching that of the in vivo tumor microenvironment. In this Review, we give an overview of 3D bioprinting methods developed for tissue engineering, which can be directly applied to constructing in vitro models of heterogeneous tumor microenvironments. We discuss considerations and limitations associated with 3D printing and highlight how these advances could be harnessed to better model metastasis and potentially guide the development of anti-cancer strategies.

  17. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    Science.gov (United States)

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  18. Brucite microbialites in living coral skeletons: Indicators of extreme microenvironments in shallow-marine settings

    Science.gov (United States)

    Nothdurft, L.D.; Webb, G.E.; Buster, N.A.; Holmes, C.W.; Sorauf, J.E.; Kloprogge, J.T.

    2005-01-01

    Brucite [Mg(OH)2] microbialites occur in vacated interseptal spaces of living scleractinian coral colonies (Acropora, Pocillopora, Porites) from subtidal and intertidal settings in the Great Barrier Reef, Australia, and subtidal Montastraea from the Florida Keys, United States. Brucite encrusts microbial filaments of endobionts (i.e., fungi, green algae, cyanobacteria) growing under organic biofilms; the brucite distribution is patchy both within interseptal spaces and within coralla. Although brucite is undersaturated in seawater, its precipitation was apparently induced in the corals by lowered pCO 2 and increased pH within microenvironments protected by microbial biofilms. The occurrence of brucite in shallow-marine settings highlights the importance of microenvironments in the formation and early diagenesis of marine carbonates. Significantly, the brucite precipitates discovered in microenvironments in these corals show that early diagenetic products do not necessarily reflect ambient seawater chemistry. Errors in environmental interpretation may arise where unidentified precipitates occur in microenvironments in skeletal carbonates that are subsequently utilized as geochemical seawater proxies. ?? 2005 Geological Society of America.

  19. Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity

    Directory of Open Access Journals (Sweden)

    Assia L. Angelova

    2017-12-01

    Full Text Available Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV, show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01, H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood–brain (tumor barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO synthase (iNOS expression in tumor-associated microglia/macrophages (TAM, and accumulation of activated TAM in cluster of differentiation (CD 40 ligand (CD40L-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (preclinical testing.

  20. Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression.

    Science.gov (United States)

    Wang, Jinheng; De Veirman, Kim; Faict, Sylvia; Frassanito, Maria Antonia; Ribatti, Domenico; Vacca, Angelo; Menu, Eline

    2016-06-01

    Multiple myeloma (MM) pathogenesis and progression largely rely on the cells and extracellular factors in the bone marrow (BM) microenvironment. Compelling studies have identified tumour exosomes as key regulators in the maintenance and education of the BM microenvironment by targeting stromal cells, immune cells, and vascular cells. However, the role of MM exosomes in the modification of the BM microenvironment and MM progression remains unclear. Here, we explored the functions of MM exosomes in angiogenesis and immunosuppression in vitro and in vivo. Murine MM exosomes carrying multiple angiogenesis-related proteins enhanced angiogenesis and directly promoted endothelial cell growth. Several pathways such as signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase, and p53 were modulated by the exosomes in endothelial and BM stromal cells. These exosomes promoted the growth of myeloid-derived suppressor cells (MDSCs) in naive mice through activation of the STAT3 pathway and changed their subsets to similar phenotypes to those seen in MM-bearing mice. Moreover, MM exosomes up-regulated inducible nitric oxide synthase and enhanced the immunosuppressive capacity of BM MDSCs in vivo. Our data show that MM exosomes modulate the BM microenvironment through enhancement of angiogenesis and immunosuppression, which will further facilitate MM progression. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. Targeting FPR1 and CXCR4 in cancer and the contribution of the tumor microenvironment

    NARCIS (Netherlands)

    Boer, Jennifer

    2015-01-01

    Solid tumors can be primarily resistant or could become resistant to therapy, due to the protective effect of their direct tumor environment, which is called the microenvironment. UMCG-researcher Jennifer Boer studied the interaction of glioblastoma (GBM) and prostate cancer cells with their tumor

  2. Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols

    NARCIS (Netherlands)

    de Jong, Daphne; Koster, Ad; Hagenbeek, Anton; Raemaekers, John; Veldhuizen, Dennis; Heisterkamp, Sabien; de Boer, Jan Paul; van Glabbeke, Martine

    2009-01-01

    BACKGROUND: The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The precise nature of the cell populations is still unclear and published data on their prognostic significance are highly conflicting. This may be partly due to

  3. Molecular imaging of the tumor microenvironment for precision medicine and theranostics.

    Science.gov (United States)

    Penet, Marie-France; Krishnamachary, Balaji; Chen, Zhihang; Jin, Jiefu; Bhujwalla, Zaver M

    2014-01-01

    Morbidity and mortality from cancer and their associated conditions and treatments continue to extract a heavy social and economic global burden despite the transformative advances in science and technology in the twenty-first century. In fact, cancer incidence and mortality are expected to reach pandemic proportions by 2025, and costs of managing cancer will escalate to trillions of dollars. The inability to establish effective cancer treatments arises from the complexity of conditions that exist within tumors, the plasticity and adaptability of cancer cells coupled with their ability to escape immune surveillance, and the co-opted stromal cells and microenvironment that assist cancer cells in survival. Stromal cells, although destroyed together with cancer cells, have an ever-replenishing source that can assist in resurrecting tumors from any residual cancer cells that may survive treatment. The tumor microenvironment landscape is a continually changing landscape, with spatial and temporal heterogeneities that impact and influence cancer treatment outcome. Importantly, the changing landscape of the tumor microenvironment can be exploited for precision medicine and theranostics. Molecular and functional imaging can play important roles in shaping and selecting treatments to match this landscape. Our purpose in this review is to examine the roles of molecular and functional imaging, within the context of the tumor microenvironment, and the feasibility of their applications for precision medicine and theranostics in humans. © 2014 Elsevier Inc. All rights reserved.

  4. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth

    Science.gov (United States)

    Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make canc...

  5. Microenvironment promotes tumor cell reprogramming in human breast cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Fabrizio D'Anselmi

    Full Text Available The microenvironment drives mammary gland development and function, and may influence significantly both malignant behavior and cell growth of mammary cancer cells. By restoring context, and forcing cells to properly interpret native signals from the microenvironment, the cancer cell aberrant behavior can be quelled, and organization re-established. In order to restore functional and morphological differentiation, human mammary MCF-7 and MDA-MB-231 cancer cells were allowed to grow in a culture medium filled with a 10% of the albumen (EW, Egg White from unfertilized chicken egg. That unique microenvironment behaves akin a 3D culture and induces MCF-7 cells to produce acini and branching duct-like structures, distinctive of mammary gland differentiation. EW-treated MDA-MB-231 cells developed buds of acini and duct-like structures. Both MCF-7 and MDA-MB-231 cells produced β-casein, a key milk component. Furthermore, E-cadherin expression was reactivated in MDA-MB-231 cells, as a consequence of the increased cdh1 expression; meanwhile β-catenin - a key cytoskeleton component - was displaced behind the inner cell membrane. Such modification hinders the epithelial-mesenchymal transition in MDA-MB-231 cells. This differentiating pathway is supported by the contemporary down-regulation of canonical pluripotency markers (Klf4, Nanog. Given that egg-conditioned medium behaves as a 3D-medium, it is likely that cancer phenotype reversion could be ascribed to the changed interactions between cells and their microenvironment.

  6. Breast cancer by proxy: can the microenvironment be both the cause and consequence?

    DEFF Research Database (Denmark)

    Rønnov-Jessen, Lone; Bissell, Mina J

    2009-01-01

    Breast cancer is one of the most clear-cut examples of a solid tumor in which systemic cues play a decisive part in its development. The breast tissue is constantly subjected to changes in hormone levels and modifications in the microenvironment. This scenario is even more striking during tumor d...

  7. Cancer prevention and therapy through the modulation of the tumor microenvironment

    Science.gov (United States)

    Casey, Stephanie C.; Amedei, Amedeo; Aquilano, Katia; Benencia, Fabian; Bhakta, Dipita; Boosani, Chandra S.; Chen, Sophie; Ciriolo, Maria Rosa; Crawford, Sarah; Fujii, Hiromasa; Georgakilas, Alexandros G.; Guha, Gunjan; Halicka, Dorota; Helferich, William G.; Heneberg, Petr; Honoki, Kanya; Kerkar, Sid P.; Mohammed, Sulma I.; Niccolai, Elena; Nowsheen, Somaira; Rupasinghe, H. P. Vasantha; Samadi, Abbas; Singh, Neetu; Talib, Wamidh H.; Venkateswaran, Vasundara; Whelan, Richard; Yang, Xujuan; Felsher, Dean W.

    2015-01-01

    Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adapative immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2, 3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer. PMID:25865775

  8. Foreign Body

    Science.gov (United States)

    ... SearchingPediatrics.com Pediatrics Common Questions, Quick Answers Foreign Body Donna D'Alessandro, M.D. Lindsay Huth, B. ... I call the doctor? What is a foreign body? A foreign body is when an object is ...

  9. Probing the electrostatics of active site microenvironments along the catalytic cycle for Escherichia coli dihydrofolate reductase.

    Science.gov (United States)

    Liu, C Tony; Layfield, Joshua P; Stewart, Robert J; French, Jarrod B; Hanoian, Philip; Asbury, John B; Hammes-Schiffer, Sharon; Benkovic, Stephen J

    2014-07-23

    Electrostatic interactions play an important role in enzyme catalysis by guiding ligand binding and facilitating chemical reactions. These electrostatic interactions are modulated by conformational changes occurring over the catalytic cycle. Herein, the changes in active site electrostatic microenvironments are examined for all enzyme complexes along the catalytic cycle of Escherichia coli dihydrofolate reductase (ecDHFR) by incorporation of thiocyanate probes at two site-specific locations in the active site. The electrostatics and degree of hydration of the microenvironments surrounding the probes are investigated with spectroscopic techniques and mixed quantum mechanical/molecular mechanical (QM/MM) calculations. Changes in the electrostatic microenvironments along the catalytic environment lead to different nitrile (CN) vibrational stretching frequencies and (13)C NMR chemical shifts. These environmental changes arise from protein conformational rearrangements during catalysis. The QM/MM calculations reproduce the experimentally measured vibrational frequency shifts of the thiocyanate probes across the catalyzed hydride transfer step, which spans the closed and occluded conformations of the enzyme. Analysis of the molecular dynamics trajectories provides insight into the conformational changes occurring between these two states and the resulting changes in classical electrostatics and specific hydrogen-bonding interactions. The electric fields along the CN axes of the probes are decomposed into contributions from specific residues, ligands, and solvent molecules that make up the microenvironments around the probes. Moreover, calculation of the electric field along the hydride donor-acceptor axis, along with decomposition of this field into specific contributions, indicates that the cofactor and substrate, as well as the enzyme, impose a substantial electric field that facilitates hydride transfer. Overall, experimental and theoretical data provide evidence for

  10. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Science.gov (United States)

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  11. Direct laser writing by two-photon polymerization as a tool for developing microenvironments for evaluation of bacterial growth

    Energy Technology Data Exchange (ETDEWEB)

    Otuka, A.J.G. [Instituto de Física de São Carlos, Universidade de São Paulo, CP.369, 13560-970 São Carlos, SP (Brazil); Corrêa, D.S. [Laboratório Nacional de Nanotecnologia para o Agronegócio (LNNA), Embrapa Instrumentação, Rua XV de Novembro, 1452, CP.741, 13560-970 São Carlos, SP (Brazil); Fontana, C.R. [Department of Clinical Analysis, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), 1621 Expedicionarios do Brasil Street, Araraquara, Sao Paulo 14801-960 (Brazil); Mendonça, C.R., E-mail: crmendon@ifsc.usp.br [Instituto de Física de São Carlos, Universidade de São Paulo, CP.369, 13560-970 São Carlos, SP (Brazil)

    2014-02-01

    Monitoring bacteria growth and motion in environments is fundamental to understand, for instance, how they proliferate and contaminate organism. Therefore, techniques to fabricate microenvironments for in situ and in vivo studies are interesting for that purpose. In this work we used two-photon polymerization to fabricate microenvironments and, as a proof of principle, we demonstrated the development of the bacteria ATCC 25922 Escherichia coli (E. coli) into the microstructure surroundings. Two varieties of polymeric microenvironments are presented: (i) a microenvironment doped at specific site with ciprofloxacin, an antibiotic typically used in the treatment of diseases caused by E. coli and (ii) micro-fences, which serve as traps for bacteria. These microenvironments, fabricated by two-photon polymerization, may be a potential platform for drug delivery system, by promoting or inhibiting the growth of bacteria in specific biological or synthetic sites. - Highlights: • Microenvironments were fabricated by two-photon polymerization. • We demonstrated the development of Escherichia coli into the microstructure surroundings. • Microenvironment doped with the antibiotic ciprofloxacin was fabricated. • Micro-fences, which serve as traps for bacteria, were also produced.

  12. Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease.

    Science.gov (United States)

    Fuster, José J; Ouchi, Noriyuki; Gokce, Noyan; Walsh, Kenneth

    2016-05-27

    Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the collateral damage of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of proinflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines. © 2016 American Heart Association, Inc.

  13. Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells

    DEFF Research Database (Denmark)

    D'Andrea, Filippo Peder; Safwat, Akmal Ahmed; Burns, Jorge S.

    2012-01-01

    Background: Resistance to radiation therapy remains a serious impediment to cancer therapy. We previously reported heterogeneity for clonogenic survival when testing in vitro radiation resistance among single cell derived clones from a human mesenchymal cancer stem cell model (hMSC). Here we aimed...... to determine whether this heterogeneity persisted in tumours established from these clones, and whether the response to radiation treatment was principally governed by cell intrinsic qualities or by factors pertaining to the tumour microenvironment, such as the degree of hypoxia and vascularisation. Methods......: Immune deficient female mice were implanted on the backs with cells from one of the clones. The subsequent tumours were subjected to either radiation treatment or had the tumour microenvironment assayed, when they reached 400mm3. Radiation was given as a single fraction of 0 to 15 Gy and the degree...

  14. Emergent Behavior from A Cellular Automaton Model for Invasive Tumor Growth in Heterogeneous Microenvironments

    CERN Document Server

    Jiao, Yang

    2011-01-01

    Understanding tumor invasion and metastasis is of crucial importance for both fundamental cancer research and clinical practice. In vitro experiments have established that the invasive growth of malignant tumors is characterized by the dendritic invasive branches composed of chains of tumor cells emanating from the primary tumor mass. The preponderance of previous tumor simulations focused on non-invasive (or proliferative) growth. The formation of the invasive cell chains and their interactions with the primary tumor mass and host microenvironment are not well understood. Here, we present a novel cellular automaton (CA) model that enables one to efficiently simulate invasive tumor growth in a heterogeneous host microenvironment. By taking into account a variety of microscopic-scale tumor-host interactions, including the short-range mechanical interactions between tumor cells and tumor stroma, degradation of extracellular matrix by the invasive cells and oxygen/nutrient gradient driven cell motions, our CA mo...

  15. Breathing and Cross-Infection Risk in the Microenvironment around People

    DEFF Research Database (Denmark)

    Nielsen, Peter Vilhelm; Zajas, Jan Jakub; Litewnicki, Michal

    2014-01-01

    The paper focuses on the characteristics of cross-infection risk in a room with an air distribution which creates fully mixed conditions. Several experiments are made to develop models for the flow in the microenvironment and models for the cross-infection risk. The first part of the measurements...... detailed analyses of the flow in the microenvironment of the two manikins and a study of the importance of the individual distance between the manikins. Also the importance of the activity level, difference in heights, breathing through mouth or nose is studied in details....... (breathing frequency and volume flow) and it includes a study of the influence of the thermal boundary layer of the manikin. Second part covers measurements with the use of two manikins. It is examined how one exhaling manikin can influence another regarding cross-infection risks. This study includes...

  16. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer

    Science.gov (United States)

    Brady, Nicholas J.; Chuntova, Pavlina; Schwertfeger, Kathryn L.

    2016-01-01

    Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer. PMID:26884646

  17. New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment

    DEFF Research Database (Denmark)

    Noël, Agnès; Gutiérrez-Fernández, Ana; Sounni, Nor Eddine

    2012-01-01

    Processes such as cell proliferation, angiogenesis, apoptosis, or invasion are strongly influenced by the surrounding microenvironment of the tumor. Therefore, the ability to change these surroundings represents an important property through which tumor cells are able to acquire specific functions......, revealing that the genes encoding metalloproteinases, such as MMP8, MMP27, ADAM7, and ADAM29, are recurrently mutated in specific tumors, while several ADAMTSs are epigenetically silenced in different cancers. The importance of these proteases in modifying the tumor microenvironment highlights the need...... necessary for tumor growth and dissemination. Matrix metalloproteinases (MMPs) constitute key players in this process, allowing tumor cells to modify the extracellular matrix (ECM) and release cytokines, growth factors, and other cell-surface molecules, ultimately facilitating protease-dependent tumor...

  18. Platinum-sensitive recurrence in ovarian cancer: The role of tumor microenvironment

    Directory of Open Access Journals (Sweden)

    Jeremy eChien

    2013-09-01

    Full Text Available Despite several advances in the understanding of ovarian cancer pathobiology, in terms of driver genetic alterations in high-grade serous cancer, histology heterogeneity of epithelial ovarian cancer, cell-of-origin for ovarian cancer, the survival rate from ovarian cancer is disappointingly low when compared to that of breast or prostate cancer. One of the factors contributing to the poor survival rate from ovarian cancer is the development of chemotherapy resistance following several rounds of chemotherapy. Although unicellular drug resistance mechanisms contribute to chemotherapy resistance, tumor microenvironment and the extracellular matrix, in particular, is emerging as a significant determinant of a tumor’s response to chemotherapy. In this review, we discuss the potential role of the tumor microenvironment in ovarian cancer recurrence and resistance to chemotherapy. Finally, we propose an alternative view of platinum-sensitive recurrence to describe a potential role of the extracellular matrix in the process.

  19. Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Carlos M. Galmarini

    2014-01-01

    Full Text Available The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc. all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.

  20. Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice.

    Science.gov (United States)

    Rosas-Taraco, Adrian G; Perez-Liñan, Amira R; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I; Salinas-Carmona, Mario C

    2012-07-01

    Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.

  1. Nocardia brasiliensis Induces an Immunosuppressive Microenvironment That Favors Chronic Infection in BALB/c Mice

    Science.gov (United States)

    Rosas-Taraco, Adrian G.; Perez-Liñan, Amira R.; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I.

    2012-01-01

    Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection. PMID:22547544

  2. Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates

    Science.gov (United States)

    Vilchis-Ordoñez, Armando; Contreras-Quiroz, Adriana; Dorantes-Acosta, Elisa; Reyes-López, Alfonso; Quintela-Nuñez del Prado, Henry Martin; Venegas-Vázquez, Jorge; Mayani, Hector; Ortiz-Navarrete, Vianney; López-Martínez, Briceida; Pelayo, Rosana

    2015-01-01

    B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNFα, IL-1β, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13+CD33+ population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow. PMID:26090405

  3. Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates

    Directory of Open Access Journals (Sweden)

    Armando Vilchis-Ordoñez

    2015-01-01

    Full Text Available B-cell acute lymphoblastic leukemia (B-ALL is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNFα, IL-1β, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13+CD33+ population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow.

  4. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

    Directory of Open Access Journals (Sweden)

    Brábek Jan

    2010-09-01

    Full Text Available Abstract During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion.

  5. The Immunomodulatory Effects of Mesenchymal Stem Cell Polarization within the Tumor Microenvironment Niche

    Directory of Open Access Journals (Sweden)

    Cosette M. Rivera-Cruz

    2017-01-01

    Full Text Available Mesenchymal stem cells (MSCs represent a promising tool for cell therapy, particularly for their antitumor effects. This cell population can be isolated from multiple tissue sources and also display an innate ability to home to areas of inflammation, such as tumors. Upon entry into the tumor microenvironment niche, MSCs promote or inhibit tumor progression by various mechanisms, largely through the release of soluble factors. These factors can be immunomodulatory by activating or inhibiting both the adaptive and innate immune responses. The mechanisms by which MSCs modulate the immune response are not well understood. Because of this, the relationship between MSCs and immune cells within the tumor microenvironment niche continues to be an active area of research in order to help explain the apparent contradictory findings currently available in the literature. The ongoing research aims to enhance the potential of MSCs in future therapeutic applications.

  6. Alexa Fluor-labeled Fluorescent Cellulose Nanocrystals for Bioimaging Solid Cellulose in Spatially Structured Microenvironments

    Energy Technology Data Exchange (ETDEWEB)

    Grate, Jay W.; Mo, Kai-For; Shin, Yongsoon; Vasdekis, Andreas; Warner, Marvin G.; Kelly, Ryan T.; Orr, Galya; Hu, Dehong; Dehoff, Karl J.; Brockman, Fred J.; Wilkins, Michael J.

    2015-03-18

    Cellulose nanocrystal materials have been labeled with modern Alexa Fluor dyes in a process that first links the dye to a cyanuric chloride molecule. Subsequent reaction with cellulose nanocrystals provides dyed solid microcrystalline cellulose material that can be used for bioimaging and suitable for deposition in films and spatially structured microenvironments. It is demonstrated with single molecular fluorescence microscopy that these films are subject to hydrolysis by cellulose enzymes.

  7. Multiphoton lithography of nanocrystalline platinum and palladium for site-specific catalysis in 3D microenvironments.

    Science.gov (United States)

    Zarzar, Lauren D; Swartzentruber, B S; Harper, Jason C; Dunphy, Darren R; Brinker, C Jeffrey; Aizenberg, Joanna; Kaehr, Bryan

    2012-03-07

    Integration of catalytic nanostructured platinum and palladium within 3D microscale structures or fluidic environments is important for systems ranging from micropumps to microfluidic chemical reactors and energy converters. We report a straightforward procedure to fabricate microscale patterns of nanocrystalline platinum and palladium using multiphoton lithography. These materials display excellent catalytic, electrical, and electrochemical properties, and we demonstrate high-resolution integration of catalysts within 3D defined microenvironments to generate directed autonomous particle and fluid transport. © 2012 American Chemical Society

  8. Forcing Stem Cells to Behave: A Biophysical Perspective of the Cellular Microenvironment

    OpenAIRE

    Sun, Yubing; Chen, Christopher S.; Fu, Jianping

    2012-01-01

    Physical factors in the local cellular microenvironment, including cell shape and geometry, matrix mechanics, external mechanical forces, and nanotopographical features of the extracellular matrix, can all have strong influences in regulating stem cell fate. Stem cells sense and respond to these insoluble biophysical signals through integrin-mediated adhesions and the force balance between intracellular cytoskeletal contractility and the resistant forces originated from the extracellular matr...

  9. Development of a Sitting MicroEnvironment Simulator for wheelchair cushion assessment.

    Science.gov (United States)

    Freeto, Tyler; Cypress, Allissa; Amalraj, Sarah; Yusufishaq, Mohamed Shaif; Bogie, Kath M

    2016-08-01

    Pressure ulcers (PU) are a common comorbidity among wheelchair users. An appropriate wheelchair cushion is essential to relieve pressure and reduce PU development during sitting. The microenvironment, specifically excessive heat and moisture, impacts risk for PU development. An effective wheelchair cushion should maintain a healthy microenvironment at the seating interface. Measurement of heat and moisture can characterize microenvironmental conditions at the wheelchair cushion interface under load. We describe the development of a Sitting MicroEnvironment Simulator (SMES) for the reliable assessment of wheelchair cushion microenvironments. The prototype SMES was developed for use mounted on a Materials Testing Systems (MTS) 810(®) uniaxial servo-hydraulic loading rig and used to assess microenvironmental conditions for Jay Medical Jay 2(®), Roho High Profile Dry Floatation(®) and Low Profile Dry Floatation(®) cushions and a novel modular gel cushion. Each cushion was assessed for two hours in triplicate. The SMES was used to load the cushions to 300N ± 10N, with an interface surface temperature of 37 °C±1 °C and fluid delivery of 13 mL/h±1 mL/h of water. Interface temperature and humidity were measured at the left ischial tuberosity (IT) region every five minutes. Heat and moisture responses were similar for the three commercial cushions. The modular gel cushion stayed cooler for at least 15 min longer than any commercial cushion. The SMES maintained performance to technical specifications for over one hundred hours of total testing and is a reliable tool for characterizing the microenvironmental conditions of wheelchair cushions. Published by Elsevier Ltd.

  10. Tumor Microenvironment Gene Signature as a Prognostic Classifier and Therapeutic Target

    Science.gov (United States)

    2015-06-01

    Metagenomic Count Data. Bioinformatics. 2014. 14. Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, et al. Prognostically relevant gene...invasion by upregulating CAF-derived versican in the tumor microenvironment. Cancer Res. 2013;73:5016-28. 24. Iwano M, Plieth D, Danoff TM, Xue C...signatures, analyzed and interpreted the data, wrote and published one manuscript, and prepared another one for publication. Name: Dong Joo Cheon

  11. Metastatic pathway and the microvascular and physicochemical microenvironments of human melanoma xenografts.

    Science.gov (United States)

    Huang, Ruixia; Andersen, Lise Mari K; Rofstad, Einar K

    2017-10-10

    Malignant melanoma of the skin can metastasize through blood vessels and lymphatics. The primary tumor develops a vascular microenvironment characterized by abnormal blood vessels and lymphatics and a physicochemical microenvironment characterized by low oxygen tension, regions with hypoxic tissue, and high interstitial fluid pressure (IFP). This study aimed at identifying relationships between the metastatic route of melanomas and characteristic features of the microvascular and physicochemical microenvironments of the primary tumor. Two patient-derived xenograft (PDX) models (E-13, N-15) and four cell line-derived xenografts (CDX) models (C-10, D-12, R-18, T-22) of human melanoma were included in the study. Tumors were transplanted to an orthotopic site in BALB/c-nu/nu mice, and when the tumors had grown to a volume of 500-600 mm3, the IFP of the primary tumor was measured and the hypoxia marker pimonidazole was administered before the host mouse was euthanized. The primary tumor, lungs, and six pairs of lymph nodes were evaluated by examining hematoxylin/eosin-stained and immunostained histological preparations. The expression of angiogenesis-related genes was assessed by quantitative PCR. C-10, D-12, and E-13 tumors disseminated primarily by the hematogenous route and developed pulmonary metastases. These tumors showed high angiogenic activity and high expression of the F3 gene as well as ANGPT2 and TIE1, genes encoding proteins of the angiopoietin-tie system. N-15, R-18, and T-22 tumors disseminated mainly by the lymphogenous route and developed metastases in draining lymph nodes. These tumors had highly elevated IFP and showed high expression of NRP2, a gene encoding neuropilin-2. The primary metastatic route of orthotopic human melanoma xenografts and the development of lung and lymph node metastases are influenced significantly by the microvascular and physicochemical microenvironments of the primary tumor.

  12. Amoeboid-mesenchymal migration plasticity promotes invasion only in complex heterogeneous microenvironments.

    Science.gov (United States)

    Talkenberger, Katrin; Cavalcanti-Adam, Elisabetta Ada; Voss-Böhme, Anja; Deutsch, Andreas

    2017-08-23

    During tissue invasion individual tumor cells exhibit two interconvertible migration modes, namely mesenchymal and amoeboid migration. The cellular microenvironment triggers the switch between both modes, thereby allowing adaptation to dynamic conditions. It is, however, unclear if this amoeboid-mesenchymal migration plasticity contributes to a more effective tumor invasion. We address this question with a mathematical model, where the amoeboid-mesenchymal migration plasticity is regulated in response to local extracellular matrix resistance. Our numerical analysis reveals that extracellular matrix structure and presence of a chemotactic gradient are key determinants of the model behavior. Only in complex microenvironments, if the extracellular matrix is highly heterogeneous and a chemotactic gradient directs migration, the amoeboid-mesenchymal migration plasticity allows a more widespread invasion compared to the non-switching amoeboid and mesenchymal modes. Importantly, these specific conditions are characteristic for in vivo tumor invasion. Thus, our study suggests that in vitro systems aiming at unraveling the underlying molecular mechanisms of tumor invasion should take into account the complexity of the microenvironment by considering the combined effects of structural heterogeneities and chemical gradients on cell migration.

  13. Essential Microenvironment for Thymopoiesis is Preserved in Human Adult and Aged Thymus

    Directory of Open Access Journals (Sweden)

    J. Shiraishi

    2003-01-01

    Full Text Available Normal human thymuses at various ages were immunohistologically examined in order to determine whether adult or aged thymus maintained the microenvironment for the T cell development and thymopoiesis was really ongoing. To analyze the thymic microenvironment, two monoclonal antibodies (MoAb were employed. One is MoAb to IL-1 receptor (IL-1R recognizing medullary and subcapsular cortical epithelial cells of normal infant human thymus. The other is UH-1 MoAb recognizing thymic epithelial cells within the cortex, which are negative with IL-1R-MoAb. Thymus of subjects over 20 years of age was split into many fragments and dispersed in the fatty tissue. However, the microenvironment of each fragment was composed of both IL-1R positive and UH-1 positive epithelial cells, and the UH-1 positive portion was populated with lymphocytes showing a follicle-like appearance. Lymphocytes in these follicle-like portions were mostly CD4+CD8+ double positive cells and contained many proliferating cells as well as apoptotic cells. Thus these follicle-like portions in adult and aged thymus were considered to be functioning as cortex as in infant thymus. Proliferative activity of thymocytes in the thymic cortex and the follicle-like portions definitely declined with advance of age, while incidence of apoptotic thymocytes increased with aging.

  14. Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment.

    Science.gov (United States)

    Polsinelli, Vincenzo B; Sinha, Arjun; Shah, Sanjiv J

    2017-12-01

    Visceral venous congestion of the gut may play a key role in the pathogenesis of right-sided heart failure (HF) and cardiorenal syndromes. Here, we review the role of right ventricular (RV) dysfunction, visceral congestion, splanchnic hemodynamics, and the intestinal microenvironment in the setting of right-sided HF. We review recent literature on this topic, outline possible mechanisms of disease pathogenesis, and discuss potential therapeutics. There are several mechanisms linking RV-gut interactions via visceral venous congestion which could result in (1) hypoxia and acidosis in enterocytes, which may lead to enhanced sodium-hydrogen exchanger 3 (NHE3) expression with increased sodium and fluid retention; (2) decreased luminal pH in the intestines, which could lead to alteration of the gut microbiome which could increase gut permeability and inflammation; (3) alteration of renal hemodynamics with triggering of the cardiorenal syndrome; and (4) altered phosphate metabolism resulting in increased pulmonary artery stiffening, thereby increasing RV afterload. A wide variety of therapeutic interventions that act on the RV, pulmonary vasculature, intestinal microenvironment, and the kidney could alter these pathways and should be tested in patients with right-sided HF. The RV-gut axis is an important aspect of HF pathogenesis that deserves more attention. Modulation of the pathways interconnecting the right heart, visceral congestion, and the intestinal microenvironment could be a novel avenue of intervention for right-sided HF.

  15. Differential role of microenvironment in microencapsulation for improved cell tolerance to stress.

    Science.gov (United States)

    Sun, Zhi-Jie; Lv, Guo-Jun; Li, Shuang-Yue; Yu, Wei-Ting; Wang, Wei; Xie, Yu-Bing; Ma, Xiaojun

    2007-07-01

    The effect of the microenvironment in alginate-chitosan-alginate (ACA) microcapsules with liquid core (LCM) and solid core (SCM) on the physiology and stress tolerance of Sacchromyces cerevisiae was studied. The suspended cells were used as control. Cells cultured in liquid core microcapsules showed a nearly twofold increase in the intracellular glycerol content, trehalose content, and the superoxide dismutase (SOD) activity, which are stress tolerance substances, while SCM did not cause the significant physiological variation. In accordance with the physiological modification after being challenged with osmotic stress (NaCl), oxidative stress (H(2)O(2)), ethanol stress, and heat shock stress, the cell survival in LCM was increased. However, SCM can only protect the cells from damaging under ethanol stress. Cells released from LCM were more resistant to hyperosmotic stress, oxidative stress, and heat shock stress than cells liberated from SCM. Based on reasonable analysis, a method was established to estimate the effect of microenvironment of LCM and SCM on the protection of cells against stress factors. It was found that the resistance of LCM to hyperosmotic stress, oxidative stress, and heat shock stress mainly depend on the domestication effect of LCM's microenvironment. The physical barrier of LCM constituted by alginate-chitosan membrane and liquid alginate matrix separated the cells from the damage of oxidative stress and ethanol stress. The significant tolerance against ethanol stress of SCM attributed to the physical barrier consists of solid alginate-calcium matrix and alginate-chitosan membrane.

  16. Construction of extracellular microenvironment to improve surface endothelialization of NiTi alloy substrate

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Peng, E-mail: liupeng79@cqu.edu.cn [Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433 (China); Zhao, Yongchun; Yan, Ying; Hu, Yan; Yang, Weihu [Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); Cai, Kaiyong, E-mail: kaiyong_cai@cqu.edu.cn [Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China)

    2015-10-01

    To mimic extracellular microenvironment of endothelial cell, a bioactive multilayered structure of gelatin/chitosan pair, embedding with vascular endothelial growth factor (VEGF), was constructed onto NiTi alloy substrate surface via a layer-by-layer assembly technique. The successful fabrication of the multilayered structure was demonstrated by scanning electron microscopy, atomic force microscopy, contact angle measurement, attenuated total reflection-fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, respectively. The growth behaviors of endothelial cells on various NiTi alloy substrates were investigated in vitro. Cytoskeleton observation, MTT assay, and wound healing assay proved that the VEGF-embedded multilayer structure positively stimulated adhesion, proliferation and motogenic responses of endothelial cells. More importantly, the present system promoted the nitric oxide production of endothelial cells. The approach affords an alternative to construct extracellular microenvironment for improving surface endothelialization of a cardiovascular implant. - Highlights: • Biofunctional multilayer films mimicking extracellular microenvironment were successfully fabricated. • Multilayered structure stimulated the biological responses of endothelial cells. • The approach affords an efficient approach for surface endothelialization of stent implant.

  17. Signals in the pancreatic islet microenvironment influence β-cell proliferation.

    Science.gov (United States)

    Aamodt, Kristie I; Powers, Alvin C

    2017-09-01

    The progressive loss of pancreatic β-cell mass that occurs in both type 1 and type 2 diabetes is a primary factor driving efforts to identify strategies for effectively increasing, enhancing or restoring β-cell mass. While factors that seem to influence β-cell proliferation in specific contexts have been described, reliable stimulation of human β-cell proliferation has remained a challenge. Importantly, β-cells exist in the context of a complex, integrated pancreatic islet microenvironment where they interact with other endocrine cells, vascular endothelial cells, extracellular matrix, neuronal projections and islet macrophages. This review highlights different components of the pancreatic microenvironment, and reviews what is known about how signaling that occurs between β-cells and these other components influences β-cell proliferation. Future efforts to further define the role of the pancreatic islet microenvironment on β-cell proliferation may lead to the development of successful approaches to increase or restore β-cell mass in diabetes. © 2017 John Wiley & Sons Ltd.

  18. Stemness in Cancer: Stem Cells, Cancer Stem Cells, and Their Microenvironment.

    Science.gov (United States)

    Aponte, Pedro M; Caicedo, Andrés

    2017-01-01

    Stemness combines the ability of a cell to perpetuate its lineage, to give rise to differentiated cells, and to interact with its environment to maintain a balance between quiescence, proliferation, and regeneration. While adult Stem Cells display these properties when participating in tissue homeostasis, Cancer Stem Cells (CSCs) behave as their malignant equivalents. CSCs display stemness in various circumstances, including the sustaining of cancer progression, and the interaction with their environment in search for key survival factors. As a result, CSCs can recurrently persist after therapy. In order to understand how the concept of stemness applies to cancer, this review will explore properties shared between normal and malignant Stem Cells. First, we provide an overview of properties of normal adult Stem Cells. We thereafter elaborate on how these features operate in CSCs. We then review the organization of microenvironment components, which enables CSCs hosting. We subsequently discuss Mesenchymal Stem/Stromal Cells (MSCs), which, although their stemness properties are limited, represent essential components of the Stem Cell niche and tumor microenvironment. We next provide insights of the therapeutic strategies targeting Stem Cell properties in tumors and the use of state-of-the-art techniques in future research. Increasing our knowledge of the CSCs microenvironment is key to identifying new therapeutic solutions.

  19. Adipocytes and Macrophages Interplay in the Orchestration of Tumor Microenvironment: New Implications in Cancer Progression

    Directory of Open Access Journals (Sweden)

    Luís Henrique Corrêa

    2017-09-01

    Full Text Available Inflammation has been known as one of the main keys to the establishment and progression of cancers. Chronic low-grade inflammation is also a strategic condition that underlies the causes and development of metabolic syndrome and obesity. Moreover, obesity has been largely related to poor prognosis of tumors by modulating tumor microenvironment with secretion of several inflammatory mediators by tumor-associated adipocytes (TAAs, which can modulate and recruit tumor-associated macrophages. Thus, the understanding of cellular and molecular mechanisms that underlay and link inflammation, obesity, and cancer is crucial to identify potential targets that interfere with this important route. Knowledge about the exact role of each component of the tumor microenvironment is not yet fully understood, but the new insights in literature highlight the essential role of adipocytes and macrophages interplay as key factor to determine the fate of cancer progression. In this review article, we focus on the functions of adipocytes and macrophages orchestrating cellular and molecular mechanisms that lead to inflammatory modulation in tumor microenvironment, which will be crucial to cancer establishment. We also emphasized the mechanisms by which the tumor promotes itself by recruiting and polarizing macrophages, discussing the role of adipocytes in this process. In addition, we discuss here the newest possible anticancer therapeutic treatments aiming to retard the development of the tumor based on what is known about cancer, adipocyte, and macrophage polarization.

  20. Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS.

    Science.gov (United States)

    Mei, Y; Zhao, B; Basiorka, A A; Yang, J; Cao, L; Zhang, J; List, A; Ji, P

    2017-11-16

    Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an aged-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.Leukemia accepted article preview online, 16 November 2017. doi:10.1038/leu.2017.326.

  1. Stromal fibroblasts and the immune microenvironment: partners in mammary gland biology and pathology?

    Science.gov (United States)

    Unsworth, Ashleigh; Anderson, Robin; Britt, Kara

    2014-07-01

    The microenvironment of a tumor has emerged recently as a critical contributor to the development of cancer. Within this environment, fibroblasts and immune cells are the cell lineages that seem to be active mediators of tumour development. The activated fibroblasts that are also present during wound healing and chronic inflammation have been studied extensively. Their activation leads to altered gene expression profiles that markedly increase growth factor and cytokine secretion, leading to major alterations in the immune cell microenvironment. To better understand normal tissue development, wound healing and the chronic inflammation that leads to cancer, we review here information available on the role of fibroblasts and immune cells in normal breast development and in cancer. We also discuss the immunogenicity of breast cancer compared to other cancers and the contribution of the immune microenvironment to the initiation, progression and metastasis of tumors. Also reviewed is the limited knowledge on the role of immune cells and fibroblasts in normal development and whether the risk of cancer increases when their control is not tightly regulated.

  2. Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Chanmee, Theerawut [Institute of Advanced Technology, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Ontong, Pawared [Division of Engineering (Biotechnology), Graduate School of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Konno, Kenjiro [Department of Animal Medical Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Itano, Naoki, E-mail: itanon@cc.kyoto-su.ac.jp [Institute of Advanced Technology, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Division of Engineering (Biotechnology), Graduate School of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan)

    2014-08-13

    During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.

  3. Dorsal root ganglia microenvironment of female BB Wistar diabetic rats with mild neuropathy.

    Science.gov (United States)

    Zochodne, D W; Ho, L T; Allison, J A

    1994-12-01

    Abnormalities in the microenvironment of dorsal root ganglia (DRG) might play a role in the pathogenesis of sensory abnormalities in human diabetic neuropathy. We examined aspects of DRG microenvironment by measuring local blood flow and oxygen tension in the L4 dorsal root ganglia of female BB Wistar (BBW) diabetic rats with mild neuropathy. The findings were compared with concurrent measurements of local sciatic endoneurial blood flow and oxygen tension. Diabetic rats were treated with insulin and underwent electrophysiological, blood flow and oxygen tension measurements at either 7-11 or 17-23 weeks after the development of glycosuria. Nondiabetic female BB Wistar rats from the same colony served as controls. At both ages, BBW diabetic rats had significant abnormalities in sensory, but not motor conduction compared to nondiabetic controls. Sciatic endoneurial blood flow in the diabetic rats of both ages was similar to control values, but the older (17-23 week diabetic) BBW diabetic rats had a selective reduction in DRG blood flow. Sciatic endoneurial oxygen tensions were not significantly altered in the diabetic rats. DRG oxygen tension appeared lowered in younger (7-11 week diabetic) but not older (17-23 week diabetic) BBW rats. Our findings indicate that there are important changes in the DRG microenvironment of diabetic rats with selective sensory neuropathy.

  4. CD47 update: a multifaceted actor in the tumour microenvironment of potential therapeutic interest

    Science.gov (United States)

    Sick, E; Jeanne, A; Schneider, C; Dedieu, S; Takeda, K; Martiny, L

    2012-01-01

    CD47 is a ubiquitous 50 kDa five-spanning membrane receptor that belongs to the immunoglobulin superfamily. This receptor, also known as integrin-associated protein, mediates cell-to-cell communication by ligation to transmembrane signal-regulatory proteins SIRPα and SIRPγ and interacts with integrins. CD47 is also implicated in cell-extracellular matrix interactions via ligation with thrombospondins. Furthermore, CD47 is involved in many and diverse cellular processes, including apoptosis, proliferation, adhesion and migration. It also plays a key role in many immune and cardiovascular responses. Thus, this multifaceted receptor might be a central actor in the tumour microenvironment. Solid tumours are composed of not only cancer cells that actively proliferate but also other cell types including immune cells and fibroblasts that make up the tumour microenvironment. Tumour cell proliferation is strongly sustained by continuous sprouting of new vessels, which also represents a gate for metastasis. Moreover, infiltration of inflammatory cells is observed in most neoplasms. Much evidence has accumulated indicating that infiltrating leukocytes promote cancer progression. Given its ubiquitous expression on all the different cell types that compose the tumour microenvironment, targeting CD47 could represent an original therapeutic strategy in the field of oncology. We present a current overview of the biological effects associated with CD47 on cancer cells and stromal cells. PMID:22774848

  5. Changes in Cytokines of the Bone Microenvironment during Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Donna M. Sosnoski

    2012-01-01

    Full Text Available It is commonly accepted that cancer cells interact with host cells to create a microenvironment favoring malignant colonization. The complex bone microenvironment produces an ever changing array of cytokines and growth factors. In this study, we examined levels of MCP-1, IL-6, KC, MIP-2, VEGF, MIG, and eotaxin in femurs of athymic nude mice inoculated via intracardiac injection with MDA-MB-231GFP human metastatic breast cancer cells, MDA-MB-231BRMS1GFP, a metastasis suppressed variant, or PBS. Animals were euthanized (day 3, 11, 19, 27 after injection to examine femoral cytokine levels at various stages of cancer cell colonization. The epiphysis contained significantly more cytokines than the diaphysis except for MIG which was similar throughout the bone. Variation among femurs was evident within all groups. By day 27, MCP-1, MIG, VEGF and eotaxin levels were significantly greater in femurs of cancer cell-inoculated mice. These pro-osteoclastic and angiogenic cytokines may manipulate the bone microenvironment to enhance cancer cell colonization.

  6. HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation

    Directory of Open Access Journals (Sweden)

    Anna Spina

    2015-01-01

    Full Text Available Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease.

  7. Periodontal-Derived Mesenchymal Cell Sheets Promote Periodontal Regeneration in Inflammatory Microenvironment.

    Science.gov (United States)

    Guo, Shujuan; Kang, Jian; Ji, Baohui; Guo, Weihua; Ding, Yi; Wu, Yafei; Tian, Weidong

    2017-07-01

    In this study, we investigated the periodontal regenerative potential of dental follicle cell (DFC) sheets and periodontal ligament cell (PDLC) sheets in the simulating inflammatory microenvironment of periodontitis, to confirm their regenerative potential for clinical application and explain the possible mechanism. The biological characteristics of DFC sheets and PDLC sheets were explored in lipopolysaccharide from Porphyromonas gingivalis (P. gingivalis LPS)-induced inflammation microenvironment in vitro, then cell sheets were transplanted into canine periodontal defects with experimental periodontitis in situ for 3 months. The results showed that P. gingivalis LPS greatly impaired the differentiation of PDLC sheets, whereas promoted gene expression of bone sialoprotein (BSP), osteopontin (OPN), and periostin (POSTN) in DFC sheets. LPS activated toll-like receptor 4 and NF-κB p65 phosphorylation in PDLC sheets. In experimental periodontitis, new periodontal attachment could be obtained in both PDLC sheets and DFC sheets. However, the complete periodontal regeneration, including periodontal ligament-cementum complex structure was observed only in DFC sheet groups, which also showed more alveolar bone formation than PDLC sheets. These results suggest that DFC sheets were more effective for periodontal regeneration in chronic inflammatory microenvironment of periodontitis. It is probably because of their ability to adapt the inflammatory environment and strong capacity to promote periodontal regeneration. This approach provides a tangible pathway toward clinical translation.

  8. Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas

    DEFF Research Database (Denmark)

    Castven, Darko; Fischer, Michael; Becker, Diana

    2017-01-01

    Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse milieu that promotes tumor-initiation and progression. A better understanding of the hepatic tumor-microenvironment interaction might infe...

  9. Body Hygiene

    Science.gov (United States)

    ... type=”submit” value=”Submit” /> Healthy Water Home Body, Facial, & Dental Hygiene Recommend on Facebook Tweet Share ... hygiene and by frequently washing parts of the body and hair with soap and clean, running water ( ...

  10. Body Alchemy

    OpenAIRE

    Zellweger, Christoph

    2015-01-01

    The exhibition "Body Alchemy" centers on the artistic concept of jewelry and metal art, new materials and the relation and dialogue between body and space. It discusses the evolution of contemporary jewelry and metal art from alchemy to casting body, from material aesthetics to conceptual art and from space shaping to body language. (subtracts from invite and event program). \\ud \\ud International contemporary jewelry artists and metal artists are invited to participate in the exhibition next ...

  11. Body Basics

    Science.gov (United States)

    ... Safe Videos for Educators Search English Español About Body Basics KidsHealth / For Parents / About Body Basics Print Remember the biology class you had ... do, lots of new knowledge about how the body works helps us to understand it now better ...

  12. 1'-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations.

    Science.gov (United States)

    In, Lionel L A; Arshad, Norhafiza M; Ibrahim, Halijah; Azmi, Mohamad Nurul; Awang, Khalijah; Nagoor, Noor Hasima

    2012-10-09

    Oral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1'S-1'-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes. Whether ACA can inhibit the growth of oral squamous cell carcinoma (SCC) cells alone or in combination with cisplatin (CDDP), was explored both in vitro using MTT assays and in vivo using Nu/Nu mice. Occurrence of apoptosis was assessed using PARP and DNA fragmentation assays, while the mode of action were elucidated through global expression profiling followed by Western blotting and IHC assays. We found that ACA alone inhibited the growth of oral SCC cells, induced apoptosis and suppressed its migration rate, while minimally affecting HMEC normal cells. ACA further enhanced the cytotoxic effects of CDDP in a synergistic manner as suggested by combination index studies. We also found that ACA inhibited the constitutive activation of NF-κB through suppression of IKKα/β activation. Human oral tumor xenografts studies in mice revealed that ACA alone was as effective as CDDP in reducing tumor volume, and further potentiated CDDP effects when used in combination with minimal body weight loss. The effects of ACA also correlated with a down-regulation of NF-κB regulated gene (FasL and Bim), including proinflammatory (NF-κB and COX-2) and proliferative (cyclin D1) biomarkers in tumor tissue. Overall, our results suggest that ACA inhibits the growth of oral SCC and further potentiates the effect of standard CDDP treatment by modulation of proinflammatory microenvironment. The current preclinical data could form the basis for further clinical trials to improve the current standards for oral cancer care using this active component from the Malaysian ginger.

  13. Cellular Microenvironment Dictates Androgen Production by Murine Fetal Leydig Cells in Primary Culture1

    Science.gov (United States)

    Carney, Colleen M.; Muszynski, Jessica L.; Strotman, Lindsay N.; Lewis, Samantha R.; O'Connell, Rachel L.; Beebe, David J.; Theberge, Ashleigh B.; Jorgensen, Joan S.

    2014-01-01

    ABSTRACT Despite the fact that fetal Leydig cells are recognized as the primary source of androgens in male embryos, the mechanisms by which steroidogenesis occurs within the developing testis remain unclear. A genetic approach was used to visualize and isolate fetal Leydig cells from remaining cells within developing mouse testes. Cyp11a1-Cre mice were bred to mT/mG dual reporter mice to target membrane-tagged enhanced green fluorescent protein (GFP) within steroidogenic cells, whereas other cells expressed membrane-tagged tandem-dimer tomato red. Fetal Leydig cell identity was validated using double-labeled immunohistochemistry against GFP and the steroidogenic enzyme 3beta-HSD, and cells were successfully isolated as indicated by qPCR results from sorted cell populations. Because fetal Leydig cells must collaborate with neighboring cells to synthesize testosterone, we hypothesized that the fetal Leydig cell microenvironment defined their capacity for androgen production. Microfluidic culture devices were used to measure androstenedione and testosterone production of fetal Leydig cells that were cultured in cell-cell contact within a mixed population, were isolated but remained in medium contact via compartmentalized co-culture with other testicular cells, or were isolated and cultured alone. Results showed that fetal Leydig cells maintained their identity and steroidogenic activity for 3–5 days in primary culture. Microenvironment dictated proficiency of testosterone production. As expected, fetal Leydig cells produced androstenedione but not testosterone when cultured in isolation. More testosterone accumulated in medium from mixed cultures than from compartmentalized co-cultures initially; however, co-cultures maintained testosterone synthesis for a longer time. These data suggest that a combination of cell-cell contact and soluble factors constitute the ideal microenvironment for fetal Leydig cell activity in primary culture. PMID:25143354

  14. Navy and black bean supplementation primes the colonic mucosal microenvironment to improve gut health.

    Science.gov (United States)

    Monk, Jennifer M; Lepp, Dion; Wu, Wenqing; Pauls, K Peter; Robinson, Lindsay E; Power, Krista A

    2017-11-01

    Common beans (Phaseolus vulgaris L.) are enriched in non-digestible fermentable carbohydrates and phenolic compounds that can modulate the colonic microenvironment (microbiota and host epithelial barrier) to improve gut health. In a comprehensive assessment of the impact of two commonly consumed bean varieties (differing in levels and types of phenolic compounds) within the colonic microenvironment, C57Bl/6 mice were fed diets supplemented with 20% cooked navy bean (NB) or black bean (BB) flours or an isocaloric basal diet control (BD) for 3 weeks. NB and BB similarly altered the fecal microbiota community structure (16S rRNA sequencing) notably by increasing the abundance of carbohydrate fermenting bacteria such as Prevotella, S24-7 and Ruminococcus flavefaciens, which coincided with enhanced short chain fatty acid (SCFA) production (microbial-derived carbohydrate fermentation products) and colonic expression of the SCFA receptors GPR-41/-43/-109a. Both NB and BB enhanced multiple aspects of mucus and epithelial barrier integrity vs. BD including: (i) goblet cell number, crypt mucus content and mucin mRNA expression, (ii) anti-microbial defenses (Reg3γ), (iii) crypt length and epithelial cell proliferation, (iv) apical junctional complex components (occludin, JAM-A, ZO-1 and E-cadherin) mRNA expression and (v) reduced serum endotoxin concentrations. Interestingly, biomarkers of colon barrier integrity (crypt height, mucus content, cell proliferation and goblet cell number) were enhanced in BB vs. NB-fed mice, suggesting added benefits attributable to unique BB components (e.g., phenolics). Overall, NB and BB improved baseline colonic microenvironment function by altering the microbial community structure and activity and promoting colon barrier integrity and function; effects which may prove beneficial in attenuating gut-associated diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  15. Ex-vivo assessment of drug response on breast cancer primary tissue with preserved microenvironments.

    Science.gov (United States)

    Muraro, Manuele G; Muenst, Simone; Mele, Valentina; Quagliata, Luca; Iezzi, Giandomenica; Tzankov, Alexandar; Weber, Walter P; Spagnoli, Giulio C; Soysal, Savas D

    2017-01-01

    Interaction between cancerous, non-transformed cells, and non-cellular components within the tumor microenvironment plays a key role in response to treatment. However, short-term culture or xenotransplantation of cancer specimens in immunodeficient animals results in dramatic modifications of the tumor microenvironment, thus preventing reliable assessment of compounds or biologicals of potential therapeutic relevance. We used a perfusion-based bioreactor developed for tissue engineering purposes to successfully maintain the tumor microenvironment of freshly excised breast cancer tissue obtained from 27 breast cancer patients and used this platform to test the therapeutic effect of antiestrogens as well as checkpoint-inhibitors on the cancer cells. Viability and functions of tumor and immune cells could be maintained for over 2 weeks in perfused bioreactors. Next generation sequencing authenticated cultured tissue specimens as closely matching the original clinical samples. Anti-estrogen treatment of cultured estrogen receptor positive breast cancer tissue as well as administration of pertuzumab to a Her2 positive breast cancer both had an anti-proliferative effect. Treatment with anti-programmed-death-Ligand (PD-L)-1 and anti-cytotoxic T lymphocyte-associated protein (CTLA)-4 antibodies lead to immune activation, evidenced by increased lymphocyte proliferation, increased expression of IFNγ, and decreased expression of IL10, accompanied by a massive cancer cell death in ex vivo triple negative breast cancer specimens. In the era of personalized medicine, the ex vivo culture of breast cancer tissue represents a promising approach for the pre-clinical evaluation of conventional and immune-mediated treatments and provides a platform for testing of innovative treatments.

  16. Oncogenic Mutations Regulate Tumor Microenvironment through Induction of Growth Factors and Angiogenic Mediators

    Science.gov (United States)

    Wang, Shizhen Emily; Yu, Yang; Criswell, Tracy L.; DeBusk, Laura M.; Lin, P. Charles; Zent, Roy; Johnson, David H.; Ren, Xiubao; Arteaga, Carlos L.

    2010-01-01

    Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared to wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to EGFR tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) β1 signaling through a mechanism involving Rac1 and JNK-AP1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor (VEGF), a target of the TGF-β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab was more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling and also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment. PMID:20383197

  17. Modeling Neurodegenerative Microenvironment Using Cortical Organoids Derived from Human Stem Cells.

    Science.gov (United States)

    Yan, Yuanwei; Song, Liqing; Bejoy, Julie; Zhao, Jing; Kanekiyo, Takahisa; Bu, Guojun; Zhou, Yi; Li, Yan

    2018-02-27

    Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using three-dimensional (3D) forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment. It is hypothesized that the 3D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the extracellular microenvironment in neural degeneration. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-related inflammatory responses, matrix remodeling and the responses to DAPT, heparin (completes with heparan sulfate proteoglycans [HSPGs] to bind Aβ42), and heparinase (digests HSPGs) treatments were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of Aβ42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated gene expression of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, upregulate syndecan-3, and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling the changes of extracellular microenvironment and provides a potential approach for AD-related drug screening.

  18. Cellular microenvironment dictates androgen production by murine fetal Leydig cells in primary culture.

    Science.gov (United States)

    Carney, Colleen M; Muszynski, Jessica L; Strotman, Lindsay N; Lewis, Samantha R; O'Connell, Rachel L; Beebe, David J; Theberge, Ashleigh B; Jorgensen, Joan S

    2014-10-01

    Despite the fact that fetal Leydig cells are recognized as the primary source of androgens in male embryos, the mechanisms by which steroidogenesis occurs within the developing testis remain unclear. A genetic approach was used to visualize and isolate fetal Leydig cells from remaining cells within developing mouse testes. Cyp11a1-Cre mice were bred to mT/mG dual reporter mice to target membrane-tagged enhanced green fluorescent protein (GFP) within steroidogenic cells, whereas other cells expressed membrane-tagged tandem-dimer tomato red. Fetal Leydig cell identity was validated using double-labeled immunohistochemistry against GFP and the steroidogenic enzyme 3beta-HSD, and cells were successfully isolated as indicated by qPCR results from sorted cell populations. Because fetal Leydig cells must collaborate with neighboring cells to synthesize testosterone, we hypothesized that the fetal Leydig cell microenvironment defined their capacity for androgen production. Microfluidic culture devices were used to measure androstenedione and testosterone production of fetal Leydig cells that were cultured in cell-cell contact within a mixed population, were isolated but remained in medium contact via compartmentalized co-culture with other testicular cells, or were isolated and cultured alone. Results showed that fetal Leydig cells maintained their identity and steroidogenic activity for 3-5 days in primary culture. Microenvironment dictated proficiency of testosterone production. As expected, fetal Leydig cells produced androstenedione but not testosterone when cultured in isolation. More testosterone accumulated in medium from mixed cultures than from compartmentalized co-cultures initially; however, co-cultures maintained testosterone synthesis for a longer time. These data suggest that a combination of cell-cell contact and soluble factors constitute the ideal microenvironment for fetal Leydig cell activity in primary culture. © 2014 by the Society for the Study of

  19. The physical interaction of myoblasts with the microenvironment during remodeling of the cytoarchitecture.

    Directory of Open Access Journals (Sweden)

    Daniel J Modulevsky

    Full Text Available Integrins, focal adhesions, the cytoskeleton and the extracellular matrix, form a structural continuum between the external and internal environment of the cell and mediate the pathways associated with cellular mechanosensitivity and mechanotransduction. This continuum is important for the onset of muscle tissue generation, as muscle precursor cells (myoblasts require a mechanical stimulus to initiate myogenesis. The ability to sense a mechanical cue requires an intact cytoskeleton and strong physical contact and adhesion to the microenvironment. Importantly, myoblasts also undergo reorientation, alignment and large scale remodeling of the cytoskeleton when they experience mechanical stretch and compression in muscle tissue. It remains unclear if such dramatic changes in cell architecture also inhibit physical contact and adhesion with the tissue microenvironment that are clearly important to myoblast physiology. In this study, we employed interference reflection microscopy to examine changes in the close physical contact of myoblasts with a substrate during induced remodeling of the cytoarchitecture (de-stabilization of the actin and microtubule cytoskeleton and inhibition of acto-myosin contractility. Our results demonstrate that while each remodeling pathway caused distinct effects on myoblast morphology and sub-cellular structure, we only observed a ~13% decrease in close physical contact with the substrate, regardless of the pathway inhibited. However, this decrease did not correlate well with changes in cell adhesion strength. On the other hand, there was a close correlation between cell adhesion and β1-integrin expression and the presence of cell-secreted fibronectin, but not with the presence of intact focal adhesions. In this study, we have shown that myoblasts are able to maintain a large degree of physical contact and adhesion to the microenvironment, even during shot periods (<60 min of large scale remodeling and physiological

  20. Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors

    Directory of Open Access Journals (Sweden)

    Hamm Christopher A

    2010-09-01

    Full Text Available Abstract Background Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established - namely, the Swarm Rat Chondrosarcoma (SRC - and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. Methods To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. Results The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression. Conclusion This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that

  1. Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids.

    Science.gov (United States)

    DiMarco, Rebecca L; Su, James; Yan, Kelley S; Dewi, Ruby; Kuo, Calvin J; Heilshorn, Sarah C

    2014-02-01

    Multiple culture techniques now exist for the long-term maintenance of neonatal primary murine intestinal organoids in vitro; however, the achievement of contractile behavior within cultured organoids has thus far been infrequent and unpredictable. Here we combine finite element simulation of oxygen transport and quantitative comparative analysis of cellular microenvironments to elucidate the critical variables that promote reproducible intestinal organoid contraction. Experimentally, oxygen distribution was manipulated by adjusting the ambient oxygen concentration along with the use of semi-permeable membranes to enhance transport. The culture microenvironment was further tailored through variation of collagen type-I matrix density, addition of exogenous R-spondin1, and specification of culture geometry. "Air-liquid interface" cultures resulted in significantly higher numbers of contractile cultures relative to traditional submerged cultures. These interface cultures were confirmed to have enhanced and more symmetric oxygen transport relative to traditional submerged cultures. While oxygen availability was found to impact in vitro contraction rate and the orientation of contractile movement, it was not a key factor in enabling contractility. For all conditions tested, reproducible contractile behavior only occurred within a consistent and narrow range of collagen type-I matrix densities with porosities of approximately 20% and storage moduli near 30 Pa. This suggests that matrix density acts as a "permissive switch" that enables contractions to occur. Similarly, contractions were only observed in cultures with diameters less than 15.5 mm that had relatively large interfacial surface area between the compliant matrix and the rigid culture dish. Taken together, these data suggest that spatial geometry and mechanics of the microenvironment, which includes both the encapsulating matrix as well as the surrounding culture device, may be key determinants of intestinal

  2. The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease.

    Science.gov (United States)

    Dotterweich, Julia; Tower, Robert J; Brandl, Andreas; Müller, Marc; Hofbauer, Lorenz C; Beilhack, Andreas; Ebert, Regina; Glüer, Claus C; Tiwari, Sanjay; Schütze, Norbert; Jakob, Franz

    2016-01-01

    Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.

  3. The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease.

    Directory of Open Access Journals (Sweden)

    Julia Dotterweich

    Full Text Available Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R, a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs and osteoprogenitor cells (OPCs when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.

  4. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.

    Science.gov (United States)

    Huang, Yuhui; Yuan, Jianping; Righi, Elda; Kamoun, Walid S; Ancukiewicz, Marek; Nezivar, Jean; Santosuosso, Michael; Martin, John D; Martin, Margaret R; Vianello, Fabrizio; Leblanc, Pierre; Munn, Lance L; Huang, Peigen; Duda, Dan G; Fukumura, Dai; Jain, Rakesh K; Poznansky, Mark C

    2012-10-23

    The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.

  5. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment.

    Science.gov (United States)

    Kim, Jong-Hyuk; Frantz, Aric M; Anderson, Katie L; Graef, Ashley J; Scott, Milcah C; Robinson, Sally; Sharkey, Leslie C; O'Brien, Timothy D; Dickerson, Erin B; Modiano, Jaime F

    2014-04-15

    Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into "IL-8 high" and "IL-8 low" groups. Genome-wide gene expression profiling showed that samples in the "IL-8 high" tumor group were enriched for genes associated with a "reactive microenvironment," including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer.

    Science.gov (United States)

    Ogiya, Rin; Niikura, Naoki; Kumaki, Nobue; Yasojima, Hiroyuki; Iwasa, Tsutomu; Kanbayashi, Chizuko; Oshitanai, Risa; Tsuneizumi, Michiko; Watanabe, Ken-Ichi; Matsui, Akira; Fujisawa, Tomomi; Saji, Shigehira; Masuda, Norikazu; Tokuda, Yutaka; Iwata, Hiroji

    2017-11-28

    Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1-70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, P L1, PD-L2, and HLA class I was also performed. There are significantly fewer TILs in brain metastases than in primary breast tumors.

  7. Nintedanib (BIBF 1120) blocks the tumor promoting signals of lung fibroblast soluble microenvironment.

    Science.gov (United States)

    Epstein Shochet, Gali; Israeli-Shani, Lilach; Koslow, Matthew; Shitrit, David

    2016-06-01

    Nintedanib is a potent, triple angiokinase inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, and has been recently approved for the treatment of non-small cell lung cancer (NSCLC), following first-line chemotherapy. It is well established that microenvironment plays an important role in tumor progression. Therefore, targeting tumor microenvironment-cancer cell interaction may provide a significant therapeutic target. In this study we tested the effect of Nintedanib on NSCLC cells directly and in the presence of normal and tumor soluble microenvironment. Primary fibroblast cultures derived from NSCLC tumors and normal lung tissues were established and their supernatants were collected. These supernatants were added to NSCLC cell lines (H1299, H460 and A549) cultured with/without Nintedanib (0.1-10μM) for 24 and 48h. Cell death (AnnexinV-PI, flow-cytometry), cell number, proliferation (PCNA), protein expression (immunoblotting) and cell migration (scratch test), were tested. Expression of 10 pro-angiogenic cytokines was measured by ELISA-based quantitative array. Tumor and normal supernatants demonstrated similar pro-metastatic effects on the NSCLC phenotype: both elevated cancer cell number, PCNA levels, reduced total and apoptotic cell death and facilitated cell migration. Nintedanib had limited but significant effects on the NSCLC cell number, cell death and migration, but required high doses. However, at lower doses Nintedanib caused cell detachment and elevated integrin-alpha 5 and EGFR levels, both markers of anoikis resistance. This suggests them as possible targets in combination with Nintedanib. Moreover, Nintedanib completely blocked the supernatants ability to facilitate the aggressive cancer cell characteristics. While cytokine array analysis showed no significant changes in FGF, PDGF or VEGF, we found that both supernatants contained high HGF levels, suggesting it as the facilitator of cell

  8. Alkaline biodegradable implants for osteoporotic bone defects--importance of microenvironment pH.

    Science.gov (United States)

    Liu, W; Wang, T; Yang, C; Darvell, B W; Wu, J; Lin, K; Chang, J; Pan, H; Lu, W W

    2016-01-01

    Change of microenvironment pH by biodegradable implants may ameliorate unbalanced osteoporotic bone remodeling. The present work demonstrated that a weak alkaline condition stimulated osteoblasts differentiation while suppressed osteoclast generation. In vivo, implants with an alkaline microenvironment pH (monitored by a pH microelectrode) exhibited a promising healing effect for the repair of osteoporotic bone defects. Under osteoporotic conditions, the response of the bone microenvironment to an endosseous implant is significantly impaired, and this substantially increases the risk of fracture, non-union and aseptic implant loosening. Acid-base equilibrium is an important factor influencing bone cell behaviour. The present purpose was to study the effect of a series of alkaline biodegradable implant materials on regeneration of osteoporotic bone defect, monitoring the microenvironment pH (μe-pH) over time. The proliferation and differentiation potential of osteoporotic rat bone marrow stromal cells and RAW 264.7 cells were examined under various pH conditions. Ovariectomized rat bone defects were filled with specific biodegradable materials, and μe-pH was measured by pH microelectrode. New osteoid and tartrate-resistant acid phosphatase-positive osteoclast-like cells were examined by Goldner's trichrome and TRAP staining, respectively. The intermediate layer between implants and new bone were studied using energy-dispersive X-ray spectroscopy (EDX) linear scanning. In vitro, weak alkaline conditions stimulated osteoporotic rat bone marrow stromal cells (oBMSC) differentiation, while inhibiting the formation of osteoclasts. In vivo, μe-pH differs from that of the homogeneous peripheral blood and exhibits variations over time particular to each material. Higher initial μe-pH was associated with more new bone formation, late response of TRAP-positive osteoclast-like cells and the development of an intermediate 'apatitic' layer in vivo. EDX suggested that

  9. Upregulation of Syndecan-1 in the bone marrow microenvironment in multiple myeloma is associated with angiogenesis

    DEFF Research Database (Denmark)

    Andersen, Niels F; Kristensen, Ida B; Preiss, Birgitte S

    2014-01-01

    : In this study, we examined the association between bone marrow angiogenesis estimated as micro-vessel density (MVD) and gene expression of SDC1, HGF, VEGF and IL6 in whole bone marrow biopsies from healthy volunteers (n = 10), patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 35...... plasma cell percentage and SDC1 gene expression was detected in patients with MM (P angiogenesis and gene...... expression of HGF, VEGF and IL6 was seen. CONCLUSION: Our study indicates that SDC1 expressed by the bone marrow microenvironment is involved in angiogenesis in MM....

  10. Cell pairing ratio controlled micro-environment with valve-less electrolytic isolation

    KAUST Repository

    Chen, Yu-Chih

    2012-01-01

    We present a ratio controlled cell-to-cell interaction chip using valve-less isolation. We incorporated electrolysis in a microfluidic channel. In each microfluidic chamber, we loaded two types of different cells at various pairing ratios. More than 80% of the microchambers were successfully loaded with a specific target pairing ratio. For the proof of concept, we have demonstrated the cell-to-cell interaction between prostate cancer cells and muscle stem cells can be controlled by cell pairing ratios through growth factor secretion. The experimental data shows that sealing of microenvironment by air generated from electrolysis does not affect cell viability and cell interaction assay results. © 2012 IEEE.

  11. Advances in Hypoxia Microenvironment and Chemotherapy-resistant 
of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yang GUO

    2014-03-01

    Full Text Available Lung cancer is one of the malignant tumors with highest incidence recently in our country. Tumor hypoxia phenomenon was first discovered in lung cancer. It plays important roles in tumor cell drug-resistance, apoptosis, invasion and metastasis, angiogenesis. Chemotherapy-resistant is one of the core reasons of treatment failure and disease progress, and many works on the study of chemotherapy-resistant have been done. This article reviewed the research progress of those mechanisms by which lung cancer hypoxia microenvironment could induce chemotherapy-resistance.

  12. Chemokines accentuating protumoral activities in oral cancer microenvironment possess an imperious stratagem for therapeutic resolutions.

    Science.gov (United States)

    Panda, Swagatika; Padhiary, Subrat Kumar; Routray, Samapika

    2016-09-01

    Chemokines, the chemotactic cytokines have established their role in tumorigenesis and tumor progression. Studies, which explored their role in oral cancer for protumoral activity, point towards targeting chemokines for oral squamous cell carcinoma therapy. The need of the hour is to emphasize/divulge in the activities of chemokine ligands and their receptors in the tumor microenvironment for augmentation of such stratagems. This progressing sentience of chemokines and their receptors has inspired this review which is an endeavour to comprehend their role as an aid in accentuating hallmarks of cancer and targeted therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes.

    Science.gov (United States)

    Allison, Katrina E; Coomber, Brenda L; Bridle, Byram W

    2017-10-01

    Altered metabolism is a hallmark of cancers, including shifting oxidative phosphorylation to glycolysis and up-regulating glutaminolysis to divert carbon sources into biosynthetic pathways that promote proliferation and survival. Therefore, metabolic inhibitors represent promising anti-cancer drugs. However, T cells must rapidly divide and survive in harsh microenvironments to mediate anti-cancer effects. Metabolic profiles of cancer cells and activated T lymphocytes are similar, raising the risk of metabolic inhibitors impairing the immune system. Immune checkpoint blockade provides an example of how metabolism can be differentially impacted to impair cancer cells but support T cells. Implications for research with metabolic inhibitors are discussed. © 2017 John Wiley & Sons Ltd.

  14. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jong-Hyuk, E-mail: jhkim@umn.edu [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); Frantz, Aric M.; Anderson, Katie L.; Graef, Ashley J.; Scott, Milcah C. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Robinson, Sally [Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Sharkey, Leslie C. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); O' Brien, Timothy D. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Dickerson, Erin B. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); Modiano, Jaime F., E-mail: modiano@umn.edu [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States)

    2014-04-15

    Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into “IL-8 high” and “IL-8 low” groups. Genome-wide gene expression profiling showed that samples in the “IL-8 high” tumor group were enriched for genes associated with a “reactive microenvironment,” including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA. - Highlights: • IL-8 is expressed in canine hemangiosarcoma tumor samples and cell lines. • IL-8 transduces a relevant biological signal in canine hemangiosarcoma cells. • IL-8 gene signature is associated

  15. Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells.

    Science.gov (United States)

    Sadtler, Kaitlyn; Estrellas, Kenneth; Allen, Brian W; Wolf, Matthew T; Fan, Hongni; Tam, Ada J; Patel, Chirag H; Luber, Brandon S; Wang, Hao; Wagner, Kathryn R; Powell, Jonathan D; Housseau, Franck; Pardoll, Drew M; Elisseeff, Jennifer H

    2016-04-15

    Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair. Copyright © 2016, American Association for the Advancement of Science.

  16. Body contact and body language

    DEFF Research Database (Denmark)

    Winther, Helle

    2008-01-01

    Body contact and body language are unique and existential and, although culturally dependent and socially embodied, they are also universal communication forms. For small children all over the world, warm, close and nourishing body contact is fundamental to their embodied experi­ence of themselves...... and the boundaries between self and world. In western societies, the modern premises for contact are in some ways developing from close contact to virtual communication. With this breadth of perspective in mind, the ques­tion is whether conscious and experimental work with body contact and body language in move......­ment psychology and education provide potential for intense personal develop­ment as well as for social and cultural learning processes. This performative research project originates from the research project entitled, Movement Psy­chol­ogy: The Language of the Body and the Psy­chol­ogy of Movement based...

  17. Body punk

    DEFF Research Database (Denmark)

    Mogensen, Kevin

    BODYPUNK - A Treatise on male body builders and the meaning of the body in the shadow of an Anti Doping Campaign Based on a qualitative study, the thesis investigates the visual representation of the male bodybuilder found in the national anti doping campaign: ‗ "The hunt has begun" along...

  18. Body Weight and Body Image

    OpenAIRE

    Olmsted, Marion P; McFarlane, Traci

    2004-01-01

    Abstract Health Issue Body weight is of physical and psychological importance to Canadian women; it is associated with health status, physical activity, body image, and self-esteem. Although the problems associated with overweight and obesity are indeed serious, there are also problems connected to being underweight. Weight prejudice and the dieting industry intensify body image concerns for Canadian women and can have a major negative impact on self-esteem. Key Findings Women have lower BMIs...

  19. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    Energy Technology Data Exchange (ETDEWEB)

    Goffart, Nicolas [Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège 4000 (Belgium); Kroonen, Jérôme [Human Genetics, CHU and University of Liège, Liège 4000 (Belgium); The T& P Bohnenn Laboratory for Neuro-Oncology, Department of Neurology and Neurosurgery, UMC Utrecht, Utrecht 3556 (Netherlands); Rogister, Bernard, E-mail: Bernard.Register@ulg.ac.be [Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège 4000 (Belgium); Department of Neurology, CHU and University of Liège, Liège 4000 (Belgium); GIGA-Development, Stem Cells and Regenerative Medicine, University of Liège, Liège 4000 (Belgium)

    2013-08-14

    Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

  20. Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

    Directory of Open Access Journals (Sweden)

    Björn L.D.M. Brücher

    2014-07-01

    Full Text Available The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine, and adjacent communication with nearby cells (juxtacrine, which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling or over large distances via hormones (endocrine. The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins, occluding junctions (Tight Junctions, and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes. The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM via the different transmembrane adhesion proteins (Cadherins and Integrins. We have here reviewed cell-cell communication involving (1 the components of junctions and their dynamic interplay with the other aspects of communication, including (2 the tumor microenvironment and carcinogenesis, (3 coupling and migration, (4 the underlying cell-cell and sub-cellular communication mechanisms (signaling of anticancer treatments, and finally, (5 aspects of recent research on cell-cell communication.

  1. Acidic Microenvironments in Waste Rock Characterized by Neutral Drainage: Bacteria–Mineral Interactions at Sulfide Surfaces

    Directory of Open Access Journals (Sweden)

    John W. Dockrey

    2014-03-01

    Full Text Available Microbial populations and microbe-mineral interactions were examined in waste rock characterized by neutral rock drainage (NRD. Samples of three primary sulfide-bearing waste rock types (i.e., marble-hornfels, intrusive, exoskarn were collected from field-scale experiments at the Antamina Cu–Zn–Mo mine, Peru. Microbial communities within all samples were dominated by neutrophilic thiosulfate oxidizing bacteria. However, acidophilic iron and sulfur oxidizers were present within intrusive waste rock characterized by bulk circumneutral pH drainage. The extensive development of microbially colonized porous Fe(III (oxyhydroxide and Fe(III (oxyhydroxysulfate precipitates was observed at sulfide-mineral surfaces during examination by field emission-scanning electron microscopy-energy dispersive X-ray spectroscopy (FE-SEM-EDS. Linear combination fitting of bulk extended X-ray absorption fine structure (EXAFS spectra for these precipitates indicated they were composed of schwertmannite [Fe8O8(OH6–4.5(SO41–1.75], lepidocrocite [γ-FeO(OH] and K-jarosite [KFe3(OH6(SO42]. The presence of schwertmannite and K-jarosite is indicative of the development of localized acidic microenvironments at sulfide-mineral surfaces. Extensive bacterial colonization of this porous layer and pitting of underlying sulfide-mineral surfaces suggests that acidic microenvironments can play an important role in sulfide-mineral oxidation under bulk circumneutral pH conditions. These findings have important implications for water quality management in NRD settings.

  2. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

    Science.gov (United States)

    Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie; Behera, Reeti; Ndoye, Abibatou; Kugel, Curtis H; Dang, Vanessa M; Appleton, Jessica; O'Connell, Michael P; Cheng, Phil; Valiga, Alexander A; Morissette, Rachel; McDonnell, Nazli B; Ferrucci, Luigi; Kossenkov, Andrew V; Meeth, Katrina; Tang, Hsin-Yao; Yin, Xiangfan; Wood, William H; Lehrmann, Elin; Becker, Kevin G; Flaherty, Keith T; Frederick, Dennie T; Wargo, Jennifer A; Cooper, Zachary A; Tetzlaff, Michael T; Hudgens, Courtney; Aird, Katherine M; Zhang, Rugang; Xu, Xiaowei; Liu, Qin; Bartlett, Edmund; Karakousis, Giorgos; Eroglu, Zeynep; Lo, Roger S; Chan, Matthew; Menzies, Alexander M; Long, Georgina V; Johnson, Douglas B; Sosman, Jeffrey; Schilling, Bastian; Schadendorf, Dirk; Speicher, David W; Bosenberg, Marcus; Ribas, Antoni; Weeraratna, Ashani T

    2016-04-14

    Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

  3. Engineering Enriched Microenvironments with Gradients of Platelet Lysate in Hydrogel Fibers.

    Science.gov (United States)

    Santo, Vítor E; Babo, Pedro; Amador, Miguel; Correia, Cláudia; Cunha, Bárbara; Coutinho, Daniela F; Neves, Nuno M; Mano, João F; Reis, Rui L; Gomes, Manuela E

    2016-06-13

    Gradients of physical and chemical cues are characteristic of specific tissue microenvironments and contribute toward morphogenesis and tissue regeneration upon injury. Recent advances on microfluidics and hydrogel manipulation raised the possibility of generating biomimetic biomaterials enriched with bioactive factors and encapsulating cells following designs specifically tailored for a target application. The novelty of this work relies on the combination of methacrylated gellan gum (MeGG) with platelet lysate (PL), aiming to generate novel advanced 3D PL-enriched photo-cross-linkable hydrogels and overcoming the lack of adhesion sites provided by the native MeGG hydrogels. This combination takes advantage of the availability, enriched growth factor composition, and potential autologous application of PL while simultaneously preserving the ability provided by MeGG to tailor mechanical properties, protein release kinetics, and shape of the construct according to the desired goal. Incorporation of PL in the hydrogels significantly improved cellular adhesion and viability in the constructs. The use of microfluidic tools allowed the design of a fiber-like hydrogel incorporating a gradient of PL along the length of the fiber. These spatial protein gradients led to the viability and cell number gradients caused by maintenance of human umbilical vein endothelial cells (HUVECs) survival in the fibers toward the PL-enriched sections in comparison with the nonloaded MeGG sections of the fibers. Altogether, we propose a proof of concept strategy to design a PL gradient biomaterial with potential in tissue engineering approaches and analysis of cell-microenvironment interactions.

  4. Human pluripotent stem cells on artificial microenvironments: a high content perspective

    Science.gov (United States)

    Viswanathan, Priyalakshmi; Gaskell, Terri; Moens, Nathalie; Culley, Oliver J.; Hansen, Darrick; Gervasio, Mia K. R.; Yeap, Yee J.; Danovi, Davide

    2014-01-01

    Self-renewing stem cell populations are increasingly considered as resources for cell therapy and tools for drug discovery. Human pluripotent stem (hPS) cells in particular offer a virtually unlimited reservoir of homogeneous cells and can be differentiated toward diverse lineages. Many diseases show impairment in self-renewal or differentiation, abnormal lineage choice or other aberrant cell behavior in response to chemical or physical cues. To investigate these responses, there is a growing interest in the development of specific assays using hPS cells, artificial microenvironments and high content analysis. Several hurdles need to be overcome that can be grouped into three areas: (i) availability of robust, homogeneous, and consistent cell populations as a starting point; (ii) appropriate understanding and use of chemical and physical microenvironments; (iii) development of assays that dissect the complexity of cell populations in tissues while mirroring specific aspects of their behavior. Here we review recent progress in the culture of hPS cells and we detail the importance of the environment surrounding the cells with a focus on synthetic material and suitable high content analysis approaches. The technologies described, if properly combined, have the potential to create a paradigm shift in the way diseases are modeled and drug discovery is performed. PMID:25071572

  5. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance

    Directory of Open Access Journals (Sweden)

    Susana eRomero-Garcia

    2016-02-01

    Full Text Available Malignant transformation of cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate, even under normoxic conditions; this phenomenon of aerobic glycolysis is largely known as the Warburg effect. This metabolic reprogramming serves to generate biosynthetic precursors, thus facilitating the survival of rapidly proliferating malignant cells. Extracellular lactate directs the metabolic reprogramming of tumor cells, thereby serving as an additional selective pressure. Besides tumor cells, stromal cells are another source of lactate production in the tumor microenvironment, whose role in both tumor growth and the anti-tumor immune response is the subject of intense research. In this review, we provide an integral perspective of the relationship between lactate and the overall tumor microenvironment, from lactate structure to metabolic pathways for its synthesis, receptors, signaling pathways, lactate-producing cells, lactate-responding cells, and how all contribute to the tumor outcome. We discuss the role of lactate as a immunosuppressor molecule that contributes to tumor evasion and explore the possibility of targeting lactate metabolism for cancer treatment, as well as of using lactate as a prognostic biomarker.

  6. Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

    Science.gov (United States)

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-07-01

    Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Human pluripotent stem cells on artificial microenvironments: a high content perspective.

    Directory of Open Access Journals (Sweden)

    Priyalakshmi eViswanathan

    2014-07-01

    Full Text Available Self-renewing stem cell populations are increasingly considered as resources for cell therapy and tools for drug discovery. Human pluripotent stem (hPS cells in particular offer a virtually unlimited reservoir of homogeneous cells and can be differentiated towards diverse lineages. Many diseases show impairment in self-renewal or differentiation, abnormal lineage choice or other aberrant cell behavior in response to chemical or physical cues. To investigate these responses, there is a growing interest in the development of specific assays using hPS cells artificial microenvironments and high content analysis. Several hurdles need to be overcome that can be grouped in: (i availability of robust, homogeneous and consistent cell populations as a starting point; (ii appropriate understanding and use of chemical and physical microenvironments; (iii development of assays that dissect the complexity of cell populations in tissues while mirroring specific aspects of their behavior. Here we review recent progress in the culture of hPS cells and we detail the importance of the environment surrounding the cells with a focus on synthetic material and suitable high content analysis approaches. The technologies described if properly combined have the potential to create a paradigm shift in the way diseases are modelled and drug discovery is performed.

  8. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease

    Science.gov (United States)

    Cruz, Nelly M.; Song, Xuewen; Czerniecki, Stefan M.; Gulieva, Ramila E.; Churchill, Angela J.; Kim, Yong Kyun; Winston, Kosuke; Tran, Linh M.; Diaz, Marco A.; Fu, Hongxia; Finn, Laura S.; Pei, York; Himmelfarb, Jonathan; Freedman, Benjamin S.

    2017-11-01

    Polycystic kidney disease (PKD) is a life-threatening disorder, commonly caused by defects in polycystin-1 (PC1) or polycystin-2 (PC2), in which tubular epithelia form fluid-filled cysts. A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids. Here we show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls. These biomaterials establish a highly efficient model of PKD cystogenesis that directly implicates the microenvironment at the earliest stages of the disease.

  9. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    Directory of Open Access Journals (Sweden)

    Nicolas Goffart

    2013-08-01

    Full Text Available Glioblastoma multiforme (GBM, WHO grade IV is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

  10. Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling: Opportunities to Engineer the Therapeutic Effect.

    Science.gov (United States)

    Kusuma, Gina D; Carthew, James; Lim, Rebecca; Frith, Jessica E

    2017-05-01

    Cues from the extracellular environment, including physical stimuli, are well known to affect mesenchymal stem cell (MSC) properties in terms of proliferation and differentiation. Many therapeutic strategies are now targeting this knowledge to increase the efficacy of cell therapies, typically employed to repair tissue functions in the event of injury, either by direct engraftment into the target tissue or differentiation into mature tissues. However, it is now envisioned that harnessing the repertoire of factors secreted by MSCs (termed the secretome) may provide an alternate to these cell therapies. Of current interest are both direct protein secretions and two major subpopulations of bioactive extracellular vesicles (EVs), namely exosomes and microvesicles. EVs released by MSCs are reflective of their cells of origin, able to impact upon the activities of other cells in the local microenvironment, making the rational design of MSC paracrine activities an encouraging strategy to reproducibly modulate cell therapies. The precise mechanisms by which the secretome is modulated by the microenvironment, however, remain elusive. Controlling MSC growth conditions with oxygen tension, growth factor composition, and mechanical properties may serve to directly influence paracrine activity. Our growing understanding implicates components of the mechanotransduction machinery in translating both mechanical and chemical cues from the environment into alterations in gene regulation and varied paracrine activity. As technologies are developed to manufacture MSCs, advances in bioengineering and novel insight of how the extracellular environment affects MSC paracrine activity will play a pivotal role in the generation of widespread, successful, clinical MSC therapies.

  11. Effect of DNA microenvironment on photosensitized reaction of watersoluble cationic porphyrins.

    Science.gov (United States)

    Hirakawa, Kazutaka; Nakajima, Shuku

    2014-01-01

    Endogenous and exogenous photosensitizers induce DNA damage, leading to carcinogenesis. Further, DNA is an important target biomacromolecule of photodynamic therapy (PDT) for cancer. Since the solar-induced DNA damage and PDT reaction occur in a complex biological environment, the interaction between biomolecule and photosensitizer is important. In this study, we examined the effect of a DNA microenvironment on the photosensitized reaction by watersoluble porphyrin derivatives, tetrakis(N-methyl-p-pyridinio)porphyrin (H(2)TMPyP) and its zinc complex (ZnTMPyP). In the presence of a sufficient concentration of DNA, H(2)TMPyP mainly intercalates to calf thymus DNA, whereas ZnTMPyP binds into a DNA groove. An electrostatic interaction with DNA raises the redox potential of the binding porphyrins. This effect suppressed the photoinduced electron transfer from an electron donor to the DNA-binding porphyrins, whereas the electron transfer from the porphyrins to the electron acceptor was enhanced. In the case of hydrophobic electron acceptors, static complexes with porphyrins were formed, making rapid electron transfer possible. Since the interaction with DNA cleaved this complex, the electron transfer rate was decreased in the presence of DNA. The microenvironment of a DNA strand may assist or inhibit its oxidative damage by photoinduced electron transfer through an electrostatic interaction with binding photosensitizers and the steric effect.

  12. Cancer Microenvironment: What Can We Learn from the Stem Cell Niche

    Directory of Open Access Journals (Sweden)

    Lukas Lacina

    2015-10-01

    Full Text Available Epidermal stem cells (ESCs are crucial for maintenance and self- renewal of skin epithelium and also for regular hair cycling. Their role in wound healing is also indispensable. ESCs reside in a defined outer root sheath portion of hair follicle—also known as the bulge region. ECS are also found between basal cells of the interfollicular epidermis or mucous membranes. The non-epithelial elements such as mesenchymal stem cell-like elements of dermis or surrounding adipose tissue can also contribute to this niche formation. Cancer stem cells (CSCs participate in formation of common epithelial malignant diseases such as basal cell or squamous cell carcinoma. In this review article, we focus on the role of cancer microenvironment with emphasis on the effect of cancer-associated fibroblasts (CAFs. This model reflects various biological aspects of interaction between cancer cell and CAFs with multiple parallels to interaction of normal epidermal stem cells and their niche. The complexity of intercellular interactions within tumor stroma is depicted on example of malignant melanoma, where keratinocytes also contribute the microenvironmental landscape during early phase of tumor progression. Interactions seen in normal bulge region can therefore be an important source of information for proper understanding to melanoma. The therapeutic consequences of targeting of microenvironment in anticancer therapy and for improved wound healing are included to article.

  13. Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma.

    Science.gov (United States)

    Eckert, Alexander W; Wickenhauser, Claudia; Salins, Paul C; Kappler, Matthias; Bukur, Juergen; Seliger, Barbara

    2016-04-05

    Changes in the tumor microenvironment and immune surveillance represent crucial hallmarks of various kinds of cancer, including oral squamous cell carcinoma (OSCC), and a close crosstalk of hypoxia regulating genes, an activation of chemokines and immune cells has been described. A review about the pivotal role of HIF-1, its crosstalk to various cornerstones in OSCC tumorigenesis is presented. Hypoxia is a frequent event in OSCC and leads to a reprogramming of the cellular metabolism in order to prevent cell death. Hypoxic OSCC cells induce different adaptive changes such as anaerobic glycolysis, pH stabilisation and alterations of the gene and protein expression profile. This complex metabolic program is orchestrated by the hypoxia inducible factor (HIF)-1, the master regulator of early tumor progression. Hypoxia-dependent and -independent alterations in immune surveillance lead to different immune evasion strategies, which are partially mediated by alterations of the tumor cells, changes in the frequency, activity and repertoire of immune cell infiltrates and of soluble and environmental factors of the tumor micromilieu with consecutive generation of an immune escape phenotype, progression of disease and poor clinical outcome of OSCC patients. This review focusses on the importance of HIF-1 in the adaption and reprogramming of the metabolic system to reduced oxygen values as well as on the role of the tumor microenvironment for evasion of OSCC from immune recognition and destruction.

  14. Cell and Signal Components of the Microenvironment of Bone Metastasis Are Affected by Hypoxia

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    Paola Bendinelli

    2016-05-01

    Full Text Available Bone metastatic cells release bone microenvironment proteins, such as the matricellular protein SPARC (secreted protein acidic and rich in cysteine, and share a cell signaling typical of the bone metabolism controlled by Runx2. The megakaryocytes in the bone marrow engrafted by the metastases seem to be one of the principal microenvironment sources of the biological stimuli, implicated in the formation of an osteoblastic niche, and affecting metastasis phenotype and colonization. Educated platelets in the circulation might derive from megakaryocytes in bone metastasis. The evaluation of predictive markers in the circulating platelets might be useful for the stratification of patients for therapeutic purposes. The hypoxic environment in bone metastasis is one of the key regulators of the network of the biological soluble and structural components of the matrix. In bone metastatic cells under hypoxia, similar patterns of Runx2 and SPARC are observed, both showing downregulation. Conversely, hypoxia induces Endothelin 1, which upregulates SPARC, and these biological stimuli may be considered prognostic markers of bone metastasis in breast carcinoma patients.

  15. Uterine Micro-Environment and Estrogen-Dependent Regulation of Osteopontin Expression in Mouse Blastocyst

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    Qing-Zhen Xie

    2013-07-01

    Full Text Available Embryo implantation is a highly synchronized bioprocess between an activated blastocyst and a receptive uterus. In mice, successful implantation relies on the dynamic interplay of estrogen and progesterone; however, the key mediators downstream of these hormones that act on blastocyst competency and endometrium receptivity acquisition are largely unknown. In this study, we showed that the expression of osteopontin (OPN in mouse blastocysts is regulated by ovarian estrogen and uterine micro-environment. OPN mRNA is up-regulated in mouse blastocyst on day 4 of pregnancy, which is associated with ovarian estrogen secretion peak. Hormone treatment in vivo demonstrated that OPN expression in a blastocyst is regulated by estrogen through an estrogen receptor (ER. Our results of the delayed and activated implantation model showed that OPN expression is induced after estrogen injection. While estrogen treatment during embryo culture in vitro showed less effect on OPN expression, the tubal ligation model on day 3 of pregnancy confirmed that the regulation of estrogen on OPN expression in blastocyst might, through some specific cytokines, have existed in a uterine micro-environment. Collectively, our study presents that estrogen regulates OPN expression and it may play an important role during embryo implantation by activating blastocyst competence and facilitating the endometrium acceptable for active blastocyst.

  16. Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

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    Alessandro Poggi

    2016-11-01

    Full Text Available The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT, a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

  17. The extracellular microenvironment explains variations in passive drug transport across different airway epithelial cell types.

    Science.gov (United States)

    Min, Kyoung Ah; Talattof, Arjang; Tsume, Yasuhiro; Stringer, Kathleen A; Yu, Jing-Yu; Lim, Dong Hyun; Rosania, Gus R

    2013-08-01

    We sought to identify key variables in cellular architecture and physiology that might explain observed differences in the passive transport properties of small molecule drugs across different airway epithelial cell types. Propranolol (PR) was selected as a weakly basic, model compound to compare the transport properties of primary (NHBE) vs. tumor-derived (Calu-3) cells. Differentiated on Transwell™ inserts, the architecture of pure vs. mixed cell co-cultures was studied with confocal microscopy followed by quantitative morphometric analysis. Cellular pharmacokinetic modeling was used to identify parameters that differentially affect PR uptake and transport across these two cell types. Pure Calu-3 and NHBE cells possessed different structural and functional properties. Nevertheless, mixed Calu-3 and NHBE cell co-cultures differentiated as stable cell monolayers. After measuring the total mass of PR, the fractional areas covered by Calu-3 and NHBE cells allowed deconvoluting the transport properties of each cell type. Based on the apparent thickness of the unstirred, cell surface aqueous layer, local differences in the extracellular microenvironment explained the measured variations in passive PR uptake and permeation between Calu-3 and NHBE cells. Mixed cell co-cultures can be used to compare the local effects of the extracellular microenvironment on drug uptake and transport across two epithelial cell types.

  18. Effects of the local environment on CNT-based nanoelectronics: development of a microenvironment probe station.

    Science.gov (United States)

    McClain, Devon; Thomas, Nicole; Nguyen, Tri; O'Brien, Kevin P; Jiao, Jun

    2010-11-01

    In this study, we report the development of a microenvironment probe station capable of detecting the effect of small changes to the local environment around a carbon nanotube conduction channel. The microenvironment probe station is highly versatile and is used to characterize alterations in carbon nanotube field effect transistor electrical behavior in response to changes in temperature, gas species, infrared and ultraviolet light. All devices were electrically characterized in atmospheric, ultrahigh vacuum and oxygen-rich environments. The results suggest that devices could be changed from n-type at 1 x 10(-8) torr through an intermediate ambipolar state at 1 x 10(-4) torr to p-type at atmosphere solely by increasing the oxygen concentration. The average resistance of these carbon nanotube field effect transistors after annealing was observed to decrease by approximately 54% from their initial value under ultrahigh vacuum to their final value in the presence of pure oxygen while corresponding threshold voltages shifts were also observed. Illumination with infrared light resulted in a approximately 10% increase in drain current with an estimated response time <1 fs due to photon-induced electron-hole pair generation. Illumination with ultraviolet light resulted in approximately 5-15% reduction in drain current due to photon-induced desorption of oxygen adsorbate.

  19. Biomimetic strategies to recapitulate organ specific microenvironments for studying breast cancer metastasis.

    Science.gov (United States)

    Narkhede, Akshay A; Shevde, Lalita A; Rao, Shreyas S

    2017-09-15

    The progression of breast cancer from the primary tumor setting to the metastatic setting is the critical event defining Stage IV disease, no longer considered curable. The microenvironment at specific organ sites is known to play a key role in influencing the ultimate fate of metastatic cells; yet microenvironmental mediated-molecular mechanisms underlying organ specific metastasis in breast cancer are not well understood. This review discusses biomimetic strategies employed to recapitulate metastatic organ microenvironments, particularly, bone, liver, lung and brain to elucidate the mechanisms dictating metastatic breast cancer cell homing and colonization. These biomimetic strategies include in vitro techniques such as biomaterial-based co-culturing techniques, microfluidics, organ-mimetic chips, bioreactor technologies, and decellularized matrices as well as cutting edge in vivo techniques to better understand the interactions between metastatic breast cancer cells and the stroma at the metastatic site. The advantages and disadvantages of these systems are discussed. In addition, how creation of biomimetic models will impact breast cancer metastasis research and their broad utility is explored. © 2017 UICC.

  20. Personal day-time exposure to ultrafine particles in different microenvironments.

    Science.gov (United States)

    Gu, Jianwei; Kraus, Ute; Schneider, Alexandra; Hampel, Regina; Pitz, Mike; Breitner, Susanne; Wolf, Kathrin; Hänninen, Otto; Peters, Annette; Cyrys, Josef

    2015-03-01

    In order to assess the personal exposure to ultrafine particles (UFP) during individual day-time activities and to investigate the impact of different microenvironments on exposure, we measured personal exposure to particle number concentrations (PNC), a surrogate for UFP, among 112 non-smoking participants in Augsburg, Germany over a nearly two-year period from March 2007 to December 2008. We obtained 337 personal PNC measurements from 112 participants together with dairies of their activities and locations. The measurements lasted on average 5.5h and contained on average 330 observations. In addition, ambient PNC were measured at an urban background stationary monitoring site. Personal PNC were highly variable between measurements (IQR of mean: 11780-24650cm(-3)) and also within a single measurement. Outdoor personal PNC in traffic environments were about two times higher than in non-traffic environments. Higher indoor personal PNC were associated with activities like cooking, being in a bistro or exposure to passive smoking. Overall, personal and stationary PNC were weakly to moderately correlated (rshopping (ratio: 2.4), and indoors with water vapor (ratio: 2.5). Additive mixed models were applied to predict personal PNC by participants' activities and locations. Traffic microenvironments were significant determinants for outdoor personal PNC. Being in a bistro, passive smoking, and cooking contributed significantly to an increased indoor personal PNC. Copyright © 2014 Elsevier GmbH. All rights reserved.

  1. Efficacy of Honeycomb TCP-induced Microenvironment on Bone Tissue Regeneration in Craniofacial Area.

    Science.gov (United States)

    Watanabe, Satoko; Takabatake, Kiyofumi; Tsujigiwa, Hidetsugu; Watanabe, Toshiyuki; Tokuyama, Eijiro; Ito, Satoshi; Nagatsuka, Hitoshi; Kimata, Yoshihiro

    2016-01-01

    Artificial bone materials that exhibit high biocompatibility have been developed and are being widely used for bone tissue regeneration. However, there are no biomaterials that are minimally invasive and safe. In a previous study, we succeeded in developing honeycomb β-tricalcium phosphate (β-TCP) which has through-and-through holes and is able to mimic the bone microenvironment for bone tissue regeneration. In the present study, we investigated how the difference in hole-diameter of honeycomb β-TCP (hole-diameter: 75, 300, 500, and 1600 μm) influences bone tissue regeneration histologically. Its osteoconductivity was also evaluated by implantation into zygomatic bone defects in rats. The results showed that the maximum bone formation was observed on the β-TCP with hole-diameter 300μm, included bone marrow-like tissue and the pattern of bone tissue formation similar to host bone. Therefore, the results indicated that we could control bone tissue formation by creating a bone microenvironment provided by β-TCP. Also, in zygomatic bone defect model with honeycomb β-TCP, the result showed there was osseous union and the continuity was reproduced between the both edges of resected bone and β-TCP, which indicated the zygomatic bone reproduction fully succeeded. It is thus thought that honeycomb β-TCP may serve as an excellent biomaterial for bone tissue regeneration in the head, neck and face regions, expected in clinical applications.

  2. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy.

    Science.gov (United States)

    Soto-Pantoja, David R; Terabe, Masaki; Ghosh, Arunima; Ridnour, Lisa A; DeGraff, William G; Wink, David A; Berzofsky, Jay A; Roberts, David D

    2014-12-01

    Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8(+) T cells restored combinatorial efficacy. Furthermore, ablation of CD8(+) T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8(+) CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8(+) T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses. ©2014 American Association for Cancer Research.

  3. Redirection of Human Cancer Cells upon the Interaction with the Regenerating Mouse Mammary Gland Microenvironment

    Directory of Open Access Journals (Sweden)

    Sonia M. Rosenfield

    2013-01-01

    Full Text Available Tumorigenesis is often described as a result of accumulated mutations that lead to growth advantage and clonal expansion of mutated cells. There is evidence in the literature that cancer cells are influenced by the microenvironment. Our previous studies demonstrated that the mouse mammary gland is capable of redirecting mouse cells of non-mammary origins as well as Mouse Mammary Tumor Virus (MMTV-neu transformed cells toward normal mammary epithelial cell fate during gland regeneration. Interestingly, the malignant phenotype of MMTV-neu transformed cells was suppressed during serial transplantation experiments. Here, we discuss our studies that demonstrated the potential of the regenerating mouse mammary gland to redirect cancer cells of different species into a functional tumor-free mammary epithelial cell progeny. Immunochemistry for human specific CD133, mitochondria, cytokeratins as well as milk proteins and FISH for human specific probe identified human epithelial cell progeny in ducts, lobules, and secretory acini. Fluorescent In Situ Hybridization (FISH for human centromeric DNA and FACS analysis of propidium iodine staining excluded the possibility of mouse-human cell fusion. To our knowledge this is the first evidence that human cancer cells of embryonic or somatic origins respond to developmental signals generated by the mouse mammary gland microenvironment during gland regeneration in vivo.

  4. Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments.

    Science.gov (United States)

    Wojtkowiak, Jonathan W; Rothberg, Jennifer M; Kumar, Virendra; Schramm, Karla J; Haller, Edward; Proemsey, Joshua B; Lloyd, Mark C; Sloane, Bonnie F; Gillies, Robert J

    2012-08-15

    Tumor cell survival relies upon adaptation to the acidic conditions of the tumor microenvironment. To investigate potential acidosis survival mechanisms, we examined the effect of low pH (6.7) on human breast carcinoma cells. Acute low pH exposure reduced proliferation rate, induced a G1 cell cycle arrest, and increased cytoplasmic vacuolization. Gene expression analysis revealed elevated levels of ATG5 and BNIP3 in acid-conditioned cells, suggesting cells exposed to low pH may utilize autophagy as a survival mechanism. In support of this hypothesis, we found that acute low pH stimulated autophagy as defined by an increase in LC3-positive punctate vesicles, double-membrane vacuoles, and decreased phosphorylation of AKT and ribosomal protein S6. Notably, cells exposed to low pH for approximately 3 months restored their proliferative capacity while maintaining the cytoplasmic vacuolated phenotype. Although autophagy is typically transient, elevated autophagy markers were maintained chronically in low pH conditioned cells as visualized by increased protein expression of LC3-II and double-membrane vacuoles. Furthermore, these cells exhibited elevated sensitivity to PI3K-class III inhibition by 3-methyladenine. In mouse tumors, LC3 expression was reduced by systemic treatment with sodium bicarbonate, which raises intratumoral pH. Taken together, these results argue that acidic conditions in the tumor microenvironment promote autophagy, and that chronic autophagy occurs as a survival adaptation in this setting. ©2012 AACR.

  5. Extracellular Vesicles As Modulators of Tumor Microenvironment and Disease Progression in Glioma

    Directory of Open Access Journals (Sweden)

    Abir Mondal

    2017-07-01

    Full Text Available Diffuse gliomas are lethal tumors of the central nervous system (CNS characterized by infiltrative growth, aggressive nature, and therapeutic resistance. The recent 2016 WHO classification for CNS tumors categorizes diffuse glioma into two major types that include IDH wild-type glioblastoma, which is the predominant type and IDH-mutant glioblastoma, which is less common and displays better prognosis. Recent studies suggest presence of a distinct cell population with stem cell features termed as glioma stem cells (GSCs to be causal in driving tumor growth in glioblastoma. The presence of a stem and progenitor population possibly makes glioblastoma highly heterogeneous. Significantly, tumor growth is driven by interaction of cells residing within the tumor with the surrounding milieu termed as the tumor microenvironment. It comprises of various cell types such as endothelial cells, secreted factors, and the surrounding extracellular matrix, which altogether help perpetuate the proliferation of GSCs. One of the important mediators critical to the cross talk is extracellular vesicles (EVs. These nano-sized vesicles play important roles in intercellular communication by transporting bioactive molecules into the surrounding milieu, thereby altering cellular functions and/or reprogramming recipient cells. With the growing information on the contribution of EVs in modulation of the tumor microenvironment, it is important to determine their role in both supporting as well as promoting tumor growth in glioma. In this review, we provide a comprehensive overview of the role of EVs in tumor progression and glioma pathogenesis.

  6. Bone Microenvironment Modulates Expression and Activity of Cathepsin B in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Izabela Podgorski

    2005-03-01

    Full Text Available Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DOcollagen I (a bone matrix protein and, for comparison, DO-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, this degradation was reduced by inhibitors of matrix metallo, serine, cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells-cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.

  7. An analysis system of human motion based on micro-environment

    Science.gov (United States)

    Ou, Changjiang; Chen, Xiaoning

    2017-08-01

    Aiming at the problem that the traditional positioning device cannot carry on the high precision positioning and the motion characteristic analysis problem to the moving target in the micro environment, a small wear device capable of low power consumption can be designed, which can record the human movement trajectory and time, Analysis of the Motion Characteristics of Software. To achieve a ± 0.5m high-precision positioning, the device uses GPS positioning which can reduce the power consumption of GPRS data transmission by optimizing the structure; finally, through the program we write, the system can analyze the flow and behavior analysis of people within the scope already. From the test we can know that: the device can complete the analysis and processing of information such as high-precision positioning and behavioral path of the moving target (human) in the micro-environment of the specific area; Also the analysis software can deal with the information such as residence time, moving target number and single target position of some specific areas in the micro-environment.

  8. Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma

    Science.gov (United States)

    Sung, Pi-Lin; Jan, Yi-Hua; Lin, Shih-Chieh; Huang, Chao-Cheng; Lin, Hao; Wen, Kuo-Chang; Chao, Kuan-Chong; Lai, Chiung-Ru; Wang, Peng-Hui; Chuang, Chi-Mu; Wu, Hua-Hsi; Twu, Nae-Fang; Yen, Ming-Shyen; Hsiao, Michael; Huang, Chi-Ying F.

    2016-01-01

    The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics. PMID:26716408

  9. Manipulation of Microenvironment with a Built-in Electrochemical Actuator in Proximity of a Dissolved Oxygen Microsensor

    Science.gov (United States)

    Kim, Chang-Soo; Lee, Cae-Hyang; Fiering, Jason O.; Ufer, Stefan; Scarantino, Charles W.; Nagle, H. Troy; Fiering, Jason O.; Ufer, Stefan; Nagle, H. Troy; Scarantino, Charles W.

    2004-01-01

    Abstract - Biochemical sensors for continuous monitoring require dependable periodic self- diagnosis with acceptable simplicity to check its functionality during operation. An in situ self- diagnostic technique for a dissolved oxygen microsensor is proposed in an effort to devise an intelligent microsensor system with an integrated electrochemical actuation electrode. With a built- in platinum microelectrode that surrounds the microsensor, two kinds of microenvironments, called the oxygen-saturated or oxygen-depleted phases, can be created by water electrolysis depending on the polarity. The functionality of the microsensor can be checked during these microenvironment phases. The polarographic oxygen microsensor is fabricated on a flexible polyimide substrate (Kapton) and the feasibility of the proposed concept is demonstrated in a physiological solution. The sensor responds properly during the oxygen-generating and oxygen- depleting phases. The use of these microenvironments for in situ self-calibration is discussed to achieve functional integration as well as structural integration of the microsensor system.

  10. Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas

    DEFF Research Database (Denmark)

    Castven, Darko; Fischer, Michael; Becker, Diana

    2017-01-01

    Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse milieu that promotes tumor-initiation and progression. A better understanding of the hepatic tumor-microenvironment interaction might infer.......Prognostic significance of the permissive liver microenvironment might be a consequence of a pro-oncogenic field effect that is caused by chronic regenerative processes. Activation of key oncogenic features and immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising...... profound therapeutic implications.Integrative whole genome and transcriptome analyses of different tumor regions, the invasive tumor border and tumor-surrounding liver (SL) were performed to identify associated molecular alterations and integrated with our existing HCC database. Expression levels...

  11. Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Sara D. [Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425 (United States); De Costa, Anna-Maria A. [Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425 (United States); Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 (United States); Young, M. Rita I., E-mail: rita.young@va.gov [Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425 (United States); Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 (United States); Medical Research Service (151), Ralph H. Johnson Veterans Affairs Medical Center, 109 Bee Street, Charleston, SC 29401 (United States)

    2014-04-02

    Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE{sub 2} compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.

  12. Ibrutinib and idelalisib block immunophenotypic changes associated with the adhesion and activation of CLL cells in the tumor microenvironment.

    Science.gov (United States)

    Shen, Yandong; Best, O Giles; Mulligan, Stephen P; Christopherson, Richard I

    2017-11-22

    The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow.

  13. Bog bodies

    DEFF Research Database (Denmark)

    Lynnerup, Niels

    2015-01-01

    the bog bodies have been studied using medical and natural scientific methods, and recently many bog bodies have been re-examined using especially modern, medical imaging techniques. Because of the preservation of soft tissue, especially the skin, it has been possible to determine lesions and trauma......In northern Europe during the Iron Age, many corpses were deposited in bogs. The cold, wet and anaerobic environment leads in many cases to the preservation of soft tissues, so that the bodies, when found and excavated several thousand years later, are remarkably intact. Since the 19th century....... Conversely, the preservation of bones is less good, as the mineral component has been leached out by the acidic bog. Together with water-logging of collagenous tissue, this means that if the bog body is simply left to dry out when found, as was the case pre-19th century, the bones may literally warp...

  14. Modelling the buried human body environment in upland climes using three contrasting field sites.

    Science.gov (United States)

    Wilson, Andrew S; Janaway, Robert C; Holland, Andrew D; Dodson, Hilary I; Baran, Eve; Pollard, A Mark; Tobin, Desmond J

    2007-06-14

    Despite an increasing literature on the decomposition of human remains, whether buried or exposed, it is important to recognise the role of specific microenvironments which can either trigger or delay the rate of decomposition. Recent casework in Northern England involving buried and partially buried human remains has demonstrated a need for a more detailed understanding of the effect of contrasting site conditions on cadaver decomposition and on the microenvironment created within the grave itself. Pigs (Sus scrofa) were used as body analogues in three inter-related taphonomy experiments to examine differential decomposition of buried human remains. They were buried at three contrasting field sites (pasture, moorland, and deciduous woodland) within a 15 km radius of the University of Bradford, West Yorkshire, UK. Changes to the buried body and the effect of these changes on hair and associated death-scene textile materials were monitored as was the microenvironment of the grave. At recovery, 6, 12 and 24 months post-burial, the extent of soft tissue decomposition was recorded and samples of fat and soil were collected for gas chromatography mass spectrometry (GCMS) analysis. The results of these studies demonstrated that (1) soil conditions at these three burial sites has a marked effect on the condition of the buried body but even within a single site variation can occur; (2) the process of soft tissue decomposition modifies the localised burial microenvironment in terms of microbiological load, pH, moisture and changes in redox status. These observations have widespread application for the investigation of clandestine burial and time since deposition, and in understanding changes within the burial microenvironment that may impact on biomaterials such as hair and other associated death scene materials.

  15. Stromal-epithelial crosstalk provides a suitable microenvironment for the progression of ovarian cancer cells in vitro.

    Science.gov (United States)

    Fu, Shilong; Dong, Lihua; Sun, Wei; Xu, Yi; Gao, Li; Miao, Yi

    2013-11-01

    The tumor microenvironment plays an important role in the progression of cancer. This study focused on carcinoma-associated fibroblasts (CAFs) and stromal-epithelial interaction between CAFs and epithelial ovarian carcinoma (EOC) cells. We isolated and established primary cultures of CAFs and co-cultured CAFs and EOC cells in vitro. The co-culture conditioned medium (CC-CM) was harvested and its influence on EOC cells was examined. Cytokine, chemokine, and growth factor levels were screened using a biotin label-based human antibody array system. We found that the stromal-epithelial crosstalk provided a suitable microenvironment for the progression of ovarian cancer cells in vitro.

  16. Heterogeneity of passenger exposure to air pollutants in public transport microenvironments

    Science.gov (United States)

    Yang, Fenhuan; Kaul, Daya; Wong, Ka Chun; Westerdahl, Dane; Sun, Li; Ho, Kin-fai; Tian, Linwei; Brimblecombe, Peter; Ning, Zhi

    2015-05-01

    Epidemiologic studies have linked human exposure to pollutants with adverse health effects. Passenger exposure in public transport systems contributes an important fraction of daily burden of air pollutants. While there is extensive literature reporting the concentrations of pollutants in public transport systems in different cities, there are few studies systematically addressing the heterogeneity of passenger exposure in different transit microenvironments, in cabins of different transit vehicles and in areas with different characteristics. The present study investigated PM2.5 (particulate matter with aerodynamic diameters smaller than 2.5 μm), black carbon (BC), ultrafine particles (UFP) and carbon monoxide (CO) pollutant concentrations in various public road transport systems in highly urbanized city of Hong Kong. Using a trolley case housing numerous portable air monitors, we conducted a total of 119 trips during the campaign. Transit microenvironments, classified as 1). busy and secondary roadside bus stops; 2). open and enclosed termini; 3). above- and under-ground Motor Rail Transport (MTR) platforms, were investigated and compared to identify the factors that may affect passenger exposures. The pollutants inside bus and MTR cabins were also investigated together with a comparison of time integrated exposure between the transit modes. Busy roadside and enclosed termini demonstrated the highest average particle concentrations while the lowest was found on the MTR platforms. Traffic-related pollutants BC, UFP and CO showed larger variations than PM2.5 across different microenvironments and areas confirming their heterogeneity in urban environments. In-cabin pollutant concentrations showed distinct patterns with BC and UFP high in diesel bus cabins and CO high in LPG bus cabins, suggesting possible self-pollution issues and/or penetration of on-road pollutants inside cabins during bus transit. The total passenger exposure along selected routes, showed bus

  17. Effect of Irradiation on Tumor Microenvironment and Bone Marrow Cell Migration in a Preclinical Tumor Model

    Energy Technology Data Exchange (ETDEWEB)

    Kane, Jonathan L. [Department of Biological Sciences, Oakland University, Rochester, Michigan (United States); Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan (United States); Krueger, Sarah A.; Hanna, Alaa [Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan (United States); Raffel, Thomas R. [Department of Biological Sciences, Oakland University, Rochester, Michigan (United States); Wilson, George D. [Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan (United States); Madlambayan, Gerard J. [Department of Biological Sciences, Oakland University, Rochester, Michigan (United States); Marples, Brian, E-mail: Brian.Marples@beaumont.edu [Department of Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan (United States)

    2016-09-01

    Purpose: To characterize the tumor microenvironment after standard radiation therapy (SRT) and pulsed radiation therapy (PRT) in Lewis lung carcinoma (LLC) allografts. Methods and Materials: Subcutaneous LLC tumors were established in C57BL/6 mice. Standard RT or PRT was given at 2 Gy/d for a total dose of 20 Gy using a 5 days on, 2 days off schedule to mimic clinical delivery. Radiation-induced tumor microenvironment changes were examined after treatment using flow cytometry and antibody-specific histopathology. Normal tissue effects were measured using noninvasive {sup 18}F-fluorodeoxyglucose positron emission tomography/computed tomography after naïve animals were given whole-lung irradiation to 40 Gy in 4 weeks using the same 2-Gy/d regimens. Results: Over the 2 weeks of therapy, PRT was more effective than SRT at reducing tumor growth rate (0.31 ± 0.02 mm{sup 3}/d and 0.55 ± 0.04 mm{sup 3}/d, respectively; P<.007). Histopathology showed a significant comparative reduction in the levels of Ki-67 (14.5% ± 3%), hypoxia (10% ± 3.5%), vascular endothelial growth factor (2.3% ± 1%), and stromal-derived factor-1α (2.5% ± 1.4%), as well as a concomitant decrease in CD45{sup +} bone marrow–derived cell (BMDC) migration (7.8% ± 2.2%) after PRT. The addition of AMD3100 also decreased CD45{sup +} BMDC migration in treated tumors (0.6% ± 0.1%). Higher vessel density was observed in treated tumors. No differences were observed in normal lung tissue after PRT or SRT. Conclusions: Pulsed RT–treated tumors exhibited slower growth and reduced hypoxia. Pulsed RT eliminated initiation of supportive mechanisms utilized by tumors in low oxygen microenvironments, including angiogenesis and recruitment of BMDCs.

  18. Body Imaging

    Science.gov (United States)

    2001-01-01

    The high-tech art of digital signal processing (DSP) was pioneered at NASA's Jet Propulsion Laboratory (JPL) in the mid-1960s for use in the Apollo Lunar Landing Program. Designed to computer enhance pictures of the Moon, this technology became the basis for the Landsat Earth resources satellites and subsequently has been incorporated into a broad range of Earthbound medical and diagnostic tools. DSP is employed in advanced body imaging techniques including Computer-Aided Tomography, also known as CT and CATScan, and Magnetic Resonance Imaging (MRI). CT images are collected by irradiating a thin slice of the body with a fan-shaped x-ray beam from a number of directions around the body's perimeter. A tomographic (slice-like) picture is reconstructed from these multiple views by a computer. MRI employs a magnetic field and radio waves, rather than x-rays, to create images.

  19. Serum biomarkers for personalization of nanotherapeutics-based therapy in different tumor and organ microenvironments.

    Science.gov (United States)

    Yokoi, Kenji; Tanei, Tomonori; Godin, Biana; van de Ven, Anne L; Hanibuchi, Masaki; Matsunoki, Aika; Alexander, Jenolyn; Ferrari, Mauro

    2014-04-01

    Enhanced permeation and retention (EPR) effect, the mechanism by which nanotherapeutics accumulate in tumors, varies in patients based on differences in the tumor and organ microenvironment. Surrogate biomarkers for the EPR effect will aid in selecting patients who will accumulate higher amounts of nanotherapeutics and show better therapeutic efficacy. Our data suggest that the differences in the vascular permeability and pegylated liposomal doxorubicin (PLD) accumulation are tumor type as well as organ-specific and significantly correlated with the relative ratio of MMP-9 to TIMP-1 in the circulation, supporting development of these molecules as biomarkers for the personalization of nanoparticle-based therapy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. Recombinant Poxvirus and the Tumor Microenvironment: Oncolysis, Immune Regulation and Immunization

    Directory of Open Access Journals (Sweden)

    Daniel W. Sharp

    2016-08-01

    Full Text Available Oncolytic viruses (OVs are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by encoding and delivering immunostimulatory molecules. This combination makes them an effective platform for the development of immunotherapeutic strategies beyond their primary lytic function. Engineering the viruses to also express tumor-associated antigens (TAAs allows them to simultaneously serve as therapeutic vaccines, targeting and amplifying an immune response to TAAs. Our group and others have shown that vaccinating intratumorally with a poxvirus that encodes TAAs, in addition to immune stimulatory molecules, can modulate the tumor microenvironment, overcome immune inhibitory pathways, and drive both local and systemic tumor specific immune responses.

  1. Regulation of tumor progression and metastasis by bone marrow-derived microenvironments

    DEFF Research Database (Denmark)

    El Rayes, Tina; Gao, Dingcheng; Altorki, Nasser K.

    2017-01-01

    Activating mutations in driver oncogenes and loss-of-function mutations in tumor suppressor genes contribute to tumor progression and metastasis. Accordingly, therapies targeting key tumor cell-intrinsic signaling pathways are being used in clinical trials, and some have met FDA approval. However......, these treatments benefit only a small proportion of patients harboring key driver mutations, and acquired resistance to these therapies presents a major impediment to effective treatment. More recently, the contribution of the tumor microenvironment (TME) has been an area of active investigation and has begun......, extravasation, and outgrowth at the metastatic site. While the tumor-reprogrammed BM cells constitute attractive targets for anticancer therapy, recent studies have also begun to unravel their role as prognostic and predictive molecular markers of the disease....

  2. Microbial Mats on the Orkney Islands Revisited: Microenvironment and Microbial Community Composition

    DEFF Research Database (Denmark)

    Wieland, A.; Kühl, M.; McGowan, L.

    2003-01-01

    The microenvironment and community composition of microbial mats developing on beaches in Scapa Flow (Orkney Islands) were investigated. Analysis of characteristic biomarkers (major fatty acids, hydrocarbons, alcohols, and alkenones) revealed the presence of different groups of bacteria and micro...... an important role in the stratification and diversity of these two major bacterial groups involved in sulfur cycling in Swanbister beach mats....... and microalgae in mats from Waulkmill and Swanbister beach, including diatoms, Haptophyceae, cyanobacteria, and sulfate-reducing bacteria. These analyses also indicated the presence of methanogens, especially in Swanbister beach mats, and therefore a possible role of methanogenesis for the carbon cycle...... fragment length polymorphism) analysis in Swanbister beach mats, the depth distribution of different populations of purple and sulfate-reducing bacteria could be related to the microenvironmental conditions. Oxygen, but also sulfide and other (inorganic and organic) sulfur compounds, seems to play...

  3. Interplay of chemical microenvironment and redox environment on thiol-disulfide exchange kinetics.

    Science.gov (United States)

    Wu, Chuanliu; Belenda, Cristina; Leroux, Jean-Christophe; Gauthier, Marc A

    2011-08-29

    The interplay between the chemical microenvironment surrounding disulfides and the redox environment of the media on thiol-disulfide exchange kinetics was examined by using a peptide platform. Exchange kinetics of up to 34 cysteine-containing peptides were measured in several redox buffers. The electrostatic attraction/repulsion between charged peptides and reducing agents such as glutathione was found to have a very pronounced effect on thiol-disulfide exchange kinetics (differences of ca. three orders of magnitude). Exchange kinetics could be directly correlated to peptide charge over the entire range examined. This study highlights the possibility of finely and predictably tuning thiol-disulfide exchange, and demonstrates the importance of considering both the local environment surrounding the disulfide and the nature of the major reducing species present in the environment for which their use is intended (e.g., in drug delivery systems, sensors, etc). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Recreating the Cardiac Microenvironment in Pluripotent Stem Cell Models of Human Physiology and Disease.

    Science.gov (United States)

    Atmanli, Ayhan; Domian, Ibrahim John

    2017-05-01

    The advent of human pluripotent stem cell (hPSC) biology has opened unprecedented opportunities for the use of tissue engineering to generate human cardiac tissue for in vitro study. Engineering cardiac constructs that recapitulate human development and disease requires faithful recreation of the cardiac niche in vitro. Here we discuss recent progress in translating the in vivo cardiac microenvironment into PSC models of the human heart. We review three key physiologic features required to recreate the cardiac niche and facilitate normal cardiac differentiation and maturation: the biochemical, biophysical, and bioelectrical signaling cues. Finally, we discuss key barriers that must be overcome to fulfill the promise of stem cell biology in preclinical applications and ultimately in clinical practice. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment.

    Science.gov (United States)

    Katlinski, Kanstantsin V; Gui, Jun; Katlinskaya, Yuliya V; Ortiz, Angelíca; Chakraborty, Riddhita; Bhattacharya, Sabyasachi; Carbone, Christopher J; Beiting, Daniel P; Girondo, Melanie A; Peck, Amy R; Puré, Ellen; Chatterji, Priya; Rustgi, Anil K; Diehl, J Alan; Koumenis, Constantinos; Rui, Hallgeir; Fuchs, Serge Y

    2017-02-13

    Refractoriness of solid tumors, including colorectal cancers (CRCs), to immunotherapies is attributed to the immunosuppressive tumor microenvironment that protects malignant cells from cytotoxic T lymphocytes (CTLs). We found that downregulation of the type I interferon receptor chain IFNAR1 occurs in human CRC and mouse models of CRC. Downregulation of IFNAR1 in tumor stroma stimulated CRC development and growth, played a key role in formation of the immune-privileged niche, and predicted poor prognosis in human CRC patients. Genetic stabilization of IFNAR1 improved CTL survival and increased the efficacy of the chimeric antigen receptor T cell transfer and PD-1 inhibition. Likewise, pharmacologic stabilization of IFNAR1 suppressed tumor growth providing the rationale for upregulating IFNAR1 to improve anti-cancer therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. The tumor microenvironment underlies acquired resistance to CSF1R inhibition in gliomas

    Science.gov (United States)

    Quail, Daniela F.; Bowman, Robert L.; Akkari, Leila; Quick, Marsha L.; Schuhmacher, Alberto J.; Huse, Jason T.; Holland, Eric C.; Sutton, James C.; Joyce, Johanna A.

    2017-01-01

    Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that while overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas re-establish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors. PMID:27199435

  7. Immune Microenvironments of Anal Cancer Precursors Differ by HIV-serostatus, Affecting Ablation Outcomes.

    Science.gov (United States)

    Liu, Yuxin; Gaisa, Michael M; Wang, Xiaofei; Swartz, Talia H; Arens, Yotam; Dresser, Karen A; Sigel, Carlie; Sigel, Keith

    2017-09-02

    Anal high-grade squamous intraepithelial lesions (HSILs) are the precursors to anal cancer and frequently persist or recur following electrocautery ablation (EA). Impaired mucosal immunity may facilitate anal carcinogenesis. We characterized the immune microenvironment of anal HSIL in correlation with HIV-serostatus and ablation outcomes. Using immunohistochemistry, mucosa-infiltrating CD4+ and CD8+ lymphocytes were quantified in HSIL and benign mucosa from 70 HIV+ and 45 HIV- patients. Clinicopathological parameters were compared. Anal HSIL harbored more T lymphocytes than benign mucosa regardless of HIV status (p≤0.03). Total T lymphocyte count and CD8+ subset were significantly higher in HIV+ HSIL vs. HIV- HSIL (median cell count 71 vs. 47; 47 vs. 22/HPF, panal HSIL manifested by increased local lymphocytic infiltrates, predominately CD8+. HIV seropositivity and excess CD8+ cells may be associated with ablation resistance.

  8. An Accurate Perception Method for Low Contrast Bright Field Microscopy in Heterogeneous Microenvironments

    Directory of Open Access Journals (Sweden)

    Keshav Rajasekaran

    2017-12-01

    Full Text Available Automated optical tweezers-based robotic manipulation of microscale objects requires real-time visual perception for estimating the states, i.e., positions and orientations, of the objects. Such visual perception is particularly challenging in heterogeneous environments comprising mixtures of biological and colloidal objects, such as cells and microspheres, when the popular imaging modality of low contrast bright field microscopy is used. In this paper, we present an accurate method to address this challenge. Our method combines many well-established image processing techniques such as blob detection, histogram equalization, erosion, and dilation with a convolutional neural network in a novel manner. We demonstrate the effectiveness of our processing pipeline in perceiving objects of both regular and irregular shapes in heterogeneous microenvironments of varying compositions. The neural network, in particular, helps in distinguishing the individual microspheres present in dense clusters.

  9. Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Fabian Flores-Borja

    2016-01-01

    Full Text Available Our knowledge and understanding of the tumor microenvironment (TME have been recently expanded with the recognition of the important role of innate lymphoid cells (ILC. Three different groups of ILC have been described based on their ability to produce cytokines that mediate the interactions between innate and adaptive immune cells in a variety of immune responses in infection, allergy, and autoimmunity. However, recent evidence from experimental models and clinical studies has demonstrated that ILC contribute to the mechanisms that generate suppressive or tolerant environments that allow tumor regression or progression. Defining the complex network of interactions and crosstalk of ILC with other immune cells and understanding the specific contributions of each type of ILC leading to tumor development will allow the manipulation of their function and will be important to develop new interventions and therapeutic strategies.

  10. Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment

    Science.gov (United States)

    Irshad, Sheeba; Gordon, Peter; Wong, Felix; Sheriff, Ibrahim; Tutt, Andrew; Ng, Tony

    2016-01-01

    Our knowledge and understanding of the tumor microenvironment (TME) have been recently expanded with the recognition of the important role of innate lymphoid cells (ILC). Three different groups of ILC have been described based on their ability to produce cytokines that mediate the interactions between innate and adaptive immune cells in a variety of immune responses in infection, allergy, and autoimmunity. However, recent evidence from experimental models and clinical studies has demonstrated that ILC contribute to the mechanisms that generate suppressive or tolerant environments that allow tumor regression or progression. Defining the complex network of interactions and crosstalk of ILC with other immune cells and understanding the specific contributions of each type of ILC leading to tumor development will allow the manipulation of their function and will be important to develop new interventions and therapeutic strategies. PMID:27882334

  11. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma.

    Science.gov (United States)

    Wu, Qi; Tian, Ying; Zhang, Jingqiu; Zhang, Hongpeng; Gu, Fengming; Lu, Yongdie; Zou, Shengnan; Chen, Yuji; Sun, Pengxiang; Xu, Mengyue; Sun, Xiaoming; Xia, Chao; Chi, Hao; Ying Zhu, A; Tang, Dong; Wang, Daorong

    2017-11-24

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with poor prognosis because it is highly resistant to traditional chemotherapy and radiotherapy and it has a low rate of surgical resection eligibility. Pancreatic stellate cells (PSC) have become a research hotspot in recent years, and play a vital role in PDAC microenvironment by secreting soluble factors such as transforming growth factor β, interleukin-6, stromal cell-derived factor-1, hepatocyte growth factor and galectin-1. These PSC-derived cytokines and proteins contribute to PSC activation, participating in PDAC cell proliferation, migration, fibrosis, angiogenesis, immunosuppression, epithelial-mesenchymal transition, and chemoradiation resistance, leading to malignant outcome. Consequently, targeting these cytokines and proteins or their downstream signaling pathways is promising for treating PDAC.

  12. Gene Expression Profiling for In Silico Microdissection of Hodgkin's Lymphoma Microenvironment and Identification of Prognostic Features

    Directory of Open Access Journals (Sweden)

    François Bertucci

    2011-01-01

    Full Text Available Gene expression profiling studies based on DNA microarrays have demonstrated their ability to define the interaction pathways between neoplastic and nonmalignant stromal cells in cancer tissues. During the past ten years, a number of approaches including microdissection have tried to resolve the variability in DNA microarray measurements stemming from cancer tissue sample heterogeneity. Another approach, designated as virtual or in silico microdissection, avoids the laborious and time-consuming step of anatomic microdissection. It consists of confronting the gene expression profiles of complex tissue samples to those of cell lines representative of different cell lineages, different differentiation stages, or different signaling pathways. This strategy has been used in recent studies aiming to analyze microenvironment alterations using gene expression profiling of nonmicrodissected classical Hodgkin lymphoma tissues in order to generate new prognostic factors. These recent contributions are detailed and discussed in the present paper.

  13. Novel Luminescent Multilayer Films Containing π-Conjugated Anionic Polymer with Electronic Microenvironment

    Directory of Open Access Journals (Sweden)

    Tianlei Wang

    2016-09-01

    Full Text Available Layered double hydroxides (LDHs, luminescent π-conjugated anionic polymer and montmorillonite (MMT were orderly assembled into luminescent multilayer films via layer-by-layer self-assembly method. The electronic microenvironment (EME, the structure of which is like a traditional capacitor, can be constructed by exfoliated LDHs or MMT nanosheets. In addition, the rigid inorganic laminated configuration can offer stable surroundings between the interlayers. As a result, we conclude that EME can extend the luminescent lifespans of multilayer films substantially, due to affecting relaxation times of π-conjugated anionic polymer. Consequently, because of the remarkable impact on better photoemission behaviors of luminescent π-conjugated anionic polymer, EME assembled by LDHs or MMT nanosheets have had high hopes attached to them. They are expected to have the potential for designing, constructing, and investigating novel light-emitting thin films.

  14. Strategies to Target Glucose Metabolism in Tumor Microenvironment on Cancer by Flavonoids.

    Science.gov (United States)

    Wang, Gang; Wang, Jun-Jie; Guan, Rui; Du, Li; Gao, Jing; Fu, Xing-Li

    2017-01-01

    The imbalance between glucose metabolism and cancer cell growth in tumor microenvironment (TME), which are closely related with the occurrence and progression of cancer. Accumulating evidence has demonstrated that flavonoids exert many biological properties, including antioxidant and anticarcinogenic activities. Recently, the roles and applications of flavonoids, particularly in relation to glucose metabolism in cancers, have been highlighted. Thus, the identification of flavonoids targeting alternative glucose metabolism pathways in TME may represent an attractive approach to the more effective therapeutic strategies for cancer. In this review, we will focus on the roles of flavonoids in regulating glucose metabolism and cancer cell growth in TME, such as proliferation advantage, cell mobility, and chemoresistance to cancer, as well as modifiers of thermal sensitivity. Not only have such large-scale endeavors been useful in providing fundamental insights into natural and synthesized flavonoids that can prevent and treat cancer, but also have led to the discovery of potential targets for cancer therapy.

  15. Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific

    Directory of Open Access Journals (Sweden)

    Lisa H. Tostanoski

    2016-09-01

    Full Text Available Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS, aim to bias T cells toward tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the CNS. Our findings suggest that local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic but antigen specific.

  16. Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma

    DEFF Research Database (Denmark)

    Kristensen, Ida B; Christensen, Jacob Haaber; Lyng, Maria Bibi

    2014-01-01

    of osteoclast regulators (RANK, RANKL, OPG, TRAIL, MIP1A), Wnt inhibitors (DKK1, SFRP2, SFRP3, sclerostin, WIF1) and osteoblast transcription factors (RUNX2, osterix) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in the bone marrow (BM) microenvironment using snap-frozen BM biopsies......Multiple myeloma (MM) lytic bone disease (LBD) is caused by osteoclast activation and osteoblast inhibition. RANK/RANKL/OPG play central roles in osteoclast activation and Wnt inhibitor DKK1 in osteoblast inhibition. The role of other Wnt inhibitors is less clear. We evaluated gene expression...... radiographs and the bone resorption marker CTX-1. Protein levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Among Wnt inhibitors, only SFRP3 and DKK1 were significantly overexpressed in advanced LBD, correlating with protein levels. SFRP3 correlated with CTX-1. Our...

  17. Complement components of nerve regeneration conditioned fluid influence the microenvironment of nerve regeneration

    Directory of Open Access Journals (Sweden)

    Guang-shuai Li

    2016-01-01

    Full Text Available Nerve regeneration conditioned fluid is secreted by nerve stumps inside a nerve regeneration chamber. A better understanding of the proteinogram of nerve regeneration conditioned fluid can provide evidence for studying the role of the microenvironment in peripheral nerve regeneration. In this study, we used cylindrical silicone tubes as the nerve regeneration chamber model for the repair of injured rat sciatic nerve. Isobaric tags for relative and absolute quantitation proteomics technology and western blot analysis confirmed that there were more than 10 complement components (complement factor I, C1q-A, C1q-B, C2, C3, C4, C5, C7, C8ß and complement factor D in the nerve regeneration conditioned fluid and each varied at different time points. These findings suggest that all these complement components have a functional role in nerve regeneration.

  18. Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction

    DEFF Research Database (Denmark)

    Idorn, Manja; Olsen, Maria; Halldórsdóttir, Hólmfrídur Rósa

    2018-01-01

    suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were......Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune...... analyzed by flow cytometry. We found that FoxP3+ regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22...

  19. Effector CD4 and CD8 T Cells and Their Role in the Tumor Microenvironment

    DEFF Research Database (Denmark)

    Hadrup, Sine; Donia, Marco; thor Straten, Per

    2012-01-01

    with colo-rectal cancer (CRC), and also for others solid cancers. These data goes hand in hand with studies of clonality of TIL showing the T cells among TIL are expanded clonally, and also that tumor specific T cells of CD4 as well as CD8 type are enriched at the tumor site. The tumor microenvironment......T cells in tumors-the so-called tumor infiltrating lymphocytes (TIL) have been studied intensively over the past years. Compelling evidence point to a clinical relevance for high numbers of T cells at the tumor site with CD8 memory T cells as a key denominator for overall survival (OS) in patients...... is hostile to T cell function e.g., due to expression of enzymes that depletes the amino acids tryptophan and arginine, high concentration of tumor secreted lactate, and presence innate cells or regulatory T cells both with suppressive activity. Analyses of the specificity of TILs in melanoma demonstrate...

  20. Evidence of morphometric differentiation among Antarctic moss populations as a response to local microenvironment

    Directory of Open Access Journals (Sweden)

    Rayssa Garay Medina

    2015-09-01

    Full Text Available ABSTRACTStudies on phenotypic variation among populations growing in different microenvironments may provide information about plasticity related to environmental pressures, and thus help to elucidate the potential evolutionary forces contributing to the origin and maintenance of diversity in any region. In this study we investigate morphometric variation on a small geographic scale for three species of Antarctic mosses. All species revealed significant differentiation among populations for all evaluated traits. The comparison of morphometric measures of populations of Polytrichum juniperinumfrom Nelson Island and from southern Brazil suggests that the effects of a small geographic scale in Antarctica are the same as a large geographic scale in environments where the climate is more homogeneous and microhabitats have minor influence on vegetation. However, further investigations over a larger area, evaluating more species, and using controlled garden experiments are recommended in order to evaluate the capacity for plasticity of moss species in different climatic conditions and on different geographic scales.

  1. Modulation of the Tumor Microenvironment for Cancer Treatment: A Biomaterials Approach

    Directory of Open Access Journals (Sweden)

    Isaac M. Adjei

    2015-02-01

    Full Text Available Tumors are complex tissues that consist of stromal cells, such as fibroblasts, immune cells and mesenchymal stem cells, as well as non-cellular components, in addition to neoplastic cells. Increasingly, there is evidence to suggest that these non-neoplastic cell components support cancer initiation, progression and metastasis and that their ablation or reprogramming can inhibit tumor growth. Our understanding of the activities of different parts of the tumor stroma in advancing cancer has been improved by the use of scaffold and matrix-based 3D systems originally developed for regenerative medicine. Additionally, drug delivery systems made from synthetic and natural biomaterials deliver drugs to kill stromal cells or reprogram the microenvironment for tumor inhibition. In this article, we review the impact of 3D tumor models in increasing our understanding of tumorigenesis. We also discuss how different drug delivery systems aid in the reprogramming of tumor stroma for cancer treatment.

  2. Cell microenvironment stimuli-responsive controlled-release delivery systems based on mesoporous silica nanoparticles

    Directory of Open Access Journals (Sweden)

    Chun-Ling Zhu

    2014-03-01

    Full Text Available To develop novel tumor cell microenvironment stimuli-responsive smart controlled-release delivery systems is one of the current common interests of materials science and clinical medicine. Meanwhile, mesoporous silica nanoparticles as a promising drug carrier have become the new area of interest in the field of biomedical application in recent years because of their unique characteristics and abilities to efficiently and specifically entrap cargo molecules. This review describes the more recent developments and achievements of mesoporous silica nanoparticles in drug delivery. In particular, we focus on the stimuli-responsive controlled-release systems that are able to respond to tumor cell environmental changes, such as pH, glucose, adenosine-5′-triphosphate (ATP, glutathione (GSH, and H2O2.

  3. Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment.

    Science.gov (United States)

    Scarfò, Irene; Maus, Marcela V

    2017-01-01

    Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-cells is crucial to improve the potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-cells, with particular emphasis on the translational potential of these approaches.

  4. Heterotypic Cellular Interactions in the Ovarian Tumor Microenvironment: Biological Significance and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Honami eNaora

    2014-02-01

    Full Text Available The majority of women who are diagnosed with epithelial ovarian cancer present with extensive peritoneal carcinomatosis and are rarely cured by conventional chemotherapy. Ovarian cancer cells typically disseminate by shedding into the peritoneal fluid and implant on the mesothelium-lined peritoneal surfaces that overlie connective and white adipose tissues. Emerging evidence indicates that ovarian tumor progression is orchestrated by dynamic interplay between tumor cells and a variety of stromal cells such as adipocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages and other immune cells. This mini-review discusses the biological significance of the heterotypic cellular interactions in the ovarian tumor microenvironment and the therapeutic implications of targeting these interactions.

  5. Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial.

    Science.gov (United States)

    Curry, Joseph; Johnson, Jennifer; Tassone, Patrick; Vidal, Marina Domingo; Menezes, Diana Whitaker; Sprandio, John; Mollaee, Mehri; Cotzia, Paolo; Birbe, Ruth; Lin, Zhao; Gill, Kurren; Duddy, Elizabeth; Zhan, Tingting; Leiby, Benjamin; Reyzer, Michelle; Cognetti, David; Luginbuhl, Adam; Tuluc, Madalina; Martinez-Outschoorn, Ubaldo

    2017-08-01

    The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors. Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery. Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay and Ki-67 IHC, were performed in pre- and postmetformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels also was performed in three subjects. Metformin was well tolerated. The average treatment course was 13.6 days. Posttreatment specimens showed a significant increase in stromal CAV1 (P < 0.001) and GALB (P < 0.005), as well as tumor cell apoptosis by TUNEL assay (P < 0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold postmetformin (P < 0.05), as measured by MSI. Metformin increases markers of reduced catabolism and increases senescence in stromal cells as well as carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment. 4. Laryngoscope, 127:1808-1815, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  6. Characterization of PM2.5exposure concentration in transport microenvironments using portable monitors.

    Science.gov (United States)

    Li, Zhiyuan; Che, Wenwei; Frey, H Christopher; Lau, Alexis K H; Lin, Changqing

    2017-09-01

    Recently, portable monitors have been increasingly used to quantify air pollutant concentrations at high spatiotemporal resolution. A sampling campaign was conducted to measure the fine particulate matter (PM 2.5 ) and carbon monoxide (CO) exposure concentrations in transport microenvironments (TMEs) in Hong Kong in January and June 2015 using TSI DustTrak and Q-Trak portable monitors. The objectives were to: (1) calibrate DustTrak and Q-Trak; (2) evaluate variability between seasons and microenvironments; (3) estimate indoor/outdoor relationships; and (4) determine minimum sample size. Calibration equations, obtained through side-by-side measurement against stationary reference methods in winter and summer, were applied to correct the measured PM 2.5 data set. In general, PM 2.5 concentrations in all TMEs were significantly higher in winter than in summer. The mean PM 2.5 concentration in winter was lower for underground sections of the Mass Transit Railway (MTR) metro system (31 μg/m 3 ) than for other TMEs, whereas in summer TMEs had mean PM 2.5 concentrations in the range of 10-15 μg/m 3 , with above-ground MTR train as an exception, at 23 μg/m 3 . PM 2.5 concentrations measured in TMEs were strongly correlated with nearby air quality monitoring stations (AQMSs) measurements in winter, but in summer there was little correlation. The minimum sample size estimates varied more among TMEs in summer versus winter because of the differences in PM 2.5 concentration distributions related to changes in ambient PM 2.5 concentrations and ventilation practices. This study provides a feasible protocol on the calibration and application of portable monitors in TME air quality measurement and develops a method for estimating minimum sample size. Copyright © 2017. Published by Elsevier Ltd.

  7. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

    LENUS (Irish Health Repository)

    Michielsen, Adriana J

    2011-01-01

    Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

  8. Targeting the Immune Niche within the Bone Marrow Microenvironment: The Rise of Immunotherapy in Multiple Myeloma.

    Science.gov (United States)

    Podar, K; Jager, D

    2017-01-01

    Multiple Myeloma (MM) cells inhibit the development of an effective anti- MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive proinflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance. The usefulness of immunotherapies in MM patients has first been supported by the identification of the graft-versus-myeloma effect in the context of allogeneic bone marrow (BM) transplantation. Subsequently, the inclusion of thalidomide and its derivatives, the Immunomodulatory Drugs (IMiDs) as well as of (immuno) proteasome inhibitors into MM regimens dramatically improved MM patients outcome during the last 15 years. Despite these unprecedented therapeutic advances MM remains an incurable disease. This article reviews novel immunotherapeutic approaches, which aim to restore the balance within the immunologic niche of the MM BM microenvironment. A systematic search was conducted of the Pubmed Medline, Embase, and Cochrane Library databases for primary articles, as well as of conference abstracts (e.g., of the American Society of Hematology, the American Society of Clinical Oncology, the American Association of Cancer Research, the European Hematology Association, and the Multiple Myeloma Workshop), practice guidelines, and registries of clinical trials. The inclusion of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor-engineered (CAR) T cells, genetically engineered T cells, and vaccination, dendritic cellbased cancer vaccines in particular, into existing regimens is likely to significantly improve MM patient outcome in the near future. Given continuing efforts to target the immune niche within the bone marrow

  9. Electrolytic Valving Isolation for Cell Co-Culture Microenvironment with Controlled Cell Pairing Ratios

    Science.gov (United States)

    Chen, Yu-Chih; Ingram, Patrick; Yoon, Euisik

    2016-01-01

    Cancer-stromal interaction is a critical process in tumorigenesis. Conventional dish-based co-culture assays simply mix two cell types in the same dish; thus, they are deficient in controlling cell locations and precisely tracking single cell behavior from heterogeneous cell populations. Microfluidic technology can provide a good spatial temporal control of microenvironments, but the control has been typically realized by using external pumps, making long-term cultures cumbersome and bulky. In this work, we present a cell-cell interaction microfluidic platform that can accurately control co-culture microenvironment by using a novel electrolytic cell isolation scheme without using any valves or pneumatic pumps. The proposed microfluidic platform can also precisely control the number of interacting cells and pairing ratios to emulate cancer niches. More than 80% of the chambers captured the desired number of cells. The duration of cell isolation can be adjusted by electrolytic bubble generation and removal. We verified that electrolytic process has a negligible effect on cell viability and proliferation in our platform. To the best of our knowledge, this work is the first attempt to incorporate electrolytic bubble generation as a cell isolation method in microfluidics. For proof of feasibility, we performed cell-cell interaction assays between prostate cancer (PC3) cells and myoblast (C2C12) cells. The preliminary results demonstrated the potential of using electrolysis for micro-environmental control during cell culture. Also, the ratio controlled cell-cell interaction assays was successfully performed showing that the cell pairing ratios of PC3 to C2C12 affected the proliferation rate of myoblast cells due to increased secretion of growth factors from prostate cancer cells. PMID:25118341

  10. Electrolytic valving isolation of cell co-culture microenvironment with controlled cell pairing ratios.

    Science.gov (United States)

    Chen, Yu-Chih; Ingram, Patrick; Yoon, Euisik

    2014-12-21

    Cancer-stromal interaction is a critical process in tumorigenesis. Conventional dish-based co-culture assays simply mix two cell types in the same dish; thus, they are deficient in controlling cell locations and precisely tracking single cell behavior from heterogeneous cell populations. Microfluidic technology can provide a good spatial-temporal control of microenvironments, but the control has been typically realized by using external pumps, making long-term cultures cumbersome and bulky. In this work, we have presented a cell-cell interaction microfluidic platform that can accurately control the co-culture microenvironment by using a novel electrolytic cell isolation scheme without using any valves or pneumatic pumps. The proposed microfluidic platform can also precisely control the number of interacting cells and pairing ratios to emulate cancer niches. More than 80% of the chambers captured the desired number of cells. The duration of cell isolation can be adjusted by electrolytic bubble generation and removal. We have verified that the electrolytic process has a negligible effect on cell viability and proliferation in our platform. To the best of our knowledge, this work is the first attempt to incorporate electrolytic bubble generation as a cell isolation method in microfluidics. For proof of feasibility, we have performed cell-cell interaction assays between prostate cancer (PC3) cells and myoblast (C2C12) cells. The preliminary results demonstrated the potential of using electrolysis for micro-environmental control during cell culture. Also, the ratio controlled cell-cell interaction assays were successfully performed which showed that the cell pairing ratios of PC3 to C2C12 affected the proliferation rate of myoblast cells due to increased secretion of growth factors from prostate cancer cells.

  11. Effects of iron overload on the bone marrow microenvironment in mice.

    Directory of Open Access Journals (Sweden)

    Yuchen Zhang

    Full Text Available Using a mouse model, Iron Overload (IO induced bone marrow microenvironment injury was investigated, focusing on the involvement of reactive oxygen species (ROS.Mice were intraperitoneally injected with iron dextran (12.5, 25, or 50 mg every three days for two, four, and six week durations. Deferasirox(DFX125 mg/ml and N-acetyl-L-cysteine (NAC 40 mM were co-administered. Then, bone marrow derived mesenchymal stem cells (BM-MSCs were isolated and assessed for proliferation and differentiation ability, as well as related gene changes. Immunohistochemical analysis assessed the expression of haematopoietic chemokines. Supporting functions of BM-MSCs were studied by co-culture system.In IO condition (25 mg/ml for 4 weeks, BM-MSCs exhibited proliferation deficiencies and unbalanced osteogenic/adipogenic differentiation. The IO BM-MSCs showed a longer double time (2.07±0.14 days than control (1.03±0.07 days (P<0.05. The immunohistochemical analysis demonstrated that chemokine stromal cell-derived factor-1, stem cell factor -1, and vascular endothelial growth factor-1 expression were decreased. The co-cultured system demonstrated that bone marrow mononuclear cells (BMMNCs co-cultured with IO BM-MSCs had decreased colony forming unit (CFU count (p<0.01, which indicates IO could lead to decreased hematopoietic supporting functions of BM-MSCs. This effect was associated with elevated phosphatidylinositol 3 kinase (PI3K and reduced of Forkhead box protein O3 (FOXO3 mRNA expression, which could induce the generation of ROS. Results also demonstrated that NAC or DFX treatment could partially attenuate cell injury and inhibit signaling pathway striggered by IO.These results demonstrated that IO can impair the bone marrow microenvironment, including the quantity and quality of BM-MSCs.

  12. Myeloid cells in circulation and tumor microenvironment of breast cancer patients.

    Science.gov (United States)

    Toor, Salman M; Syed Khaja, Azharuddin Sajid; El Salhat, Haytham; Faour, Issam; Kanbar, Jihad; Quadri, Asif A; Albashir, Mohamed; Elkord, Eyad

    2017-06-01

    Pathological conditions including cancers lead to accumulation of a morphological mixture of highly immunosuppressive cells termed as myeloid-derived suppressor cells (MDSC). The lack of conclusive markers to identify human MDSC, due to their heterogeneous nature and close phenotypical and functional proximity with other cell subsets, made it challenging to identify these cells. Nevertheless, expansion of MDSC has been reported in periphery and tumor microenvironment of various cancers. The majority of studies on breast cancers were performed on murine models and hence limited literature is available on the relation of MDSC accumulation with clinical settings in breast cancer patients. The aim of this study was to investigate levels and phenotypes of myeloid cells in peripheral blood (n = 23) and tumor microenvironment of primary breast cancer patients (n = 7), compared with blood from healthy donors (n = 21) and paired non-tumor normal breast tissues from the same patients (n = 7). Using multicolor flow cytometric assays, we found that breast cancer patients had significantly higher levels of tumor-infiltrating myeloid cells, which comprised of granulocytes (P = 0.022) and immature cells that lack the expression of markers for fully differentiated monocytes or granulocytes (P = 0.016). Importantly, this expansion was not reflected in the peripheral blood. The immunosuppressive potential of these cells was confirmed by expression of Arginase 1 (ARG1), which is pivotal for T-cell suppression. These findings are important for developing therapeutic modalities to target mechanisms employed by immunosuppressive cells that generate an immune-permissive environment for the progression of cancer.

  13. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment.

    Science.gov (United States)

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E; Geissler, Edward K; Peter, Katrin; Siska, Peter J; Kreutz, Marina

    2017-01-01

    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

  14. Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments.

    Science.gov (United States)

    Noto, Jennifer M; Chopra, Abha; Loh, John T; Romero-Gallo, Judith; Piazuelo, M Blanca; Watson, Mark; Leary, Shay; Beckett, Amber C; Wilson, Keith T; Cover, Timothy L; Mallal, Simon; Israel, Dawn A; Peek, Richard M

    2017-09-18

    Helicobacter pylori is the strongest risk factor for gastric cancer; however, the majority of infected individuals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease. Whole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed. A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034). These results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis.

    Science.gov (United States)

    Choi, Joung-Woo; Jung, Soo-Jung; Kasala, Dayananda; Hwang, June Kyu; Hu, Jun; Bae, You Han; Yun, Chae-Ok

    2015-05-10

    Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Colorectal carcinoma tumour budding and podia formation in the xenograft microenvironment.

    Science.gov (United States)

    Prall, Friedrich; Maletzki, Claudia; Hühns, Maja; Krohn, Mathias; Linnebacher, Michael

    2017-01-01

    Tumour budding and podia formation are well-appreciated in surgical pathology as an aggressive invasion phenotype of colorectal carcinoma cells that is attained in the microenvironment of the invasive margin. In this study, we addressed how tumour budding and podia formation feature in xenografts. Primary colorectal carcinomas (N = 44) of various molecular types (sporadic standard type, high-degree microsatellite-unstable, CpG island methylator phenotype) were transplanted subcutaneously into T and B cell-deficient NSG mice, making possible immunohistochemistry with routine surgical pathology antibodies. Tumor budding and podia formation were both appreciably present in the xenografts. Quantitative evaluations of cytokeratin immunostains of primaries and their corresponding xenografts showed a reduction of tumour buds in the xenografts. Furthermore, in xenografts tumour cells were completely negative by pSTAT3 immunohistochemistry, indicating absence of cytokine/chemokine signalling, but nuclear β-catenin and SMAD4 immunostainings as read-out of wnt and BMP pathway activation, respectively, were maintained. Carcinoma cells in most xenografts retained immunostaining of at least some nuclei by immunohistochemistry with antibodies against pERK1/2. K-ras/B-raf mutational status did not correlate with tumour budding or podia formation in the xenografts. Our results indicate that tumour budding and podia formation can be modelled by xenografting, and in NSG mice it can be studied with the same immunohistochemical methods as used for primaries in surgical pathology. Dysregulation of wnt and BMP signalling appears to be transferred into the xenograft microenvironment, but not cytokine/chemokine signalling.

  17. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Adriana J Michielsen

    Full Text Available Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5 could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

  18. Targeting breast cancer through its microenvironment : Current status of preclinical and clinical research in finding relevant targets

    NARCIS (Netherlands)

    Nienhuis, H. H.; Gaykema, S. B. M.; Timmer-Bosscha, H.; Jalving, M.; Brouwers, A. H.; Lub-de Hooge, M. N.; van der Vegt, B.; Overmoyer, B.; de Vries, E. G. E.; Schroder, C. P.

    It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the

  19. The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis.

    Science.gov (United States)

    Li, Hui; Xu, Fangying; Li, Si; Zhong, Anjing; Meng, Xianwen; Lai, Maode

    2016-07-03

    Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.

  20. Sacralising Bodies

    DEFF Research Database (Denmark)

    Kaur, Ravinder

    2010-01-01

    -sacrifice became central to the mass mobilisation against the monarchy. Once the revolutionary government came into existence, this sacred tradition was regulated to create ‘martyrs’ as a fixed category, in order to consolidate the legacy of the revolution. In this political theatre, the dead body is a site...

  1. Body lice

    Science.gov (United States)

    ... and pubic lice if you have body lice. Treatment To get rid of lice, take the following important steps: Bathe regularly to get rid of lice and their eggs. Change your clothes often. Wash clothes in hot water (at least 130°F/54°C) and machine ...

  2. Body / Antibody

    Directory of Open Access Journals (Sweden)

    Lawrence R. Schehr

    1996-06-01

    Full Text Available Unique object in the exchange-system, the gay body occupies a locus where a phantom identity and an imagined reciprocity define the poles of the subject-object relation. Made of the right stuff, it is an object circulating in a system that tends to reproduce the concept of identity in its search for mirror images of itself. Often rejected by the world, it has recently become a cynosure equated with sickness, pestilence, and death in the age of AIDS. The representations of that object change: no longer perceived as a part of libidinal economy, it has become a mass of symptoms, having changed from being an index of sexuality into being the visible dissipation of the flesh. The gay body in the age of AIDS is the mark of a pariah with the abject nature of the outcast. The body with AIDS takes the form of a text made of many signs and with many ways of reading the checkerboard pattern of the flesh. And the AIDS-narrative turns the body into the limit of the representable.

  3. Surface display of roGFP for monitoring redox status of extracellular microenvironments in Shewanella oneidensis biofilms.

    Science.gov (United States)

    Sivakumar, Krishnakumar; Mukherjee, Manisha; Cheng, Hsin-I; Zhang, Yingdan; Ji, Lianghui; Cao, Bin

    2015-03-01

    Biofilms are the most ubiquitous and resilient form of microbial life on earth. One most important feature of a biofilm is the presence of a self-produced matrix, which creates highly heterogeneous and dynamic microenvironments within biofilms. Redox status in biofilm microenvironments plays a critical role in biofilm development and function. However, there is a lack of non-intrusive tools to quantify extracellular redox status of microenvironments within a biofilm matrix. In this study, using Shewanella oneidensis as a model organism, we demonstrated a novel approach to monitor extracellular redox status in biofilm microenvironments. Specifically, we displayed a redox sensitive fluorescence protein roGFP onto the cell surface of S. oneidensis by fusing it to the C-terminus of BpfA, a large surface protein, and used the surface displayed roGFP as a sensor to quantify the extracellular redox status in the matrix of S. oneidensis biofilms. The fusion of roGFP into BpfA has no negative impacts on cell growth and biofilm formation. Upon exposure to oxidizing agents such as H2 O2 , Ag(+) , and SeO3 (2-) , S. oneidensis BpfA-roGFP cells exhibited a characteristic fluorescence of roGFP. Proteinase treatment assay and super-resolution structured illumination microscopy confirmed the surface localization of BpfA-roGFP. We further used the surface displayed roGFP monitored the extracellular redox status in the matrix at different depths of a biofilm exposed to H2 O2 . This study provides a novel approach to non-invasively monitor extracellular redox status in microenvironments within biofilms, which can be used to understand redox responses of biofilms to environmental perturbations. © 2014 Wiley Periodicals, Inc.

  4. PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.

    Science.gov (United States)

    Watts, Tammara L; Cui, Ruwen; Szaniszlo, Peter; Resto, Vicente A; Powell, Don W; Pinchuk, Irina V

    2016-12-08

    The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC. Confocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC. We show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-β, resulted in near arrest of MSC chemotaxis (p cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the

  5. Effects of microenvironment on growth and differentiation of human dental pulp cells

    Science.gov (United States)

    Datko, Laura Christine

    Dental pulp stem cells (DPSCs) have recently been described as a potential stem cell source for various regenerative medicine and tissue engineering applications. They appear to be multipotent, however more characterization is necessary to determine the true potential of these cells. An important aspect of using DPSCs, or any stem cell type, tissue engineering application is the microenvironment within the construct. The microenvironment could include construct mechanical properties, construct composition, and 3D dynamic conditions in vivo. This work aims to study those specific microenvironment effects on DPSCs. To determine the effects of mechanical properties of the substrate on DPSCs, they were seeded on polyacrylamide (PA) gels of different elastic moduli. These gels ranged from 3 kPa to 75 kPa and a glass coverslip was used as a control. They were also exposed to either standard stem cell media or an osteogenic differentiation media, to determine the potential of the DPSCs for osteogenic/odontogenic differentiation. The cultures were analyzed for morphological changes, osteopontin production, alkaline phosphatase (ALP) production, and mineralization. The results showed that the DPSCs adhered well to the PA gels for the first few days in culture, but by day 7, they were starting to detach from the PA gels and only remain viable in gel defects or along the edges. This selective growth was also reflected in the mineralization, which only occurred in areas of confluence for the cells on the PA gels. Interestingly, all cultures produced osteopontin and ALP, however by the end of the experiment, the cells cultured on glass had the highest ALP production. It appeared that without the addition of growth factors to induce other cell lineages, DPSCs defaulted to an osteogenic/odontogenic lineage. To determine the effect of mineral composition, preliminary studies were done on bone marrow stromal cells (BMSCs) and 7F2 osteoblasts. These two cell types were exposed to

  6. Infectious Prions in the Pregnancy Microenvironment of Chronic Wasting Disease-Infected Reeves' Muntjac Deer

    Science.gov (United States)

    Nalls, Amy V.; McNulty, Erin; Hoover, Clare E.; Pulscher, Laura A.; Hoover, Edward A.

    2017-01-01

    ABSTRACT Ample evidence exists for the presence of infectious agents at the maternal-fetal interface, often with grave outcomes to the developing fetus (i.e., Zika virus, brucella, cytomegalovirus, and toxoplasma). While less studied, pregnancy-related transmissible spongiform encephalopathies (TSEs) have been implicated in several species, including humans. Our previous work has shown that prions can be transferred from mother to offspring, resulting in the development of clinical TSE disease in offspring born to muntjac dams infected with chronic wasting disease (CWD) (1). We further demonstrated protein misfolding cyclic amplification (PMCA)-competent prions within the female reproductive tract and in fetal tissues harvested from CWD experimentally and naturally exposed cervids (1, 2). To assess whether the PMCA-competent prions residing at the maternal-fetal interface were infectious and to determine if the real-time quaking-induced conversion (RT-QuIC) methodology may enhance our ability to detect amyloid fibrils within the pregnancy microenvironment, we employed a mouse bioassay and RT-QuIC. In this study, we have demonstrated RT-QuIC seeding activity in uterus, placentome, ovary, and amniotic fluid but not in allantoic fluids harvested from CWD-infected Reeves' muntjac dams showing clinical signs of infection (clinically CWD-infected) and in some placentomes from pre-clinically CWD-infected dams. Prion infectivity was confirmed within the uterus, amniotic fluid, and the placentome, the semipermeable interface that sustains the developing fetus, of CWD-infected dams. This is the first report of prion infectivity within the cervid pregnancy microenvironment, revealing a source of fetal CWD exposure prior to the birthing process, maternal grooming, or encounters with contaminated environments. IMPORTANCE The facile dissemination of chronic wasting disease within captive and free-range cervid populations has led to questions regarding the transmission dynamics

  7. Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.

    Directory of Open Access Journals (Sweden)

    Michael DeNiro

    Full Text Available Retinal ischemia promotes the upregulation of VEGF expression and accounts for most pathological features of retinal neovascularization (NV. Paradoxically, VEGF remains the pivotal stimulator of ocular NV, despite the absence of ischemia. Therefore, the central question arises as to how the various molecular mechanisms interplay in ischemia-independent NV. It's been suggested that NFκB plays a crucial role in the pathogenesis of diabetic vasculopathies. Here, we dissected the molecular mechanism of ocular NV in the rho/VEGF transgenic mouse model, which develops subretinal NV in ischemia-independent microenvironment. Furthermore, we examined whether intravitreal administration of YC-1, a HIF-1 inhibitor, can modulate the activation of NFκB and its downstream angiogenic signaling in the mouse retina. We demonstrated that YC-1 inhibited retinal NFκB/p65 DNA binding activity and downregulated NFκB/p65, FAK, α5β1, EPO, ET-1, and MMP-9 expression at the message and the protein levels. In addition, YC-1 significantly inhibited subretinal NV by reducing the number of neovascular lesions, the area of each lesion and the total area of NV per retina. We further investigated the influence of VEGF signaling pathway on HIF-1α transcriptional activity to substantiate that this mouse model develops subretinal NV in an ischemia-independent microenvironment. Our data demonstrated that VEGF overexpression didn't have any impact on HIF-1α transcriptional activity, whereas treatment with YC-1 significantly inhibited endogenous HIF-1 activity. Our study suggests that retinal NFκB transcriptional activity is pivotal to ischemia-independent mechanisms, which lead to the local activation of angiogenic cascades. Our data also indicate that the nexus between VEGF and NFκB is implicated in triggering the angiogenic cascade that promotes retinal NV. Hence, targeting the VEGF/NFκB axis may act in a negative feedback loop to suppress ocular NV. This study suggests

  8. Linking N Cycling to Microbial Function Within Soil Microenvironments in Cover Crop Systems

    Science.gov (United States)

    Kong, A. Y.; Scow, K. M.; Hristova, K.; Six, J.

    2007-12-01

    Cover crops have emerged as a crop management strategy to achieve agricultural sustainability and maintain environmental quality. Thus, fundamental knowledge of microbial-mediated C and N cycling is vital to understanding soil organic matter (SOM) dynamics in cover cropped agroecosystems. We investigated the effects of short-term cover crop-C input on N processing by microbial communities within SOM microenvironments and in bulk soil, across a gradient of organic to conventional crop management. We hypothesized that cover crop C and N inputs promote soil aggregation, which increases the abundance of ammonia oxidizing bacteria (AOB) and stimulates greater microbial cycling of N within soil microenvironments, thereby leading to potential increases in N stabilization coupled with decreases in N loss. Our hypothesis was tested on the long-term organic, low-input, and conventional maize-tomato rotations at the Center for Integrated Farming Systems experiment (Davis, CA). We collected soil samples (0-15cm) across the cover crop and subsequent maize growing seasons and then isolated three SOM fractions soil: coarse particulate organic matter (cPOM; >250um), microaggregates (53-250um), and silt-and-clay (<53um). Total C and N were measured on both bulk soil and SOM fractions. Real-time polymerase chain reaction (PCR) using primers for the functional genes, amoA and nosZ, were employed to quantify AOB and denitrifier population sizes, respectively. We also measured gross ammonification and nitrification rates in short-term 15N-incubations of the bulk soil to link cover crop induced N cycling to N-transforming bacteria. Total soil C and N concentrations and soil aggregation were higher in the organic than conventional and low-input systems. The amoA and no Z copy numbers g-1 dry soil were highest in the microaggregate fraction and similar between the cPOM and silt-and-clay fractions, among all cropping treatments. Abundances of AOB and denitrifiers were lower in bulk soil

  9. Radiofrequency electromagnetic field exposure in everyday microenvironments in Europe: A systematic literature review.

    Science.gov (United States)

    Sagar, Sanjay; Dongus, Stefan; Schoeni, Anna; Roser, Katharina; Eeftens, Marloes; Struchen, Benjamin; Foerster, Milena; Meier, Noëmi; Adem, Seid; Röösli, Martin

    2017-08-02

    The impact of the introduction and advancement in communication technology in recent years on exposure level of the population is largely unknown. The main aim of this study is to systematically review literature on the distribution of radiofrequency electromagnetic field (RF-EMF) exposure in the everyday environment in Europe and summarize key characteristics of various types of RF-EMF studies conducted in the European countries. We systematically searched the ISI Web of Science for relevant literature published between 1 January 2000 and 30 April 2015, which assessed RF-EMF exposure levels by any of the methods: spot measurements, personal measurement with trained researchers and personal measurement with volunteers. Twenty-one published studies met our eligibility criteria of which 10 were spot measurements studies, 5 were personal measurement studies with trained researchers (microenvironmental), 5 were personal measurement studies with volunteers and 1 was a mixed methods study combining data collected by volunteers and trained researchers. RF-EMF data included in the studies were collected between 2005 and 2013. The mean total RF-EMF exposure for spot measurements in European "Homes" and "Outdoor" microenvironments was 0.29 and 0.54 V/m, respectively. In the personal measurements studies with trained researchers, the mean total RF-EMF exposure was 0.24 V/m in "Home" and 0.76 V/m in "Outdoor". In the personal measurement studies with volunteers, the population weighted mean total RF-EMF exposure was 0.16 V/m in "Homes" and 0.20 V/m in "Outdoor". Among all European microenvironments in "Transportation", the highest mean total RF-EMF 1.96 V/m was found in trains of Belgium during 2007 where more than 95% of exposure was contributed by uplink. Typical RF-EMF exposure levels are substantially below regulatory limits. We found considerable differences between studies according to the type of measurements procedures, which precludes cross

  10. NFAT Signaling in Osteoblasts Regulates the Hematopoietic Niche in the Bone Microenvironment

    Directory of Open Access Journals (Sweden)

    Cheryl L. Sesler

    2013-01-01

    Full Text Available Osteoblasts support hematopoietic cell development, including B lymphopoiesis. We have previously shown that the nuclear factor of activated T cells (NFAT negatively regulates osteoblast differentiation and bone formation. Interestingly, in smooth muscle, NFAT has been shown to regulate the expression of vascular cellular adhesion molecule-1 (VCAM-1, a mediator of cell adhesion and signaling during leukocyte development. To examine whether NFAT signaling in osteoblasts regulates hematopoietic development in vivo, we generated a mouse model expressing dominant-negative NFAT driven by the 2.3 kb fragment of the collagen-αI promoter to disrupt NFAT activity in osteoblasts (dnNFATOB. Bone histomorphometry showed that dnNFATOB mice have significant increases in bone volume (44% and mineral apposition rate (131% and decreased trabecular thickness (18%. In the bone microenvironment, dnNFATOB mice displayed a significant increase (87% in Lineage−cKit+Sca-1+ (LSK cells and significant decreases in B220+CD19−IgM− pre-pro-B cells (41% and B220+CD19+IgM+ immature B cells (40%. Concurrent with these findings, LSK cell differentiation into B220+ cells was inhibited when cocultured on differentiated primary osteoblasts harvested from dnNFATOB mice. Gene expression and protein levels of VCAM-1 in osteoblasts decreased in dnNFATOB mice compared to controls. These data suggest that osteoblast-specific NFAT activity mediates early B lymphopoiesis, possibly by regulating VCAM-1 expression on osteoblasts.

  11. Human mammary progenitor cell fate decisions are products of interactions with combinatorial microenvironments

    Energy Technology Data Exchange (ETDEWEB)

    LaBarge, Mark A; Nelson, Celeste M; Villadsen, Rene; Fridriksdottir, Agla; Ruth, Jason R; Stampfer, Martha R; Petersen, Ole W; Bissell, Mina J

    2008-09-19

    In adult tissues, multi-potent progenitor cells are some of the most primitive members of the developmental hierarchies that maintain homeostasis. That progenitors and their more mature progeny share identical genomes, suggests that fate decisions are directed by interactions with extrinsic soluble factors, ECM, and other cells, as well as physical properties of the ECM. To understand regulation of fate decisions, therefore, would require a means of understanding carefully choreographed combinatorial interactions. Here we used microenvironment protein microarrays to functionally identify combinations of cell-extrinsic mammary gland proteins and ECM molecules that imposed specific cell fates on bipotent human mammary progenitor cells. Micropatterned cell culture surfaces were fabricated to distinguish between the instructive effects of cell-cell versus cell-ECM interactions, as well as constellations of signaling molecules; and these were used in conjunction with physiologically relevant 3 dimensional human breast cultures. Both immortalized and primary human breast progenitors were analyzed. We report on the functional ability of those proteins of the mammary gland that maintain quiescence, maintain the progenitor state, and guide progenitor differentiation towards myoepithelial and luminal lineages.

  12. Engineering anisotropic biomimetic fibrocartilage microenvironment by bioprinting mesenchymal stem cells in nanoliter gel droplets.

    Science.gov (United States)

    Gurkan, Umut A; El Assal, Rami; Yildiz, Simin E; Sung, Yuree; Trachtenberg, Alexander J; Kuo, Winston P; Demirci, Utkan

    2014-07-07

    Over the past decade, bioprinting has emerged as a promising patterning strategy to organize cells and extracellular components both in two and three dimensions (2D and 3D) to engineer functional tissue mimicking constructs. So far, tissue printing has neither been used for 3D patterning of mesenchymal stem cells (MSCs) in multiphase growth factor embedded 3D hydrogels nor been investigated phenotypically in terms of simultaneous differentiation into different cell types within the same micropatterned 3D tissue constructs. Accordingly, we demonstrated a biochemical gradient by bioprinting nanoliter droplets encapsulating human MSCs, bone morphogenetic protein 2 (BMP-2), and transforming growth factor β1 (TGF- β1), engineering an anisotropic biomimetic fibrocartilage microenvironment. Assessment of the model tissue construct displayed multiphasic anisotropy of the incorporated biochemical factors after patterning. Quantitative real time polymerase chain reaction (qRT-PCR) results suggested genomic expression patterns leading to simultaneous differentiation of MSC populations into osteogenic and chondrogenic phenotype within the multiphasic construct, evidenced by upregulation of osteogenesis and condrogenesis related genes during in vitro culture. Comprehensive phenotypic network and pathway analysis results, which were based on genomic expression data, indicated activation of differentiation related mechanisms, via signaling pathways, including TGF, BMP, and vascular endothelial growth factor.

  13. Targeting the Tumor Microenvironment: The Protumor Effects of IL-17 Related to Cancer Type.

    Science.gov (United States)

    Fabre, Joseph; Giustiniani, Jerome; Garbar, Christian; Antonicelli, Frank; Merrouche, Yacine; Bensussan, Armand; Bagot, Martine; Al-Dacak, Reem

    2016-08-30

    The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory interleukin 17 (IL-17)-producing T helper lymphocytes, the Th17 cells, and the IL-17/IL-17 receptor (IL-17R) axis gained special attention. The IL-17 family comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. Secreted as disulfide-linked homo- or heterodimers, the IL-17 bind to the IL-17R, a type I cell surface receptor, of which there are five variants, IL-17RA to IL-17RE. This review focuses on the current advances identifying the promoting role of IL-17 in carcinogenesis, tumor metastasis and resistance to chemotherapy of diverse solid cancers. While underscoring the IL-17/IL-17R axis as promising immunotherapeutic target in the context of cancer managing, this knowledge calls upon further in vitro and in vivo studies that would allow the development and implementation of novel strategies to combat tumors.

  14. High-Efficiency Multiscale Modeling of Cell Deformations in Confined Microenvironments in Microcirculation and Microfluidic Devices

    Science.gov (United States)

    Lu, Huijie; Peng, Zhangli

    2017-11-01

    Our goal is to develop a high-efficiency multiscale modeling method to predict the stress and deformation of cells during the interactions with their microenvironments in microcirculation and microfluidic devices, including red blood cells (RBCs) and circulating tumor cells (CTCs). There are more than 1 billion people in the world suffering from RBC diseases, e.g. anemia, sickle cell diseases, and malaria. The mechanical properties of RBCs are changed in these diseases due to molecular structure alternations, which is not only important for understanding the disease pathology but also provides an opportunity for diagnostics. On the other hand, the mechanical properties of cancer cells are also altered compared to healthy cells. This can lead to acquired ability to cross the narrow capillary networks and endothelial gaps, which is crucial for metastasis, the leading cause of cancer mortality. Therefore, it is important to predict the deformation and stress of RBCs and CTCs in microcirculations. We are developing a high-efficiency multiscale model of cell-fluid interaction to study these two topics.

  15. Multitype Network-Guided Target Controllability in Phenotypically Characterized Osteosarcoma: Role of Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Ankush Sharma

    2017-07-01

    Full Text Available This study highlights the relevance of network-guided controllability analysis as a precision oncology tool. Target controllability through networks is potentially relevant to cancer research for the identification of therapeutic targets. With reference to a recent study on multiple phenotypes from 22 osteosarcoma (OS cell lines characterized both in vitro and in vivo, we found that a variety of critical proteins in OS regulation circuits were in part phenotype specific and in part shared. To generalize our inference approach and match cancer phenotypic heterogeneity, we employed multitype networks and identified targets in correspondence with protein sub-complexes. Therefore, we established the relevance for diagnostic and therapeutic purposes of inspecting interactive targets, namely those enriched by significant connectivity patterns in protein sub-complexes. Emerging targets appeared with reference to the OS microenvironment, and relatively to small leucine-rich proteoglycan members and D-type cyclins, among other collagen, laminin, and keratin proteins. These described were evidences shared across all phenotypes; instead, specific evidences were provided by critical proteins including IGFBP7 and PDGFRA in the invasive phenotype, and FGFR3 and THBS1 in the colony forming phenotype.

  16. Changes in the osmolarity of the embryonic microenvironment induce neural tube defects.

    Science.gov (United States)

    Jin, Yi-Mei; Wang, Guang; Zhang, Nuan; Wei, Yi-Fan; Li, Shuai; Chen, You-Peng; Chuai, Manli; Lee, Henry Siu Sum; Hocher, Berthold; Yang, Xuesong

    2015-05-01

    Many maternal disorders that modify the embryonic microenvironment, such as a change in osmolarity, can affect development, but how these changes influence the early embryo remains obscure. Neural tube defects, for example, are common congenital disorders found in fetus and neonates. In this study, we investigated the impact of anisotonic osmolarity (unequal osmotic pressures) on neural tube development in the early chick embryo, finding that neuronal cell differentiation was impaired in the neural tube due to enhanced apoptosis and repressed cell proliferation. Anisotonic osmolarity also affected normal development of the neural crest, which in turn influenced abnormal development of the neural tube. As neural tube development is highly dependent on the proper expression of bone morphogenetic protein 4 (BMP4), paired box 7 (PAX7), and sonic hedgehog (SHH) genes in the dorsal and ventral regions along the tube, we investigated the impact of anisotonic osmolarity on their expression. Indeed, small changes in osmolarity could positively and negatively impact the expression of these regulatory genes, which profoundly affected neural tube development. Thus, both the central and peripheral nervous systems were perturbed by anisotonic consitions as a consequence of the abnormal expression of key genes within the developing neural tube. © 2015 Wiley Periodicals, Inc.

  17. HZE Radiation Non-targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Mary Helen eBarcellos-Hoff

    2016-03-01

    Full Text Available Clear mechanistic understanding of the biological processes elicited by radiation that increase cancer risk can be used to inform prediction of health consequences of medical uses, such as radiotherapy, or occupational exposures such as those of astronauts during deep space travel. Here we review the current concepts of carcinogenesis as a multicellular process during which transformed cells escape normal tissue controls, including the immune system, and establish a tumor microenvironment. We discuss the contribution of two broad classes of radiation effects that may increase cancer: radiation targeted effects (RTE that occur as a result of direct energy deposition, e.g. DNA damage, and non-targeted effects (NTE that result from changes in cell signaling, e.g. genomic instability. It is unknown whether the potentially greater carcinogenic effect of HZE particle radiation is a function of the relative contribution or extent of NTE, or due to unique NTE. We addressed this problem using a radiation/genetic mammary chimera mouse model of breast cancer. Our experiments suggest that NTE promote more aggressive cancers, as evidenced by increased growth rate, transcriptomic signatures and metastasis, and that HZE particle NTE are more effective than reference γ-radiation. Emerging evidence suggest that HZE irradiation dampens anti-tumor immunity. These studies raise concern that HZE radiation exposure not only increases the likelihood of developing cancer but also could promote progression to more aggressive cancer with a greater risk of mortality.

  18. Mussel-inspired nano-building block assemblies for mimicking extracellular matrix microenvironments with multiple functions.

    Science.gov (United States)

    Wang, Zhenming; Jia, Zhanrong; Jiang, Yanan; Li, Pengfei; Han, Lu; Lu, Xiong; Ren, Fuzeng; Wang, Kefeng; Yuan, Huiping

    2017-08-03

    The assembly of nano-building blocks is an effective way to produce artificial extracellular matrix microenvironments with hierarchical micro/nano structures. However, it is hard to assemble different types of nano-building blocks, to form composite coatings with multiple functions, by traditional layer-by-layer (LbL) self-assembly methods. Inspired by the mussel adhesion mechanism, we developed polydopamine (PDA)-decorated bovine serum albumin microspheres (BSA-MS) and nano-hydroxyapatite (nano-HA), and assembled them to form bioactive coatings with micro/nano structures encapsulating bone morphogenetic protein-2 (BMP-2). First, PDA-decorated nano-HA (nano-pHA) was obtained by oxidative polymerization of dopamine on nano-HA. Second, BMP-2-encapsulated BSA microspheres were prepared through desolvation, and then were also decorated by PDA (pBSA-MS). Finally, the nano-pHA and pBSA-MS were assembled using the adhesive properties of PDA. Bone marrow stromal cell cultures and in vivo implantation, showed that the pHA/pBSA (BMP-2) coatings can promote cell adhesion, proliferation, and benefited for osteoinductivity. PDA decoration was also applied to assemble various functional nanoparticles, such as nano-HA, polystyrene, and Fe3O4 nanoparticles. In summary, this study provides a novel strategy for the assembly of biofunctional nano-building blocks, which surpasses traditional LbL self-assembly of polyelectrolytes, and can find broad applications in bioactive agents delivery or multi-functional coatings.

  19. Mimicking the host and its microenvironment in vitro for studying mucosal infections by Pseudomonas aeruginosa

    Science.gov (United States)

    Crabbé, Aurélie; Ledesma, Maria A.; Nickerson, Cheryl A.

    2014-01-01

    Why is a healthy person protected from Pseudomonas aeruginosa infections, while individuals with cystic fibrosis or damaged epithelium are particularly susceptible to this opportunistic pathogen? In order to address this question, it is essential to thoroughly understand the dynamic interplay between the host microenvironment and P. aeruginosa. Therefore, using modeI systems that represent key aspects of human mucosal tissues in health and disease allows recreating in vivo host-pathogen interactions in a physiologically relevant manner. In this review, we discuss how factors of mucosal tissues, such as apical-basolateral polarity, junctional complexes, extracellular matrix proteins, mucus, multicellular complexity (including indigenous microbiota), and other physicochemical factors affect P. aeruginosa pathogenesis and are thus important to mimic in vitro. We highlight in vitro cell and tissue culture model systems of increasing complexity that have been used over the past 35 years to study the infectious disease process of P. aeruginosa, mainly focusing on lung models, and their respective advantages and limitations. Continued improvements of in vitro models based on our expanding knowledge of host microenvironmental factors that participate in P. aeruginosa pathogenesis will help advance fundamental understanding of pathogenic mechanisms and increase the translational potential of research findings from bench to the patient’s bedside. PMID:24737619

  20. Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability

    Science.gov (United States)

    Barcellos-Hoff, M. H.; Brooks, A. L.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    Cell growth, differentiation and death are directed in large part by extracellular signaling through the interactions of cells with other cells and with the extracellular matrix; these interactions are in turn modulated by cytokines and growth factors, i.e. the microenvironment. Here we discuss the idea that extracellular signaling integrates multicellular damage responses that are important deterrents to the development of cancer through mechanisms that eliminate abnormal cells and inhibit neoplastic behavior. As an example, we discuss the action of transforming growth factor beta (TGFB1) as an extracellular sensor of damage. We propose that radiation-induced bystander effects and genomic instability are, respectively, positive and negative manifestations of this homeostatic process. Bystander effects exhibited predominantly after a low-dose or a nonhomogeneous radiation exposure are extracellular signaling pathways that modulate cellular repair and death programs. Persistent disruption of extracellular signaling after exposure to relatively high doses of ionizing radiation may lead to the accumulation of aberrant cells that are genomically unstable. Understanding radiation effects in terms of coordinated multicellular responses that affect decisions regarding the fate of a cell may necessitate re-evaluation of radiation dose and risk concepts and provide avenues for intervention.

  1. A model of tumor architecture and spatial interactions with tumor microenvironment in breast carcinoma

    Science.gov (United States)

    Ben Cheikh, Bassem; Bor-Angelier, Catherine; Racoceanu, Daniel

    2017-03-01

    Breast carcinomas are cancers that arise from the epithelial cells of the breast, which are the cells that line the lobules and the lactiferous ducts. Breast carcinoma is the most common type of breast cancer and can be divided into different subtypes based on architectural features and growth patterns, recognized during a histopathological examination. Tumor microenvironment (TME) is the cellular environment in which tumor cells develop. Being composed of various cell types having different biological roles, TME is recognized as playing an important role in the progression of the disease. The architectural heterogeneity in breast carcinomas and the spatial interactions with TME are, to date, not well understood. Developing a spatial model of tumor architecture and spatial interactions with TME can advance our understanding of tumor heterogeneity. Furthermore, generating histological synthetic datasets can contribute to validating, and comparing analytical methods that are used in digital pathology. In this work, we propose a modeling method that applies to different breast carcinoma subtypes and TME spatial distributions based on mathematical morphology. The model is based on a few morphological parameters that give access to a large spectrum of breast tumor architectures and are able to differentiate in-situ ductal carcinomas (DCIS) and histological subtypes of invasive carcinomas such as ductal (IDC) and lobular carcinoma (ILC). In addition, a part of the parameters of the model controls the spatial distribution of TME relative to the tumor. The validation of the model has been performed by comparing morphological features between real and simulated images.

  2. The “Trojan Horse” Approach to Tumor Immunotherapy: Targeting the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Delia Nelson

    2014-01-01

    Full Text Available Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumors may be more effective, particularly those that overcome natural suppressive factors in the tumor microenvironment. The “Trojan Horse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.

  3. When Neighbors Talk: Colon Cancer Cell Invasion and Tumor Microenvironment Myofibroblasts.

    Science.gov (United States)

    Bridelance, Jolien; Drebert, Zuzanna; De Wever, Olivier; Bracke, Marc; Beck, Ilse M

    2017-01-01

    Historically, the word cancer is derived from the Latin cancer, as the red swollen arteries near a tumor reminded the physician Galenus and his fellow Romans of a red crab. Currently, cancer remains the disease to beat as it remains a leading cause of death worldwide (WHO). Tumors do not simply consist of cancer cells, as they can recruit normal cells, which will form the tumor-associated stroma. These stromal cells together with the extracellular matrix, constitute the tumor microenvironment. Reciprocal communication between tumor-associated stromal cells and cancer cells is important for the induction of epithelial-to-mesenchymal transition and invasion. A detailed knowledge of this communication can spark the development of novel therapeutic strategies aimed at tackling yet unaddressed regulators of invasion and thus metastasis. Therefore, this review will focus not only on epithelial-to-mesenchymal transition and invasion, but also on communication between tumor cells, in particular colon cancer cells, and their stroma, with a primordial focus on cancer-associated fibroblasts, and lastly this review will discuss how this communication can affect the cancer cell's ability to invade its surroundings and form metastases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Indoor air characterization of various microenvironments in the Arctic. The case of Tromsø, Norway.

    Science.gov (United States)

    Katsoyiannis, Athanasios; Anda, Erik Eik; Cincinelli, Alessandra; Martellini, Tania; Leva, Paolo; Goetsch, Arntraut; Sandanger, Torkjel M; Huber, Sandra

    2014-10-01

    The present pilot study monitored for the first time volatile organic compounds (VOCs) and aerosols in domestic and occupational microenvironments in the Arctic Region. Differences between the two categories of samples are noted with domestic environments exhibiting higher concentrations of VOCs (total VOCs ranging between 106 and 584 μg m(-3)), while total particulate matter was highest in workplace non-office environments (ranging between 132 and 284 μg m(-3)). The terpenes were the most abundant class of VOCs, while a variety of other compounds exhibited 100% frequency of occurrence (i.e. naphthalene, D5-volatile methyl siloxane). Compared to results from other studies/regions, the concentrations of VOCs are considered as relatively low. Based on the results and the knowledge of the typical characteristics of the Arctic lifestyle, some important sources are identified. As this is the first study that deals with indoor air quality in the coldest region globally, it is expected that it will trigger the interest of Authorities to proceed to more detailed studies. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Cancer-associated fibroblasts in tumor microenvironment - Accomplices in tumor malignancy.

    Science.gov (United States)

    Liao, Zehuan; Tan, Zhen Wei; Zhu, Pengcheng; Tan, Nguan Soon

    2018-01-31

    There is much cellular heterogeneity in the tumor microenvironment. The tumor epithelia and stromal cells co-evolve, and this reciprocal relationship dictates almost every step of cancer development and progression. Despite this, many anticancer therapies are designed around druggable features of tumor epithelia, ignoring the supportive role of stromal cells. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of many tumor types. Numerous previous studies have highlighted a pro-tumorigenic role for CAFs via secretion of various growth factors, cytokines, chemokines, and the degradation of extracellular matrix. Recent works showed that CAFs secrete H 2 O 2 to effect stromal-mediated field cancerization, transform primary epithelial cells, and aggravate cancer cell aggressiveness, in addition to inflammatory and mitogenic factors. Molecular characterization of CAFs also underscores the importance of Notch and specific nuclear receptor signaling in the activation of CAFs. This review consolidates recent findings of CAFs and highlights areas for future investigations. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Microenvironments and different nanoparticle dynamics in living cells revealed by a standard nanoparticle.

    Science.gov (United States)

    Pack, Chan Gi; Song, Mi Ryoung; Tae, Eunju Lee; Hiroshima, Michio; Byun, Kyung Hee; Kim, Jun Sung; Sako, Yasushi

    2012-11-10

    For quantitative analysis of nanoparticle diffusions and submicro-environments in living cells, use of newly synthesized silica-based fluorescent nanoparticle (Si-FNP) as a standard nanoprobe is successfully demonstrated. The appropriate characteristics of a standard probe were fully analyzed in vitro by single molecule detection, transmission electron microscopy, and dynamic light scattering. Using fluorescence correlation analysis in single living cells, we quantitatively compared the diffusional properties of the standard Si-FNP with a diameter of 50 nm, peptide coated Si-FNP, streptavidin coated Qdot, and GFP molecule which have different sizes and surface properties. The result demonstrates that the standard Si-FNP without coat is minimally trapped in the vesicles in the process of cellular endocytosis. Interestingly, a large proportion of Si-FNP introduced into the cells by electroporation diffuses freely in the cells during a cell cycle suggesting free diffusing NPs are hardly trapped in the vesicles. The simple but highly sensitive method will provide insight into strategies to understanding the hydrodynamic process of nanoparticle delivery into living cells as well as the cellular microenvironment in the view of submicro-size. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.

    Science.gov (United States)

    Quail, Daniela F; Bowman, Robert L; Akkari, Leila; Quick, Marsha L; Schuhmacher, Alberto J; Huse, Jason T; Holland, Eric C; Sutton, James C; Joyce, Johanna A

    2016-05-20

    Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors. Copyright © 2016, American Association for the Advancement of Science.

  8. Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration

    Science.gov (United States)

    Brissova, Marcela; Aamodt, Kristie; Brahmachary, Priyanka; Prasad, Nripesh; Hong, Ji-Young; Dai, Chunhua; Mellati, Mahnaz; Shostak, Alena; Poffenberger, Greg; Aramandla, Radhika; Levy, Shawn E.; Powers, Alvin C.

    2014-01-01

    SUMMARY Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature, islet microenvironment, and β cell mass, we transiently increased VEGF-A production by β cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to β cell loss. After withdrawal of the VEGF-A stimulus, β cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing β cells. Bone marrow-derived macrophages (MΦs) recruited to the site of β cell injury were crucial for the β cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated β cells will improve strategies aimed at β cell regeneration and expansion. PMID:24561261

  9. Finding and tracing human MSC in 3D microenvironments with the photoconvertible protein Dendra2

    Science.gov (United States)

    Caires, Hugo R.; Gomez-Lazaro, Maria; Oliveira, Carla M.; Gomes, David; Mateus, Denisa D.; Oliveira, Carla; Barrias, Cristina C.; Barbosa, Mário A.; Almeida, Catarina R.

    2015-05-01

    Mesenchymal Stem/Stromal Cells (MSC) are a promising cell type for cell-based therapies - from tissue regeneration to treatment of autoimmune diseases - due to their capacity to migrate to damaged tissues, to differentiate in different lineages and to their immunomodulatory and paracrine properties. Here, a simple and reliable imaging technique was developed to study MSC dynamical behavior in natural and bioengineered 3D matrices. Human MSC were transfected to express a fluorescent photoswitchable protein, Dendra2, which was used to highlight and follow the same group of cells for more than seven days, even if removed from the microscope to the incubator. This strategy provided reliable tracking in 3D microenvironments with different properties, including the hydrogels Matrigel and alginate as well as chitosan porous scaffolds. Comparison of cells mobility within matrices with tuned physicochemical properties revealed that MSC embedded in Matrigel migrated 64% more with 5.2 mg protein/mL than with 9.6 mg/mL and that MSC embedded in RGD-alginate migrated 51% faster with 1% polymer concentration than in 2% RGD-alginate. This platform thus provides a straightforward approach to characterize MSC dynamics in 3D and has applications in the field of stem cell biology and for the development of biomaterials for tissue regeneration.

  10. Herpesviruses shape tumour microenvironment through exosomal transfer of viral microRNAs.

    Directory of Open Access Journals (Sweden)

    Ohad Yogev

    2017-08-01

    Full Text Available Metabolic changes within the cell and its niche affect cell fate and are involved in many diseases and disorders including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV is the etiological agent of Kaposi's sarcoma (KS. KSHV latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, these miRNAs are responsible for inducing the Warburg effect in infected cells. Here we identify a novel mechanism enabling KSHV to manipulate the metabolic nature of the tumour microenvironment. We demonstrate that KSHV infected cells specifically transfer the virus-encoded microRNAs to surrounding cells via exosomes. This flow of genetic information results in a metabolic shift toward aerobic glycolysis in the surrounding non-infected cells. Importantly, this exosome-mediated metabolic reprogramming of neighbouring cells supports the growth of infected cells, thereby contributing to viral fitness. Finally, our data show that this miRNA transfer-based regulation of cell metabolism is a general mechanism used by other herpesviruses, such as EBV, as well as for the transfer of non-viral onco-miRs. This exosome-based crosstalk provides viruses with a mechanism for non-infectious transfer of genetic material without production of new viral particles, which might expose them to the immune system. We suggest that viruses and cancer cells use this mechanism to shape a specific metabolic niche that will contribute to their fitness.

  11. Exhaustion of T lymphocytes in the tumor microenvironment: Significance and effective mechanisms.

    Science.gov (United States)

    Davoodzadeh Gholami, Mohammad; Kardar, Gholam Ali; Saeedi, Yousef; Heydari, Sahel; Garssen, Johan; Falak, Reza

    2017-12-01

    T lymphocytes play crucial roles in adaptive immune responses to tumors. However, due to different tolerance mechanisms and inhibitory effects of the tumor microenvironment (TME) on T cells, responses to tumors are insufficient. In fact, cellular and molecular suppressive mechanisms repress T cell responses in the TME, resulting in senescent, anergic and exhausted lymphocytes. Exhaustion is a poor responsive status of T cells, with up-regulated expression of inhibitory receptors, decreased production of effective cytokines, and reduced cytotoxic activity. Low immunogenicity of tumor antigens and inadequate presentation of tumor-specific antigens results in inappropriate activation of naive T lymphocytes against tumor antigens. Moreover, when effector cytotoxic T cells enter TME, they encounter a complicated network of cells and cytokines that suppress their effectiveness and turn them into exhausted T cells. Thus, the mechanism of T cell exhaustion in cancer is different from that in chronic infections. In this review we will discuss the main components such as inhibitory receptors, inflammatory cells, stromal cells, cytokine milieu as well as environmental and metabolic conditions in TME which play role in development of exhaustion. Furthermore, recent therapeutic methods available to overcome exhaustion will be discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment.

    Science.gov (United States)

    Panagopoulos, Vasilios; Leach, Damien A; Zinonos, Irene; Ponomarev, Vladimir; Licari, Giovanni; Liapis, Vasilios; Ingman, Wendy V; Anderson, Peter; DeNichilo, Mark O; Evdokiou, Andreas

    2017-04-01

    Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.

  13. Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

    Energy Technology Data Exchange (ETDEWEB)

    Chaudary, Naz [Ontario Cancer Institute/Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Pintilie, Melania [Biostatistics Department, Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Schwock, Joerg [Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Dhani, Neesha [Ontario Cancer Institute/Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Clarke, Blaise [Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Department of Pathology, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Milosevic, Michael; Fyles, Anthony [Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Hill, Richard P., E-mail: hill@uhnres.utoronto.ca [Ontario Cancer Institute/Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9 (Canada)

    2012-08-29

    Rationale: The tumor microenvironment (TME) is heterogeneous including both malignant and host cell components as well as regions of hypoxia, elevated interstitial fluid pressure (IFP) and poor nutrient supply. The quantitative extent to which the microenvironmental properties of primary tumors are recapitulated in xenograft models is not well characterized. Methods: Xenografts were generated by implanting tumor biopsies directly into the cervix of mice to create a panel of orthotopically-passaged xenografts (OCICx). Tumors were grown to ~1 cm (diameter) and IFP measurements recorded prior to sacrifice. Enlarged para-aortic lymph nodes (>1–2 mm) were excised for histologic confirmation of metastatic disease. Quantitative histological analysis was used to evaluate hypoxia, proliferation, lymphatic and blood vessels in the epithelial and stromal regions of the xenografts and original patient tumour. Results: IFP and nodal disease were not correlated with tumor engraftment. IFP measurements in the xenografts were generally lower than those in the patient’s tumor. Lymphatic metastasis increased with passage number as did levels of hypoxia in the epithelial component of the xenografts. The blood vessel density in the stromal component of the xenografts increased in parallel. When all the markers were compared between the biopsy and the respective 3rd generation xenograft 10 of 11 tumors showed a good correlation. Conclusions: This ongoing study provides characterization about tumoral and stromal heterogeneity in a unique orthotopic xenograft model.

  14. Control of uterine microenvironment by Foxp3+ cells facilitates embryo implantation

    Directory of Open Access Journals (Sweden)

    Ana eTeles

    2013-06-01

    Full Text Available Implantation of the fertilized egg into the maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes. Whilst regulatory T cells (Tregs are reportedly involved in protection of allogeneic fetuses against rejection by the maternal immune system, their role for pregnancy to establish, e.g. blastocyst implantation, is not clear. By using 2-photon imaging we show that Foxp3+ cells accumulated in the mouse uterus during the receptive phase of the oestrus cycle. Seminal fluid further fostered Treg expansion. Depletion of Tregs in two Foxp3.DTR-based models prior to pairing drastically impaired implantation and resulted in infiltration of activated T effector cells as well as in uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations. Genetic deletion of the homing receptor CCR7 interfered with accumulation of Tregs in the uterus and implantation indicating that homing of Tregs to the uterus was mediated by CCR7. Our results demonstrate that Tregs play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment.

  15. Finding and tracing human MSC in 3D microenvironments with the photoconvertible protein Dendra2.

    Science.gov (United States)

    Caires, Hugo R; Gomez-Lazaro, Maria; Oliveira, Carla M; Gomes, David; Mateus, Denisa D; Oliveira, Carla; Barrias, Cristina C; Barbosa, Mário A; Almeida, Catarina R

    2015-05-14

    Mesenchymal Stem/Stromal Cells (MSC) are a promising cell type for cell-based therapies - from tissue regeneration to treatment of autoimmune diseases - due to their capacity to migrate to damaged tissues, to differentiate in different lineages and to their immunomodulatory and paracrine properties. Here, a simple and reliable imaging technique was developed to study MSC dynamical behavior in natural and bioengineered 3D matrices. Human MSC were transfected to express a fluorescent photoswitchable protein, Dendra2, which was used to highlight and follow the same group of cells for more than seven days, even if removed from the microscope to the incubator. This strategy provided reliable tracking in 3D microenvironments with different properties, including the hydrogels Matrigel and alginate as well as chitosan porous scaffolds. Comparison of cells mobility within matrices with tuned physicochemical properties revealed that MSC embedded in Matrigel migrated 64% more with 5.2 mg protein/mL than with 9.6 mg/mL and that MSC embedded in RGD-alginate migrated 51% faster with 1% polymer concentration than in 2% RGD-alginate. This platform thus provides a straightforward approach to characterize MSC dynamics in 3D and has applications in the field of stem cell biology and for the development of biomaterials for tissue regeneration.

  16. Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles.

    Science.gov (United States)

    Dreaden, Erik C; Morton, Stephen W; Shopsowitz, Kevin E; Choi, Jae-Hyeok; Deng, Zhou J; Cho, Nam-Joon; Hammond, Paula T

    2014-08-26

    Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.

  17. SU-8 based microdevices to study self-induced chemotaxis in 3D microenvironments

    Directory of Open Access Journals (Sweden)

    Jose Maria Ayuso

    2015-05-01

    Full Text Available Tissues are complex three-dimensional structures in which cell behaviour is frequently guided by chemotactic signals. Although starvation and nutrient restriction induce many different chemotactic processes, the recreation of such conditions in vitro remains difficult when using standard cell culture equipment. Recently, microfluidic techniques have arisen as powerful tools to mimic such physiological conditions. In this context, microfluidic three-dimensional cell culture systems require precise control of cell/hydrogel location because samples need to be placed within a microchamber without obstruction of surrounding elements. In this article, SU-8 is studied as structural material for the fabrication of complex cell culture devices due to its good mechanical properties, low gas permeability and sensor integration capacity. In particular, this manuscript presents a SU-8 based microdevice designed to create self-induced medium starvation, based on the combination of nutrient restriction and natural cell metabolism. Results show a natural migratory response towards nutrient source, showing how cells adapt to their own microenvironment modifications. The presented results demonstrate the SU-8 potential for microdevice fabrication applied to cell culture.

  18. Noninvasive multiparametric imaging of metastasis-permissive microenvironments in a human prostate cancer xenograft.

    Science.gov (United States)

    Penet, Marie-France; Pathak, Arvind P; Raman, Venu; Ballesteros, Paloma; Artemov, Dmitri; Bhujwalla, Zaver M

    2009-11-15

    Metastasis continues to be one of the major causes of mortality from prostate cancer. Because human malignant cell lines metastasize more readily from orthotopic sites than from heterotopic sites, to identify metastasis-permissive tumor microenvironments, we used noninvasive imaging to compare the in vivo vascular, metabolic, and physiologic characteristics of a human prostate cancer xenograft implanted orthotopically in the prostate or s.c. in the flank. Hypoxia was detected in these xenografts by placing an enhanced green fluorescence protein optical reporter under the control of a hypoxia response element. A multiparametric analysis of hypoxia, extracellular pH, vascularization, and metabolism provided a characterization of environments that are permissive for metastasis to occur. We found that orthotopic tumors, which metastasized more easily, were characterized by higher vascular volume, permeability, and total choline and a more acidic extracellular pH. Interestingly, metastatic deposits in the lymph nodes as well as cancer cells in ascites fluid were found to be hypoxic, explaining, in part, the refractory nature of metastatic disease. These results also provide the basis for clinically translatable noninvasive imaging markers for predicting metastatic risk in prostate cancer.

  19. Noninvasive Multi-parametric Imaging of Metastasis-Permissive Microenvironments in a Human Prostate Cancer Xenograft

    Science.gov (United States)

    Penet, Marie-France; Pathak, Arvind P.; Raman, Venu; Ballesteros, Paloma; Artemov, Dmitri; Bhujwalla, Zaver M.

    2009-01-01

    Metastasis continues to be one of the major causes of mortality from prostate cancer. Since human malignant cell lines metastasize more readily from orthotopic sites than from heterotopic sites, to identify metastasis-permissive tumor microenvironments, we used noninvasive imaging to compare the in vivo vascular, metabolic and physiological characteristics of a human prostate cancer xenograft implanted orthotopically in the prostate or subcutaneously in the flank. Hypoxia was detected in these xenografts by placing an enhanced green fluorescent protein (EGFP) optical reporter under the control of a hypoxia response element (HRE). A multi-parametric analysis of hypoxia, extracellular pH (pHe), vascularization and metabolism provided a characterization of environments that are permissive for metastasis to occur. We found that orthotopic tumors, which metastasized more easily, were characterized by higher vascular volume, permeability, and total choline, and a more acidic pHe. Interestingly, metastatic deposits in the lymph nodes as well as cancer cells in ascites fluid were found to be hypoxic, explaining in part, the refractory nature of metastatic disease. These results also provide the basis for clinically translatable noninvasive imaging markers for predicting metastatic risk in prostate cancer. PMID:19861534

  20. IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.

    Science.gov (United States)

    Nirschl, Christopher J; Suárez-Fariñas, Mayte; Izar, Benjamin; Prakadan, Sanjay; Dannenfelser, Ruth; Tirosh, Itay; Liu, Yong; Zhu, Qian; Devi, K Sanjana P; Carroll, Shaina L; Chau, David; Rezaee, Melika; Kim, Tae-Gyun; Huang, Ruiqi; Fuentes-Duculan, Judilyn; Song-Zhao, George X; Gulati, Nicholas; Lowes, Michelle A; King, Sandra L; Quintana, Francisco J; Lee, Young-Suk; Krueger, James G; Sarin, Kavita Y; Yoon, Charles H; Garraway, Levi; Regev, Aviv; Shalek, Alex K; Troyanskaya, Olga; Anandasabapathy, Niroshana

    2017-06-29

    Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Engineering Anisotropic Biomimetic Fibrocartilage Microenvironment by Bioprinting Mesenchymal Stem Cells in Nanoliter Gel Droplets

    Science.gov (United States)

    2015-01-01

    Over the past decade, bioprinting has emerged as a promising patterning strategy to organize cells and extracellular components both in two and three dimensions (2D and 3D) to engineer functional tissue mimicking constructs. So far, tissue printing has neither been used for 3D patterning of mesenchymal stem cells (MSCs) in multiphase growth factor embedded 3D hydrogels nor been investigated phenotypically in terms of simultaneous differentiation into different cell types within the same micropatterned 3D tissue constructs. Accordingly, we demonstrated a biochemical gradient by bioprinting nanoliter droplets encapsulating human MSCs, bone morphogenetic protein 2 (BMP-2), and transforming growth factor β1 (TGF- β1), engineering an anisotropic biomimetic fibrocartilage microenvironment. Assessment of the model tissue construct displayed multiphasic anisotropy of the incorporated biochemical factors after patterning. Quantitative real time polymerase chain reaction (qRT-PCR) results suggested genomic expression patterns leading to simultaneous differentiation of MSC populations into osteogenic and chondrogenic phenotype within the multiphasic construct, evidenced by upregulation of osteogenesis and condrogenesis related genes during in vitro culture. Comprehensive phenotypic network and pathway analysis results, which were based on genomic expression data, indicated activation of differentiation related mechanisms, via signaling pathways, including TGF, BMP, and vascular endothelial growth factor. PMID:24495169

  2. High Throughput Screening of Valganciclovir in Acidic Microenvironments of Polyester Thin Films

    Directory of Open Access Journals (Sweden)

    Teilo Schaller

    2015-04-01

    Full Text Available Ganciclovir and valganciclor are antiviral agents used for the treatment of cytomegalovirus retinitis. The conventional method for administering ganciclovir in cytomegalovirus retinitis patients is repeated intravitreal injections. In order to obviate the possible detrimental effects of repeated intraocular injections, to improve compliance and to eliminate systemic side-effects, we investigated the tuning of the ganciclovir pro-drug valganciclovir and the release from thin films of poly(lactic-co-glycolic acid (PLGA, polycaprolactone (PCL, or mixtures of both, as a step towards prototyping periocular valganciclovir implants. To investigate the drug release, we established and evaluated a high throughput fluorescence-based quantification screening assay for the detection of valganciclovir. Our protocol allows quantifying as little as 20 ng of valganciclovir in 96-well polypropylene plates and a 50× faster analysis compared to traditional HPLC measurements. This improvement can hence be extrapolated to other polyester matrix thin film formulations using a high-throughput approach. The acidic microenvironment within the polyester matrix was found to protect valganciclovir from degradation with resultant increases in the half-life of the drug in the periocular implant to 100 days. Linear release profiles were obtained using the pure polyester polymers for 10 days and 60 days formulations; however, gross phase separations of PCL and acid-terminated PLGA prevented tuning within these timeframes due to the phase separation of the polymer, valganciclovir, or both.

  3. Peptide ligand-modified nanomedicines for targeting cells at the tumor microenvironment.

    Science.gov (United States)

    David, Ayelet

    2017-09-15

    Since their initial discovery more than 30years ago, tumor-homing peptides have become an increasingly useful tool for targeted delivery of therapeutic and diagnostic agents into tumors. Today, it is well accepted that cells at the tumor microenvironment (TME) contribute in many ways to cancer development and progression. Tumor-homing peptide-decorated nanomedicines can interact specifically with surface receptors expressed on cells in the TME, improve cellular uptake of nanomedicines by target cells, and impair tumor growth and progression. Moreover, peptide ligand-modified nanomedicines can potentially accumulate in the target tissue at higher concentrations than would small conjugates, thus increasing overall target tissue exposure to the therapeutic agent, enhance therapeutic efficacy and reduce side effects. This review describes the most studied peptide ligands aimed at targeting cells in the TME, discusses major obstacles and principles in the design of ligands for drug targeting and provides an overview of homing peptides in ligand-targeted nanomedicines that are currently in development for cancer therapy and diagnosis. Copyright © 2017. Published by Elsevier B.V.

  4. Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

    Science.gov (United States)

    Lorger, Mihaela; Felding-Habermann, Brunhilde

    2010-01-01

    Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Up-regulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might codetermine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases. PMID:20382702

  5. Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Microenvironment

    Directory of Open Access Journals (Sweden)

    Sundary Sormendi

    2018-01-01

    Full Text Available Low oxygen tension or hypoxia is a determining factor in the course of many different processes in animals, including when tissue expansion and cellular metabolism result in high oxygen demands that exceed its supply. This is mainly happening when cells actively proliferate and the proliferating mass becomes distant from the blood vessels, such as in growing tumors. Metabolic alterations in response to hypoxia can be triggered in a direct manner, such as the switch from oxidative phosphorylation to glycolysis or inhibition of fatty acid desaturation. However, as the modulated action of hypoxia-inducible factors or the oxygen sensors (prolyl hydroxylase domain-containing enzymes can also lead to changes in enzyme expression, these metabolic changes can also be indirect. With this review, we want to summarize our current knowledge of the hypoxia-induced changes in metabolism during cancer development, how they are affected in the tumor cells and in the cells of the microenvironment, most prominently in immune cells.

  6. Multiple genome sequences reveal adaptations of a phototrophic bacterium to sediment microenvironments.

    Science.gov (United States)

    Oda, Yasuhiro; Larimer, Frank W; Chain, Patrick S G; Malfatti, Stephanie; Shin, Maria V; Vergez, Lisa M; Hauser, Loren; Land, Miriam L; Braatsch, Stephan; Beatty, J Thomas; Pelletier, Dale A; Schaefer, Amy L; Harwood, Caroline S

    2008-11-25

    The bacterial genus Rhodopseudomonas is comprised of photosynthetic bacteria found widely distributed in aquatic sediments. Members of the genus catalyze hydrogen gas production, carbon dioxide sequestration, and biomass turnover. The genome sequence of Rhodopseudomonas palustris CGA009 revealed a surprising richness of metabolic versatility that would seem to explain its ability to live in a heterogeneous environment like sediment. However, there is considerable genotypic diversity among Rhodopseudomonas isolates. Here we report the complete genome sequences of four additional members of the genus isolated from a restricted geographical area. The sequences confirm that the isolates belong to a coherent taxonomic unit, but they also have significant differences. Whole genome alignments show that the circular chromosomes of the isolates consist of a collinear backbone with a moderate number of genomic rearrangements that impact local gene order and orientation. There are 3,319 genes, 70% of the genes in each genome, shared by four or more strains. Between 10% and 18% of the genes in each genome are strain specific. Some of these genes suggest specialized physiological traits, which we verified experimentally, that include expanded light harvesting, oxygen respiration, and nitrogen fixation capabilities, as well as anaerobic fermentation. Strain-specific adaptations include traits that may be useful in bioenergy applications. This work suggests that against a backdrop of metabolic versatility that is a defining characteristic of Rhodopseudomonas, different ecotypes have evolved to take advantage of physical and chemical conditions in sediment microenvironments that are too small for human observation.

  7. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes.

    Science.gov (United States)

    Lopes, Matheus Rodrigues; Pereira, João Kleber Novais; de Melo Campos, Paula; Machado-Neto, João Agostinho; Traina, Fabiola; Saad, Sara T Olalla; Favaro, Patricia

    2017-01-13

    The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.

  8. Harnessing biomaterials to engineer the lymph node microenvironment for immunity or tolerance.

    Science.gov (United States)

    Andorko, James I; Hess, Krystina L; Jewell, Christopher M

    2015-03-01

    Nanoparticles, microparticles, and other biomaterials are advantageous in vaccination because these materials provide opportunities to modulate specific characteristics of immune responses. This idea of "tuning" immune responses has recently been used to combat infectious diseases and cancer, and to induce tolerance during organ transplants or autoimmune disease. Lymph nodes and other secondary lymphoid organs such as the spleen play crucial roles in determining if and how these responses develop following vaccination or immunotherapy. Thus, by manipulating the local microenvironments within these immunological command centers, the nature of systemic immune response can be controlled. This review provides recent examples that harness the interactions between biomaterials and lymph nodes or other secondary lymphoid organs to generate immunity or promote tolerance. These strategies draw on mechanical properties, surface chemistry, stability, and targeting to alter the interactions of cells, signals, and vaccine components in lymph nodes. While there are still many unanswered questions surrounding how best to design biomaterial-based vaccines to promote specific structures or functions in lymph nodes, features such as controlled release and targeting will help pave the way for the next generation of vaccines and immunotherapies that generate immune responses tuned for specific applications.

  9. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  10. The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

    Directory of Open Access Journals (Sweden)

    Drenka Trivanović

    2016-01-01

    Full Text Available State of tumor microenvironment (TME is closely linked to regulation of tumor growth and progression affecting the final outcome, refractoriness, and relapse of disease. Interactions of tumor, immune, and mesenchymal stromal/stem cells (MSCs have been recognized as crucial for understanding tumorigenesis. Due to their outstanding features, stem cell-like properties, capacity to regulate immune response, and dynamic functional phenotype dependent on microenvironmental stimuli, MSCs have been perceived as important players in TME. Signals provided by tumor-associated chronic inflammation educate MSCs to alter their phenotype and immunomodulatory potential in favor of tumor-biased state of MSCs. Adjustment of phenotype to TME and acquisition of tumor-promoting ability by MSCs help tumor cells in maintenance of permissive TME and suppression of antitumor immune response. Potential utilization of MSCs in treatment of tumor is based on their inherent ability to home tumor tissue that makes them suitable delivery vehicles for immune-stimulating factors and vectors for targeted antitumor therapy. Here, we review data regarding intrusive effects of inflammatory TME on MSCs capacity to affect tumor development through modification of their phenotype and interactions with immune system.

  11. Improving cancer therapies by targeting the physical and chemical hallmarks of the tumor microenvironment.

    Science.gov (United States)

    Ivey, Jill W; Bonakdar, Mohammad; Kanitkar, Akanksha; Davalos, Rafael V; Verbridge, Scott S

    2016-09-28

    Tumors are highly heterogeneous at the patient, tissue, cellular, and molecular levels. This multi-scale heterogeneity poses significant challenges for effective therapies, which ideally must not only distinguish between tumorous and healthy tissue, but also fully address the wide variety of tumorous sub-clones. Commonly used therapies either leverage a biological phenotype of cancer cells (e.g. high rate of proliferation) or indiscriminately kill all the cells present in a targeted volume. Tumor microenvironment (TME) targeting represents a promising therapeutic direction, because a number of TME hallmarks are conserved across different tumor types, despite the underlying genetic heterogeneity. Historically, TME targeting has largely focused on the cells that support tumor growth (e.g. vascular endothelial cells). However, by viewing the intrinsic physical and chemical alterations in the TME as additional therapeutic opportunities rather than barriers, a new class of TME-inspired treatments has great promise to complement or replace existing therapeutic strategies. In this review we summarize the physical and chemical hallmarks of the TME, and discuss how these tumor characteristics either currently are, or may ultimately be targeted to improve cancer therapies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Matrix mechanics and fluid shear stress control stem cells fate in three dimensional microenvironment.

    Science.gov (United States)

    Chen, Guobao; Lv, Yonggang; Guo, Pan; Lin, Chongwen; Zhang, Xiaomei; Yang, Li; Xu, Zhiling

    2013-07-01

    Stem cells have the ability to self-renew and to differentiate into multiple mature cell types during early life and growth. Stem cells adhesion, proliferation, migration and differentiation are affected by biochemical, mechanical and physical surface properties of the surrounding matrix in which stem cells reside and stem cells can sensitively feel and respond to the microenvironment of this matrix. More and more researches have proven that three dimensional (3D) culture can reduce the gap between cell culture and physiological environment where cells always live in vivo. This review summarized recent findings on the studies of matrix mechanics that control stem cells (primarily mesenchymal stem cells (MSCs)) fate in 3D environment, including matrix stiffness and extracellular matrix (ECM) stiffness. Considering the exchange of oxygen and nutrients in 3D culture, the effect of fluid shear stress (FSS) on fate decision of stem cells was also discussed in detail. Further, the difference of MSCs response to matrix stiffness between two dimensional (2D) and 3D conditions was compared. Finally, the mechanism of mechanotransduction of stem cells activated by matrix mechanics and FSS in 3D culture was briefly pointed out.

  13. The Scaffold Immune Microenvironment: Biomaterial-Mediated Immune Polarization in Traumatic and Nontraumatic Applications.

    Science.gov (United States)

    Sadtler, Kaitlyn; Allen, Brian W; Estrellas, Kenneth; Housseau, Franck; Pardoll, Drew M; Elisseeff, Jennifer H

    2017-10-01

    The immune system mediates tissue growth and homeostasis and is the first responder to injury or biomaterial implantation. Recently, it has been appreciated that immune cells play a critical role in wound healing and tissue repair and should thus be considered potentially beneficial, particularly in the context of scaffolds for regenerative medicine. In this study, we present a flow cytometric analysis of cellular recruitment to tissue-derived extracellular matrix scaffolds, where we quantitatively describe the infiltration and polarization of several immune subtypes, including macrophages, dendritic cells, neutrophils, monocytes, T cells, and B cells. We define a specific scaffold-associated macrophage (SAM) that expresses CD11b+F4/80+CD11c+/-CD206hiCD86+MHCII+ that are characteristic of an M2-like cell (CD206hi) with high antigen presentation capabilities (MHCII+). Adaptive immune cells tightly regulate the phenotype of a mature SAM. These studies provide a foundation for detailed characterization of the scaffold immune microenvironment of a given biomaterial scaffold to determine the effect of scaffold changes on immune response and subsequent therapeutic outcome of that material.

  14. Foreign Body Retrieval

    Medline Plus

    Full Text Available ... Physician Resources Professions Site Index A-Z Foreign Body Retrieval Foreign body retrieval is the removal of ... foreign body detection and removal? What is Foreign Body Retrieval? Foreign body retrieval involves the removal of ...

  15. Foreign Body Retrieval

    Science.gov (United States)

    ... Physician Resources Professions Site Index A-Z Foreign Body Retrieval Foreign body retrieval is the removal of ... foreign body detection and removal? What is Foreign Body Retrieval? Foreign body retrieval involves the removal of ...

  16. TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases

    DEFF Research Database (Denmark)

    Ham, Boram; Wang, Ni; D'Costa, Zarina

    2015-01-01

    Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this st......Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked....... In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD...

  17. Intra-operative label-free multimodal multiphoton imaging of breast cancer margins and microenvironment (Conference Presentation)

    Science.gov (United States)

    Sun, Yi; You, Sixian; Tu, Haohua; Spillman, Darold R.; Marjanovic, Marina; Chaney, Eric J.; Liu, George Z.; Ray, Partha S.; Higham, Anna; Boppart, Stephen A.

    2017-02-01

    Label-free multi-photon imaging has been a powerful tool for studying tissue microstructures and biochemical distributions, particularly for investigating tumors and their microenvironments. However, it remains challenging for traditional bench-top multi-photon microscope systems to conduct ex vivo tumor tissue imaging in the operating room due to their bulky setups and laser sources. In this study, we designed, built, and clinically demonstrated a portable multi-modal nonlinear label-free microscope system that combined four modalities, including two- and three- photon fluorescence for studying the distributions of FAD and NADH, and second and third harmonic generation, respectively, for collagen fiber structures and the distribution of micro-vesicles found in tumors and the microenvironment. Optical realignments and switching between modalities were motorized for more rapid and efficient imaging and for a light-tight enclosure, reducing ambient light noise to only 5% within the brightly lit operating room. Using up to 20 mW of laser power after a 20x objective, this system can acquire multi-modal sets of images over 600 μm × 600 μm at an acquisition rate of 60 seconds using galvo-mirror scanning. This portable microscope system was demonstrated in the operating room for imaging fresh, resected, unstained breast tissue specimens, and for assessing tumor margins and the tumor microenvironment. This real-time label-free nonlinear imaging system has the potential to uniquely characterize breast cancer margins and the microenvironment of tumors to intraoperatively identify structural, functional, and molecular changes that could indicate the aggressiveness of the tumor.

  18. Accomplices of the Hypoxic Tumor Microenvironment Compromising Antitumor Immunity: Adenosine, Lactate, Acidosis, Vascular Endothelial Growth Factor, Potassium Ions, and Phosphatidylserine.

    Science.gov (United States)

    Vaupel, Peter; Multhoff, Gabriele

    2017-01-01

    In this minireview, we aim to highlight key factors of the tumor microenvironment, including adenosine, lactate, acidosis, vascular endothelial growth factor, phosphatidylserine, high extracellular K + levels, and tumor hypoxia with respect to antitumor immune functions. Most solid tumors have an immature chaotic microvasculature that results in tumor hypoxia. Hypoxia is a key determinant of tumor aggressiveness and therapy resistance and hypoxia-related gene products can thwart antitumor immune responses.

  19. Accomplices of the Hypoxic Tumor Microenvironment Compromising Antitumor Immunity: Adenosine, Lactate, Acidosis, Vascular Endothelial Growth Factor, Potassium Ions, and Phosphatidylserine

    Directory of Open Access Journals (Sweden)

    Peter Vaupel

    2017-12-01

    Full Text Available In this minireview, we aim to highlight key factors of the tumor microenvironment, including adenosine, lactate, acidosis, vascular endothelial growth factor, phosphatidylserine, high extracellular K+ levels, and tumor hypoxia with respect to antitumor immune functions. Most solid tumors have an immature chaotic microvasculature that results in tumor hypoxia. Hypoxia is a key determinant of tumor aggressiveness and therapy resistance and hypoxia-related gene products can thwart antitumor immune responses.

  20. Intratumoral oncolytic adenoviral treatment modulates the glioma microenvironment and facilitates systemic tumor-antigen-specific T cell therapy

    OpenAIRE

    Qiao, Jian; Dey, Mahua; Chang, Alan L; Kim, Julius W; Miska, Jason; Ling, Alex; M Nettlebeck, Dirk; Han, Yu; Zhang, Lingjiao; Lesniak, Maciej S

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenviron...

  1. Expression of B7-H2 on CD8+T cells in colorectal cancer microenvironment and its clinical significance.

    Science.gov (United States)

    Cao, Ya; Cao, Tinghua; Zhao, Weidong; He, Fanghua; Lu, Ye; Zhang, Guangbo; Hu, Hao; Wang, Zhenxin

    2018-02-01

    The knowledge about B7-H2 expression in tumor is growing, but many questions remain unresolved. Especially in human tumor microenvironment, little studies were done. To explore the expression and clinical significance of B7-H2 on T cells in colorectal cancer microenvironment, fresh tumor tissues and paired non-tumor tissues collected from 25 patients with colorectal cancer were made to research B7-H2 expression on the infiltrating T cells including CD8 + T cells and CD4 + T cells. Also, tumor bearing mice were sacrificed on day 5, day 10, day 15, day 20, day 25 and flow cytometry was used to analyze B7-H2 expression on CD8 + T cells and CD4 + T cells in mouse tumors and spleens. Then, it was found that B7-H2 expression on CD8 + T cells in patients' tumor tissues was significantly higher than in non-tumor tissues. The expression of B7-H2 on CD8 + T cells in tumor microenvironment was significantly higher in patients with age ≤60 years old and the stage I-II. The expression level of B7-H2 on CD8 + T cells in mouse tumors and spleens both reached the highest level at the early stage of inoculation (on day 5), decreased to the lowest level on day 10 and day 15 separately, and then gradually increased. In mouse spleens, B7-H2 expression on CD8 + T cells was all significantly higher than on CD4 + T cells in five time periods. So, in this study, it was found that B7-H2 expression on CD8 + T cells in tumor microenvironment was closely related to the progression of colorectal cancer. Copyright © 2018. Published by Elsevier B.V.

  2. Aluminium, carbonyls and cytokines in human nipple aspirate fluids: Possible relationship between inflammation, oxidative stress and breast cancer microenvironment.

    Science.gov (United States)

    Mannello, F; Ligi, D; Canale, M

    2013-11-01

    The human breast is likely exposed to Al (aluminium) from many sources including diet and personal care products. Underarm applications of aluminium salt-based antiperspirant provide a possible long-term source of exposure, especially after underarm applications to shaved and abraded skin. Al research in breast fluids likely reflects the intraductal microenvironment. We found increased levels of aluminium in noninvasively collected nipple aspirate fluids (NAF) from 19 breast cancer patients compared with 16 healthy control subjects (268 vs 131 μg/l, respectively; p Aluminium content and carbonyl levels showed a significant positive linear correlation (r(2) 0.6628, p aluminium salts) we also found a significantly increased levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-12 p70, and TNF-α) and chemoattractant CC and CXC chemokines (IL-8, MIP-1α and MCP-1). In 12 invasive cancer NAF samples we found a significant positive linear correlation among aluminium, carbonyls and pro-inflammatory IL-6 cytokine (Y = 64.79x-39.63, r(2) 0.8192, p aluminium ions in oxidative and inflammatory status perturbations of breast cancer microenvironment, suggesting aluminium accumulation in breast microenvironment as a possible risk factor for oxidative/inflammatory phenotype of breast cells. © 2013.

  3. Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells.

    Science.gov (United States)

    Xiao, Peng; Wan, Xiaopeng; Cui, Bijun; Liu, Yang; Qiu, Chenyang; Rong, Jiabing; Zheng, Mingzhu; Song, Yinjing; Chen, Luoquan; He, Jia; Tan, Qinchun; Wang, Xiaojia; Shao, Xiying; Liu, Yuhua; Cao, Xuetao; Wang, Qingqing

    Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) - a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-κB and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2-/- mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral capacity of MDSCs. Our results identify IL-33 as a critical mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion.

  4. The O2, pH and Ca2+ microenvironment of benthic foraminifera in a high CO2 world.

    Directory of Open Access Journals (Sweden)

    Martin S Glas

    Full Text Available Ocean acidification (OA can have adverse effects on marine calcifiers. Yet, phototrophic marine calcifiers elevate their external oxygen and pH microenvironment in daylight, through the uptake of dissolved inorganic carbon (DIC by photosynthesis. We studied to which extent pH elevation within their microenvironments in daylight can counteract ambient seawater pH reductions, i.e. OA conditions. We measured the O(2 and pH microenvironment of four photosymbiotic and two symbiont-free benthic tropical foraminiferal species at three different OA treatments (~432, 1141 and 2151 µatm pCO(2. The O(2 concentration difference between the seawater and the test surface (ΔO(2 was taken as a measure for the photosynthetic rate. Our results showed that O(2 and pH levels were significantly higher on photosymbiotic foraminiferal surfaces in light than in dark conditions, and than on surfaces of symbiont-free foraminifera. Rates of photosynthesis at saturated light conditions did not change significantly between OA treatments (except in individuals that exhibited symbiont loss, i.e. bleaching, at elevated pCO(2. The pH at the cell surface decreased during incubations at elevated pCO(2, also during light incubations. Photosynthesis increased the surface pH but this increase was insufficient to compensate for ambient seawater pH decreases. We thus conclude that photosynthesis does only partly protect symbiont bearing foraminifera against OA.

  5. Tumor Microenvironment Regulates Metastasis and Metastasis Genes of Mouse MMTV-PymT Mammary Cancer Cells In Vivo

    Science.gov (United States)

    Werbeck, J. L.; Thudi, N. K.; Martin, C. K.; Premanandan, C.; Yu, L.; Ostrowksi, M. C.; Rosol, T. J.

    2014-01-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment. PMID:24091811

  6. Influence of microenvironment pH, humidity, and temperature on the stability of polymorphic and amorphous forms of clopidogrel bisulfate

    DEFF Research Database (Denmark)

    Raijada, Dhara K; Singh, Saranjit; Bansal, Arvind K

    2010-01-01

    The effect of microenvironment pH, humidity, and temperature was evaluated on the stability of polymorphic and amorphous forms of clopidogrel bisulfate, when present alone or in combinations. Oxalic acid and sodium carbonate were used as solid stressors to create acidic and alkaline pH, respectiv......The effect of microenvironment pH, humidity, and temperature was evaluated on the stability of polymorphic and amorphous forms of clopidogrel bisulfate, when present alone or in combinations. Oxalic acid and sodium carbonate were used as solid stressors to create acidic and alkaline p......H, respectively. The samples without and with stressors were subjected for 3 months to (1) 0% RH, 25% RH, 75% RH, and 85% RH at 40 degrees C and also to (2) 60 degrees C, 80 degrees C, and 100 degrees C at 0% RH. In case of solid samples without stressors, the mixture of polymorphic and amorphous forms showed...... more degradation than the individual forms above critical relative humidity (85% RH). Similar higher degradation was observed between 75% RH and 85% RH in case of acid-stressed samples. In alkaline microenvironment, all the samples showed identical decomposition attributed to conversion of bisulfate...

  7. Functional tomographic fluorescence imaging of pH microenvironments in microbial biofilms by use of silica nanoparticle sensors.

    Science.gov (United States)

    Hidalgo, Gabriela; Burns, Andrew; Herz, Erik; Hay, Anthony G; Houston, Paul L; Wiesner, Ulrich; Lion, Leonard W

    2009-12-01

    Attached bacterial communities can generate three-dimensional (3D) physicochemical gradients that create microenvironments where local conditions are substantially different from those in the surrounding solution. Given their ubiquity in nature and their impacts on issues ranging from water quality to human health, better tools for understanding biofilms and the gradients they create are needed. Here we demonstrate the use of functional tomographic imaging via confocal fluorescence microscopy of ratiometric core-shell silica nanoparticle sensors (C dot sensors) to study the morphology and temporal evolution of pH microenvironments in axenic Escherichia coli PHL628 and mixed-culture wastewater biofilms. Testing of 70-, 30-, and 10-nm-diameter sensor particles reveals a critical size for homogeneous biofilm staining, with only the 10-nm-diameter particles capable of successfully generating high-resolution maps of biofilm pH and distinct local heterogeneities. Our measurements revealed pH values that ranged from 5 to >7, confirming the heterogeneity of the pH profiles within these biofilms. pH was also analyzed following glucose addition to both suspended and attached cultures. In both cases, the pH became more acidic, likely due to glucose metabolism causing the release of tricarboxylic acid cycle acids and CO(2). These studies demonstrate that the combination of 3D functional fluorescence imaging with well-designed nanoparticle sensors provides a powerful tool for in situ characterization of chemical microenvironments in complex biofilms.

  8. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.

    Science.gov (United States)

    Kim-Fuchs, Corina; Le, Caroline P; Pimentel, Matthew A; Shackleford, David; Ferrari, Davide; Angst, Eliane; Hollande, Frédéric; Sloan, Erica K

    2014-08-01

    Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Tumor microenvironment regulates metastasis and metastasis genes of mouse MMTV-PymT mammary cancer cells in vivo.

    Science.gov (United States)

    Werbeck, J L; Thudi, N K; Martin, C K; Premanandan, C; Yu, L; Ostrowksi, M C; Rosol, T J

    2014-07-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment. © The Author(s) 2013.

  10. The Changes of Angiogenesis and Immune Cell Infiltration in the Intra- and Peri-Tumoral Melanoma Microenvironment

    Directory of Open Access Journals (Sweden)

    Vladimir Zidlik

    2015-04-01

    Full Text Available Malignant melanoma (MM urgently needs identification of new markers with better predictive value than currently-used clinical and histological parameters. Cancer cells stimulate the formation of a specialized tumor microenvironment, which reciprocally affects uncontrolled proliferation and migration. However, this microenvironment is heterogeneous with different sub-compartments defined by their access to oxygen and nutrients. This study evaluated microvascular density (MVD, CD3+ lymphocytes (TILs and FOXP3+ T-regulatory lymphocytes (Tregs on formalin-fixed paraffin-embedded tissue sections using light microscopy. We analyzed 82 malignant melanomas, divided according to the AJCC TNM classification into four groups—pT1 (35, pT2 (17, pT3 (18 and pT4 (12—and 25 benign pigmented nevi. All parameters were measured in both the central areas of tumors (C and at their periphery (P. A marked increase in all parameters was found in melanomas compared to nevi (p = 0.0001. There was a positive correlation between MVD, TILs, FOXP3+ Tregs and the vertical growth phase. The results show that MVD, TILs and FOXP3+ Tregs substantially influence cutaneous melanoma microenvironment. We found significant topographic differences of the parameters between central areas of tumors and their boundaries.

  11. GPS-based Microenvironment Tracker (MicroTrac) Model to Estimate Time-Location of Individuals for Air Pollution Exposure Assessments: Model Evaluation in Central North Carolina

    Science.gov (United States)

    A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure...

  12. CCL11 and GM-CSF differentially use the Rho GTPase pathway to regulate motility of human eosinophils in a three-dimensional microenvironment.

    NARCIS (Netherlands)

    Muessel, M.J.; Scott, K.S.; Friedl, P.H.A.; Bradding, P.; Wardlaw, A.J.

    2008-01-01

    Asthma is a common disease that causes considerable morbidity. Increased numbers of airway eosinophils are a hallmark of asthma. Mechanisms controlling the entry of eosinophils into asthmatic lung have been intensively investigated, but factors regulating migration within the tissue microenvironment

  13. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator initiated phase 2 study

    DEFF Research Database (Denmark)

    Niemann, Carsten U; Herman, Sarah E M; Maric, Irina

    2016-01-01

    of tumor cells from the microenvironment. While the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. EXPERIMENTAL DESIGN: Patients received single...... the chemoattraction of CLL cells. CONCLUSIONS: In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the anti-tumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL.......PURPOSE: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress...

  14. [Multifaceted body. I. The bodies of medicine].

    Science.gov (United States)

    Saraga, M; Bourquin, C; Wykretowicz, H; Stiefel, F

    2015-02-11

    The human body is the object upon which medicine is acting, but also lived reality, image, symbol, representation and the object of elaboration and theory. All these elements which constitute the body influence the way medicine is treating it. In this series of three articles, we address the human body from various perspectives: medical (1), phenomenological (2), psychosomatic and socio-anthropological (3). This first article discusses four distinct types of representation of the body within medicine, each related to a specific epistemology and shaping a distinct kind of clinical legitimacy: the body-object of anatomy, the body-machine of physiology, the cybernetic body of biology, the statistical body of epidemiology.

  15. Basal Cell Carcinoma in Gorlin's Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?

    Science.gov (United States)

    Gache, Yannick; Brellier, Florence; Rouanet, Sophie; Al-Qaraghuli, Sahar; Goncalves-Maia, Maria; Burty-Valin, Elodie; Barnay, Stéphanie; Scarzello, Sabine; Ruat, Martial; Sevenet, Nicolas; Avril, Marie-Françoise; Magnaldo, Thierry

    2015-01-01

    Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings

  16. The extracellular matrix niche microenvironment of neural and cancer stem cells in the brain.

    Science.gov (United States)

    Reinhard, Jacqueline; Brösicke, Nicole; Theocharidis, Ursula; Faissner, Andreas

    2016-12-01

    Numerous studies demonstrated that neural stem cells and cancer stem cells (NSCs/CSCs) share several overlapping characteristics such as self-renewal, multipotency and a comparable molecular repertoire. In addition to the intrinsic cellular properties, NSCs/CSCs favor a similar environment to acquire and maintain their characteristics. In the present review, we highlight the shared properties of NSCs and CSCs in regard to their extracellular microenvironment called the NSC/CSC niche. Moreover, we point out that extracellular matrix (ECM) molecules and their complementary receptors influence the behavior of NSCs/CSCs as well as brain tumor progression. Here, we focus on the expression profile and functional importance of the ECM glycoprotein tenascin-C, the chondroitin sulfate proteoglycan DSD-1-PG/phosphacan but also on other important glycoprotein/proteoglycan constituents. Within this review, we specifically concentrate on glioblastoma multiforme (GBM). GBM is the most common malignant brain tumor in adults and is associated with poor prognosis despite intense and aggressive surgical and therapeutic treatment. Recent studies indicate that GBM onset is driven by a subpopulation of CSCs that display self-renewal and recapitulate tumor heterogeneity. Based on the CSC hypothesis the cancer arises just from a small subpopulation of self-sustaining cancer cells with the exclusive ability to self-renew and maintain the tumor. Besides the fundamental stem cell properties of self-renewal and multipotency, GBM stem cells share further molecular characteristics with NSCs, which we would like to review in this article. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. An integrated in vitro imaging platform for characterizing filarial parasite behavior within a multicellular microenvironment.

    Science.gov (United States)

    Kassis, Timothy; Skelton, Henry M; Lu, Iris M; Moorhead, Andrew R; Dixon, J Brandon

    2014-11-01

    Lymphatic Filariasis, a Neglected Tropical Disease, is caused by thread-like parasitic worms, including B. malayi, which migrate to the human lymphatic system following transmission. The parasites reside in collecting lymphatic vessels and lymph nodes for years, often resulting in lymphedema, elephantiasis or hydrocele. The mechanisms driving worm migration and retention within the lymphatics are currently unknown. We have developed an integrated in vitro imaging platform capable of quantifying B. malayi migration and behavior in a multicellular microenvironment relevant to the initial site of worm injection by incorporating the worm in a Polydimethylsiloxane (PDMS) microchannel in the presence of human dermal lymphatic endothelial cells (LECs) and human dermal fibroblasts (HDFs). The platform utilizes a motorized controllable microscope with CO2 and temperature regulation to allow for worm tracking experiments with high resolution over large length and time scales. Using post-acquisition algorithms, we quantified four parameters: 1) speed, 2) thrashing intensity, 3) percentage of time spent in a given cell region and 4) persistence ratio. We demonstrated the utility of our system by quantifying these parameters for L3 B. malayi in the presence of LECs and HDFs. Speed and thrashing increased in the presence of both cell types and were altered within minutes upon exposure to the anthelmintic drug, tetramisole. The worms displayed no targeted migration towards either cell type for the time course of this study (3 hours). When cells were not present in the chamber, worm thrashing correlated directly with worm speed. However, this correlation was lost in the presence of cells. The described platform provides the ability to further study B. malayi migration and behavior.

  18. An integrated in vitro imaging platform for characterizing filarial parasite behavior within a multicellular microenvironment.

    Directory of Open Access Journals (Sweden)

    Timothy Kassis

    2014-11-01

    Full Text Available Lymphatic Filariasis, a Neglected Tropical Disease, is caused by thread-like parasitic worms, including B. malayi, which migrate to the human lymphatic system following transmission. The parasites reside in collecting lymphatic vessels and lymph nodes for years, often resulting in lymphedema, elephantiasis or hydrocele. The mechanisms driving worm migration and retention within the lymphatics are currently unknown. We have developed an integrated in vitro imaging platform capable of quantifying B. malayi migration and behavior in a multicellular microenvironment relevant to the initial site of worm injection by incorporating the worm in a Polydimethylsiloxane (PDMS microchannel in the presence of human dermal lymphatic endothelial cells (LECs and human dermal fibroblasts (HDFs. The platform utilizes a motorized controllable microscope with CO2 and temperature regulation to allow for worm tracking experiments with high resolution over large length and time scales. Using post-acquisition algorithms, we quantified four parameters: 1 speed, 2 thrashing intensity, 3 percentage of time spent in a given cell region and 4 persistence ratio. We demonstrated the utility of our system by quantifying these parameters for L3 B. malayi in the presence of LECs and HDFs. Speed and thrashing increased in the presence of both cell types and were altered within minutes upon exposure to the anthelmintic drug, tetramisole. The worms displayed no targeted migration towards either cell type for the time course of this study (3 hours. When cells were not present in the chamber, worm thrashing correlated directly with worm speed. However, this correlation was lost in the presence of cells. The described platform provides the ability to further study B. malayi migration and behavior.

  19. Transgenic nude mice ubiquitously expressing fluorescent proteins for color-coded imaging of the tumor microenvironment.

    Science.gov (United States)

    Hoffman, Robert M

    2014-01-01

    We have developed a transgenic green fluorescent protein (GFP) nude mouse with ubiquitous GFP expression. The GFP nude mouse was obtained by crossing nontransgenic nude mice with the transgenic C57/B6 mouse in which the β-actin promoter drives GFP expression in essentially all tissues. In the adult mice, many organs brightly expressed GFP, including the spleen, heart, lungs, spleen, pancreas, esophagus, stomach, and duodenum as well as the circulatory system. The liver expressed GFP at a lesser level. The red fluorescent protein (RFP) transgenic nude mouse was obtained by crossing non-transgenic nude mice with the transgenic C57/B6 mouse in which the beta-actin promoter drives RFP (DsRed2) expression in essentially all tissues. In the RFP nude mouse, the organs all brightly expressed RFP, including the heart, lungs, spleen, pancreas, esophagus, stomach, liver, duodenum, the male and female reproductive systems; brain and spinal cord; and the circulatory system, including the heart, and major arteries and veins. The skinned skeleton highly expressed RFP. The bone marrow and spleen cells were also RFP positive. The cyan fluorescent protein (CFP) nude mouse was developed by crossing nontransgenic nude mice with the transgenic CK/ECFP mouse in which the β-actin promoter drives expression of CFP in almost all tissues. In the CFP nude mice, the pancreas and reproductive organs displayed the strongest fluorescence signals of all internal organs, which vary in intensity. The GFP, RFP, and CFP nude mice when transplanted with cancer cells of another color are powerful models for color-coded imaging of the tumor microenvironment (TME) at the cellular level.

  20. CCR1-mediated accumulation of myeloid cells in the liver microenvironment promoting mouse colon cancer metastasis.

    Science.gov (United States)

    Hirai, Hideyo; Fujishita, Teruaki; Kurimoto, Kazuki; Miyachi, Hitoshi; Kitano, Satsuki; Inamoto, Susumu; Itatani, Yoshiro; Saitou, Mitinori; Maekawa, Taira; Taketo, M Mark

    2014-12-01

    To understand colon cancer metastasis, we earlier analyzed a mouse model that developed liver metastasis of cancer cells disseminated from the spleen. We suggested that CCR1(+) bone marrow (BM)-derived cells are recruited to the microenvironment of disseminated colon cancer cells, and produce metalloproteinases MMP9 and MMP2, helping metastatic colonization. In the present study, we have examined these myeloid cells expressing CCR1 and/or MMPs in detail. To this end, we have established bacterial artificial chromosome (BAC)-based transgenic mouse lines in which membrane-targeted Venus fluorescent protein (mVenus) was expressed under the control of Ccr1 gene promoter. Then, myeloid cells obtained from the BM and liver metastatic foci were analyzed by the combination of flow cytometry and cytology/immunohistochemistry, in situ RNA hybridization, or quantitative RT-PCR. We have found four distinct types of myeloid cells recruited to the metastatic foci; neutrophils, eosinophils, monocytes and fibrocytes. These cell types exhibited distinct expression patterns for CCR1, MMP2 and MMP9. Namely, neutrophils found in the early phase of cancer cell dissemination expressed CCR1 exclusively and MMP9 preferentially, whereas fibrocytes accumulated in later phase expressed MMP2 exclusively. Either genetic inactivation of Ccr1 or antibody-mediated neutrophil depletion reduced subsequent recruitment of fibrocytes. The recruitment of CCR1(+) neutrophils in early phase of colon cancer dissemination appears to cause that of fibrocytes in late phase. These results implicate the key role of CCR1 in colon cancer metastasis in this mouse model, and explain why both MMP9 and MMP2 are essential as genetically demonstrated previously. The results also suggest relevant mechanisms in humans.

  1. The Role of Butylidenephthalide in Targeting Microenvironment Contributes to the Ameliorate of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Hong-Meng eChuang

    2016-04-01

    Full Text Available The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial–mesenchymal transition (EMT promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 weeks and 4 weeks, which resulted in a significantly reduced fibrosis score (p<0.05 and (p<0.001, respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-β, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.

  2. The effects of aging on the molecular and cellular composition of the prostate microenvironment.

    Directory of Open Access Journals (Sweden)

    Daniella Bianchi-Frias

    2010-09-01

    Full Text Available Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia (BPH and prostate carcinoma. The prostate is comprised of a functional secretory epithelium, a basal epithelium, and a supporting stroma comprised of structural elements, and a spectrum of cell types that includes smooth muscle cells, fibroblasts, and inflammatory cells. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stroma could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology.We quantitated transcript levels in microdissected glandular-adjacent stroma from young (age 4 months and old (age 20-24 months C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05. These included increases in transcripts encoding proteins associated with inflammation (e.g., Ccl8, Ccl12, genotoxic/oxidative stress (e.g., Apod, Serpinb5 and other paracrine-acting effects (e.g., Cyr61. The expression of several collagen genes (e.g., Col1a1 and Col3a1 exhibited age-associated declines. By histology, immunofluorescence, and electron microscopy we determined that the collagen matrix is abundant and disorganized, smooth muscle cell orientation is disordered, and inflammatory infiltrates are significantly increased, and are comprised of macrophages, T cells and, to a lesser extent, B cells.These findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate.

  3. Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment

    Science.gov (United States)

    Arena, Vincenzo; Arena, Manuel; Arena, Goffredo Orazio

    2017-01-01

    The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity in vitro and in vivo. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells. PMID:28068409

  4. Genomic Analysis of Tumor Microenvironment Immune Types across 14 Solid Cancer Types: Immunotherapeutic Implications.

    Science.gov (United States)

    Chen, Yu-Pei; Zhang, Yu; Lv, Jia-Wei; Li, Ying-Qin; Wang, Ya-Qin; He, Qing-Mei; Yang, Xiao-Jing; Sun, Ying; Mao, Yan-Ping; Yun, Jing-Ping; Liu, Na; Ma, Jun

    2017-01-01

    We performed a comprehensive immuno-genomic analysis of tumor microenvironment immune types (TMITs), which is classified into four groups based on PD-L1+CD8A or PD-L1+cytolytic activity (CYT) expression, across a broad spectrum of solid tumors in order to help identify patients who will benefit from anti- PD-1/PD-L1 therapy. The mRNA sequencing data from The Cancer Genome Atlas (TCGA) of 14 solid cancer types representing 6,685 tumor samples was analyzed. TMIT was classified only for those tumor types that both PD-L1 and CD8A/CYT could prefict mutation and/or neoantigen number. The mutational and neoepitope features of the tumor were compared according to the four TMITs. We found that PD-L1/CD8A/CYT subgroups could not distinguish different mutation and neoantigen numbers in certain tumor types such as glioblastoma multiforme, prostate adenocarcinoma, and head and neck and lung squamous cell carcinoma. For the remaining tumor types, compared with TIMT II (low PD-L1 and CD8A/CYT), TIMT I (high PD-L1 and CD8A/CYT) had a significantly higher number of mutations or neoantigens in bladder urothelial carcinoma, breast and cervical cancer, colorectal, stomach and lung adenocarcinoma, and melanoma. In contrast, TMIT I of kidney clear cell, liver hepatocellular, and thyroid carcinoma were negatively correlated with mutation burden or neoantigen numbers. Our findings show that the TMIT stratification proposed could serve as a favorable approach for tailoring optimal immunotherapeutic strategies in certain tumor types. Going forward, it will be important to test the clinical practicability of TMIT based on quantification of immune infiltrates using mRNA-seq to predict clinical response to these and other immunotherapeutic strategies in more different tumors.

  5. Exosome-Based Cell-Cell Communication in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Joana Maia

    2018-02-01

    Full Text Available Tumors are not isolated entities, but complex systemic networks involving cell-cell communication between transformed and non-transformed cells. The milieu created by tumor-associated cells may either support or halt tumor progression. In addition to cell-cell contact, cells communicate through secreted factors via a highly complex system involving characteristics such as ligand concentration, receptor expression and integration of diverse signaling pathways. Of these, extracellular vesicles, such as exosomes, are emerging as novel cell-cell communication mediators in physiological and pathological scenarios. Exosomes, membrane vesicles of endocytic origin released by all cells (both healthy and diseased, ranging in size from 30 to 150 nm, transport all the main biomolecules, including lipids, proteins, DNAs, messenger RNAs and microRNA, and perform intercellular transfer of components, locally and systemically. By acting not only in tumor cells, but also in tumor-associated cells such as fibroblasts, endothelium, leukocytes and progenitor cells, tumor- and non-tumor cells-derived exosomes have emerged as new players in tumor growth and invasion, tumor-associated angiogenesis, tissue inflammation and immunologic remodeling. In addition, due to their property of carrying molecules from their cell of origin to the peripheral circulation, exosomes have been increasingly studied as sources of tumor biomarkers in liquid biopsies. Here we review the current literature on the participation of exosomes in the communication between tumor and tumor-associated cells, highlighting the role of this process in the setup of tumor microenvironments that modulate tumor initiation and metastasis.

  6. The co-effect of organic matrix from carp otolith and microenvironment on calcium carbonate mineralization.

    Science.gov (United States)

    Ren, Dongni; Feng, Qingling; Bourrat, Xavier

    2013-08-01

    In vitro mineralization experiment is an effective way to study the effect of organic matrix on calcium carbonate crystallization, and to reveal the relationship between organic matrix and inorganic crystal in natural biominerals. In natural biominerals, organic matrix plays an important role in crystal formation and stability, together with microenvironment changes, they can affect crystal polymorph, morphology, density, size, orientation etc. In this work, we systematically studied the effects of different organic matrices in fish otoliths, the organic matrix concentration changes, as well as the co-effect of organic matrices with temperature, pH value and Mg ion changes in the in vitro CaCO3 mineralization experiments. The organic matrix and concentration change experiments prove that water soluble matrix (WSM) plays an important role in crystal form transition. It can induce CaCO3 crystals with same crystal polymorph as the otolith from which organic matrix was extracted. The temperature change experiment proves that CaCO3 has a tendency to form calcite, vaterite, and then aragonite in priority as temperature goes up. Under different temperature, WSM from lapillus/asteriscus still has the effect to mediate different CaCO3 crystals. The pH change experiment shows that, near the neutral environment, as pH value goes up, calcites have a tendency to form crystal aggregates with more faces exposed, the organic matrix still keeps crystal mediation effect. The Mg(2+) experiment shows that, Mg ion can promote aragonite formation, together with lapillus organic matrix, aragonites with different shapes are formed. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Bromelain ameliorates the wound microenvironment and improves the healing of firearm wounds.

    Science.gov (United States)

    Wu, Si-Yu; Hu, Wei; Zhang, Bo; Liu, Shuai; Wang, Jian-Min; Wang, Ai-Min

    2012-08-01

    In a previous study, we proposed a new therapy using topical bromelain as a supplement to simple wound-track incision for the debridement of firearm wounds. This enzymatic debridement greatly simplified the management of high-velocity gunshot wounds in a pig model, and bromelain was confirmed to improve wound healing. The purpose of the present study was to investigate the effect of bromelain on the microenvironment of firearm wounds. Sixteen Chinese landrace pigs wounded by high-velocity projectiles were divided randomly into four groups: wound incision (group I), incision + bromelain (group IB), wound excision (group E), and control. Blood perfusion, oxygen partial pressure (pO(2)), and the content of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β in wound-track tissue were measured. Wound healing was also noted. The recovery of blood perfusion in tissue and pO(2) in wound tracks was significantly more rapid in group IB and group E than in group I and control. The tissue level of TNF-α was significantly lower in group IB than in group I and control 48 h and 72 h post-wounding, and was lower than in group E 48 h post-wounding. The tissue level of TGF-β in group IB was sustained at a significantly higher level than in the other three groups. Wound healing time was also shorter in group IB. Enzymatic debridement using topical bromelain in incised wound tracks accelerates the recovery of blood perfusion, pO(2) in wound tissue, controls the expression of TNF-α and raises the expression of TGF-β. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. On-road PM2.5 pollution exposure in multiple transport microenvironments in Delhi

    Science.gov (United States)

    Goel, Rahul; Gani, Shahzad; Guttikunda, Sarath K.; Wilson, Daniel; Tiwari, Geetam

    2015-12-01

    PM2.5 pollution in Delhi averaged 150 μg/m3 from 2012 through 2014, which is 15 times higher than the World Health Organization's annual-average guideline. For this setting, we present on-road exposure of PM2.5 concentrations for 11 transport microenvironments along a fixed 8.3-km arterial route, during morning rush hour. The data collection was carried out using a portable TSI DustTrak DRX 8433 aerosol monitor, between January and May (2014). The monthly-average measured ambient concentrations varied from 130 μg/m3 to 250 μg/m3. The on-road PM2.5 concentrations exceeded the ambient measurements by an average of 40% for walking, 10% for cycle, 30% for motorised two wheeler (2W), 30% for open-windowed (OW) car, 30% for auto rickshaw, 20% for air-conditioned as well as for OW bus, 20% for bus stop, and 30% for underground metro station. On the other hand, concentrations were lower by 50% inside air-conditioned (AC) car and 20% inside the metro rail carriage. We find that the percent exceedance for open modes (cycle, auto rickshaw, 2W, OW car, and OW bus) reduces non-linearly with increasing ambient concentration. The reduction is steeper at concentrations lower than 150 μg/m3 than at higher concentrations. After accounting for air inhalation rate and speed of travel, PM2.5 mass uptake per kilometer during cycling is 9 times of AC car, the mode with the lowest exposure. At current level of concentrations, an hour of cycling in Delhi during morning rush-hour period results in PM2.5 dose which is 40% higher than an entire-day dose in cities like Tokyo, London, and New York, where ambient concentrations range from 10 to 20 μg/m3.

  9. Engineering the human pluripotent stem cell microenvironment to direct cell fate.

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    Hazeltine, Laurie B; Selekman, Joshua A; Palecek, Sean P

    2013-11-15

    Human pluripotent stem cells (hPSCs), including both embryonic stem cells and induced pluripotent stem cells, offer a potential cell source for research, drug screening, and regenerative medicine applications due to their unique ability to self-renew or differentiate to any somatic cell type. Before the full potential of hPSCs can be realized, robust protocols must be developed to direct their fate. Cell fate decisions are based on components of the surrounding microenvironment, including soluble factors, substrate or extracellular matrix, cell-cell interactions, mechanical forces, and 2D or 3D architecture. Depending on their spatio-temporal context, these components can signal hPSCs to either self-renew or differentiate to cell types of the ectoderm, mesoderm, or endoderm. Researchers working at the interface of engineering and biology have identified various factors which can affect hPSC fate, often based on lessons from embryonic development, and they have utilized this information to design in vitro niches which can reproducibly direct hPSC fate. This review highlights culture systems that have been engineered to promote self-renewal or differentiation of hPSCs, with a focus on studies that have elucidated the contributions of specific microenvironmental cues in the context of those culture systems. We propose the use of microsystem technologies for high-throughput screening of spatial-temporal presentation of cues, as this has been demonstrated to be a powerful approach for differentiating hPSCs to desired cell types. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment.

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    Munjal M Acharya

    Full Text Available The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy, few studies have been conducted at much lower doses (≤ 2 Gy, where the response of the CNS (like many other tissues may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.

  11. Microtubules are reversibly depolymerized in response to changing gaseous microenvironments within Aspergillus nidulans biofilms.

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    Shukla, Nandini; Osmani, Aysha H; Osmani, Stephen A

    2017-03-01

    How microtubules (MTs) are regulated during fungal biofilm formation is unknown. By tracking MT +end-binding proteins (+TIPS) in Aspergillus nidulans, we find that MTs are regulated to depolymerize within forming fungal biofilms. During this process, EB1, dynein, and ClipA form transient fibrous and then bar-like structures, novel configurations for +TIPS. Cells also respond in an autonomous manner, with cells separated by a septum able to maintain different MT dynamics. Surprisingly, all cells with depolymerized MTs rapidly repolymerize their MTs after air exchange above the static culture medium of biofilms. Although the specific gasotransmitter for this biofilm response is not known, we find that addition of hydrogen sulfide gas to growing cells recapitulates all aspects of reversible MT depolymerization and transient formation of +TIPs bars. However, as biofilms mature, physical removal of part of the biofilm is required to promote MT repolymerization, which occurs at the new biofilm edge. We further show MT depolymerization within biofilms is regulated by the SrbA hypoxic transcription factor and that without SrbA, MTs are maintained as biofilms form. This reveals a new mode of MT regulation in response to changing gaseous biofilm microenvironments, which could contribute to the unique characteristics of fungal biofilms in medical and industrial settings. © 2017 Shukla et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  12. The breast cancer incidence risk among females and a hazards in the microenvironments of work

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    Brunon Zemła

    2014-06-01

    Full Text Available Background. In the earlier examinations on the Silesia voivodeship territory was found ultimately that in the districts with greatest development of industry the incidence of breast cancer was significantly greater in native females (stationary population than in immigrants (no stationary population, which suggests that there is a harmful influence of industrial pollutants in the female population (a longer time living in such conditions. It is possible that various chemical compounds especially from industrial-communal emissions and in the place of work – in the atmosphere contribute to a rise in the incidence of breast cancer in females as well. Material and methods. In analyse case-control type two women populations, i.e. natives – 540 cases with a breast cancer and 687 cases of control (women born within Silesia voivodeship, and immigrants – 319 cases of ills for breast cancer and 446 not-ills (all ones born outside Silesia voivodeship – were examinated. Anywhere in this case checking thesis whether character and long-time of hazards in microenvironment of work is significant in a risk of breast cancer. Results. The females that manually working without hazards in the place of work were characterized a bigger breast cancer risk – independently from place of birth (natives, immigrants, age group (30, 31–40, 41–50, 51–60, 60 and total age and the endemic areas about statistically significantly high or low incidence and mortality (tab. II, III. It can not distinguished in this study no bigger females group with any characteristic impurities in the place of work comparatively suffering groups to controls ones. Conclusions. In this study the occupational risk factors are small significant mark in the incidence for female breast cancer.

  13. Functional Interference in the Bone Marrow Microenvironment by Disseminated Breast Cancer Cells.

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    Dhawan, Abhishek; von Bonin, Malte; Bray, Laura J; Freudenberg, Uwe; Pishali Bejestani, Elham; Werner, Carsten; Hofbauer, Lorenz C; Wobus, Manja; Bornhäuser, Martin

    2016-08-01

    Skeletal metastasis of breast cancer is associated with a poor prognosis and significant morbidity. Investigations in other solid tumors have revealed an impairment in hematopoietic function upon bone marrow invasion. However, the interaction between disseminated breast cancer cells and the bone marrow microenvironment which harbors them has not been addressed comprehensively. Employing advanced co-culture assays, proteomic studies, organotypic models as well as in vivo xenotransplant models, we define the consequences of this interaction on the stromal compartment of bone marrow, affected molecular pathways and subsequent effects on the hematopoietic stem and progenitor cells (HSPCs). The results showed a basic fibroblast growth factor (bFGF)-mediated, synergistic increase in proliferation of breast cancer cells and mesenchymal stromal cells (MSCs) in co-culture. The stromal induction was associated with elevated phosphoinositide-3 kinase (PI3K) signaling in the stroma, which coupled with elevated bFGF levels resulted in increased migration of breast cancer cells towards the MSCs. The perturbed cytokine profile in the stroma led to reduction in the osteogenic differentiation of MSCs via downregulation of platelet-derived growth factor-BB (PDGF-BB). Long term co-cultures of breast cancer cells, HSPCs, MSCs and in vivo studies in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice showed a reduced support for HSPCs in the altered niche. The resultant non- conducive phenotype of the niche for HSPC support emphasizes the importance of the affected molecular pathways in the stroma as clinical targets. These findings can be a platform for further development of therapeutic strategies aiming at the blockade of bone marrow support to disseminated breast cancer cells. Stem Cells 2016;34:2224-2235. © 2016 AlphaMed Press.

  14. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

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    Borsi, Enrica, E-mail: enrica.borsi2@unibo.it [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy); Perrone, Giulia [Fondazione IRCCS Istituto Nazionale dei Tumori, Hematology Department, Via Venezian 1, 20133 Milano (Italy); Terragna, Carolina; Martello, Marina; Zamagni, Elena; Tacchetti, Paola; Pantani, Lucia; Brioli, Annamaria; Dico, Angela Flores; Zannetti, Beatrice Anna; Rocchi, Serena; Cavo, Michele [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy)

    2014-11-01

    Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma. - Highlights: • HIF-1α inhibition induces a mild apoptotic cell death. • Down-modulation of cytokine-induced signaling cascades upon HIF-1α inhibition. • Reduced interaction between MM cells and BMSCs upon HIF-1α down-modulation. • Reduced PCs adhesion to the extracellular matrix protein induced by EZN-2968. • HIF-1α inhibition may be an attractive therapeutic strategy for Multiple Myeloma.

  15. Protein Kinase C beta in the tumor microenvironment promotes mammary tumorigenesis

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    Julie A Wallace

    2014-04-01

    Full Text Available Protein kinase C beta (PKCβ expression in breast cancer is associated with a more aggressive tumor phenotype, yet the mechanism for how PKCβ is pro-tumorigenic in this disease is still unclear. Interestingly, while it is known that PKCβ mediates angiogenesis, immunity, fibroblast function and adipogenesis, all components of the mammary tumor microenvironment (TME, no study to date has investigated whether stromal PKCβ is functionally relevant in breast cancer. Herein, we evaluate mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT induced mammary tumorigenesis in the presence and absence of PKCβ. We utilize two model systems: one where PKCβ is deleted in both the epithelial and stromal compartments to test the global requirement for PKCβ on tumor formation, and second, where PKCβ is deleted only in the stromal compartment to test its role in the TME. MMTV-PyMT mice globally lacking PKCβ live longer and develop smaller tumors with decreased proliferation and decreased macrophage infiltration. Similarly, when PKCβ is null exclusively in the stroma, PyMT-driven B6 cells form smaller tumors. These experiments reveal for the first time a tumor promoting role for stromal PKCβ in MMTV-PyMT tumorigenesis. In corroboration with these results, PKCβ mRNA (Prkcb is increased in fibroblasts isolated from MMTV-PyMT tumors. These data were confirmed in a breast cancer patient cohort. Combined these data suggest the continued investigation of PKCβ in the mammary TME is necessary to elucidate how to effectively target this signaling pathway in breast cancer.

  16. Protein kinase C Beta in the tumor microenvironment promotes mammary tumorigenesis.

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    Wallace, Julie A; Pitarresi, Jason R; Sharma, Nandini; Palettas, Marilly; Cuitiño, Maria C; Sizemore, Steven T; Yu, Lianbo; Sanderlin, Allen; Rosol, Thomas J; Mehta, Kamal D; Sizemore, Gina M; Ostrowski, Michael C

    2014-01-01

    Protein kinase C beta (PKCβ) expression in breast cancer is associated with a more aggressive tumor phenotype, yet the mechanism for how PKCβ is pro-tumorigenic in this disease is still unclear. Interestingly, while it is known that PKCβ mediates angiogenesis, immunity, fibroblast function and adipogenesis, all components of the mammary tumor microenvironment (TME), no study to date has investigated whether stromal PKCβ is functionally relevant in breast cancer. Herein, we evaluate mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) induced mammary tumorigenesis in the presence and absence of PKCβ. We utilize two model systems: one where PKCβ is deleted in both the epithelial and stromal compartments to test the global requirement for PKCβ on tumor formation, and second, where PKCβ is deleted only in the stromal compartment to test its role in the TME. MMTV-PyMT mice globally lacking PKCβ live longer and develop smaller tumors with decreased proliferation and decreased macrophage infiltration. Similarly, when PKCβ is null exclusively in the stroma, PyMT-driven B6 cells form smaller tumors with diminished collagen deposition. These experiments reveal for the first time a tumor promoting role for stromal PKCβ in MMTV-PyMT tumorigenesis. In corroboration with these results, PKCβ mRNA (Prkcb) is increased in fibroblasts isolated from MMTV-PyMT tumors. These data were confirmed in a breast cancer patient cohort. Combined these data suggest the continued investigation of PKCβ in the mammary TME is necessary to elucidate how to effectively target this signaling pathway in breast cancer.

  17. Increased asymmetric and multi-daughter cell division in mechanically confined microenvironments.

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    Henry Tat Kwong Tse

    Full Text Available As the microenvironment of a cell changes, associated mechanical cues may lead to changes in biochemical signaling and inherently mechanical processes such as mitosis. Here we explore the effects of confined mechanical environments on cellular responses during mitosis. Previously, effects of mechanical confinement have been difficult to optically observe in three-dimensional and in vivo systems. To address this challenge, we present a novel microfluidic perfusion culture system that allows controllable variation in the level of confinement in a single axis allowing observation of cell growth and division at the single-cell level. The device is capable of creating precise confinement conditions in the vertical direction varying from high (3 µm to low (7 µm confinement while also varying the substrate stiffness (E = 130 kPa and 1 MPa. The Human cervical carcinoma (HeLa model with a known 3N+ karyotype was used for this study. For this cell line, we observe that mechanically confined cell