WorldWideScience

Sample records for tumour cell migration

  1. APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner.

    Science.gov (United States)

    Yi, Yuyin; Tsai, Shu-Huei; Cheng, Jung-Chien; Wang, Evan Y; Anglesio, Michael S; Cochrane, Dawn R; Fuller, Megan; Gibb, Ewan A; Wei, Wei; Huntsman, David G; Karsan, Aly; Hoodless, Pamela A

    2017-12-01

    APELA is a small, secreted peptide that can function as a ligand for the G-protein coupled receptor, Apelin Receptor (APLNR, APJ). APELA plays an essential role in endoderm differentiation and cardiac development during embryogenesis. We investigated whether APELA exerts any functions in cancer progression. The Cancer Genome Atlas (TCGA) RNA sequencing datasets, microarray from an OCCC mouse model, and RNA isolated from fresh frozen and FFPE patient tissue were used to assess APELA expression. APELA knockout ovarian clear cell carcinoma (OCCC) cell lines were generated using CRISPR/Cas9. APELA was expressed in various ovarian cancer histotypes and was especially elevated in OCCC. Disruption of APELA expression in OCCC cell lines suppressed cell growth and migration, and altered cell-cycle progression. Moreover, addition of human recombinant APELA peptide to the OCCC cell line OVISE promoted cell growth and migration. Interestingly, OVISE cells do not express APLNR, suggesting that APELA can function through an APLNR-independent pathway. Furthermore, APELA affected cell growth and cell cycle progression in a p53-dependent manner. In addition, APELA knockdown induced p53 expression in cancer cell lines. Our findings uncover a potential oncogenic role for APELA in promoting ovarian tumour progression and provide a possible therapeutic strategy in ovarian cancer by targeting APELA. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour

    NARCIS (Netherlands)

    van der Meulen, A. A. E.; Biber, K.; Lukovac, S.; Balasubramaniyan, V.; den Dunnen, W. F. A.; Boddeke, H. W. G. M.; Mooij, J. J. A.

    2009-01-01

    Aims: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved

  3. Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization.

    Science.gov (United States)

    Benslimane-Ahmim, Zahia; Pereira, Jessica; Lokajczyk, Anna; Dizier, Blandine; Galy-Fauroux, Isabelle; Fischer, Anne-Marie; Heymann, Dominique; Boisson-Vidal, Catherine

    2017-06-01

    We previously reported that OPG is involved in ischemic tissue neovascularization through the secretion of SDF-1 by pretreated-OPG endothelial colony-forming cells (ECFCs). As the vascularization is one of the key factor influencing the tumour growth and cancer cell dissemination, we investigated whether OPG was able to modulate the invasion of human MNNG-HOS osteosarcoma and DU145 prostate cancer cell lines in vitro and in vivo. Cell motility was analysed in vitro by using Boyden chambers. Human GFP-labelled MMNG-HOS cells were inoculated in immunodeficient mice and the tumour nodules formed were then injected with OPG and/or FGF-2, AMD3100 or 0.9% NaCl (control group). Tumour growth was manually followed and angiogenesis was assessed by immunohistochemistry. In vitro, SDF-1 released by OPG-pretreated ECFCs markedly attracted both MNNG-HOS and DU145 cells and induced spontaneous migration of cancer cells. In vivo, tumour volumes were significantly increased in OPG-treated group compared to the control group and OPG potentiated the effect of FGF-2. Concomitantly, OPG alone or combined with FGF-2 increased the number of new vasculature compared to the control group. Interestingly AMD3100, an inhibitor of SDF-1, prevented the in vivo effects of OPG induced by SDF-1 This study provides experimental evidence that OPG promotes tumour development trough SDF-1/CXCR4 axis. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Saponins extracted from by-product of Asparagus officinalis L. suppress tumour cell migration and invasion through targeting Rho GTPase signalling pathway.

    Science.gov (United States)

    Wang, Jieqiong; Liu, Yali; Zhao, Jingjing; Zhang, Wen; Pang, Xiufeng

    2013-04-01

    The inedible bottom part (~30-40%) of asparagus (Asparagus officinalis L.) spears is usually discarded as waste. However, since this by-product has been reported to be rich in many bioactive phytochemicals, it might be utilisable as a supplement in foods or natural drugs for its therapeutic effects. In this study it was identifed that saponins from old stems of asparagus (SSA) exerted potential inhibitory activity on tumour growth and metastasis. SSA suppressed cell viability of breast, colon and pancreatic cancers in a concentration-dependent manner, with half-maximum inhibitory concentrations ranging from 809.42 to 1829.96 µg mL(-1). However, SSA was more functional in blocking cell migration and invasion as compared with its cytotoxic effect, with an effective inhibitory concentration of 400 µg mL(-1). A mechanistic study showed that SSA markedly increased the activities of Cdc42 and Rac1 and decreased the activity of RhoA in cancer cells. SSA inhibits tumour cell motility through modulating the Rho GTPase signalling pathway, suggesting a promising use of SSA as a supplement in healthcare foods and natural drugs for cancer prevention and treatment. © 2012 Society of Chemical Industry.

  5. Assessment of the proliferation status of glioblastoma cell and tumour tissue after nanoplatinum treatment

    DEFF Research Database (Denmark)

    Kutwin, Marta; Sawosz, Ewa; Jaworski, Slawomir

    2017-01-01

    Glioblastoma is one of the most frequent primary brain tumours of the central nervous system, with a poor survival time. With inefficient chemotherapy, it is urgent to develop new strategies for tumour therapy. The present approach is based on the inhibition of cell proliferation using platinum...... morphology, the level of DNA synthesis, the migration of cells, protein expression levels of proliferating cell nuclear antigen (PCNA) and the level of DNA oxidation in glioma tumours were investigated. The results showed that NP-Pt treatment of U87 and U118 glioma cells decreased the level of DNA synthesis...... and the migration of cancer cells but also downregulated the level of PCNA protein expression in tumour tissue. Furthermore, NP-Pt caused oxidative DNA damage in tumour tissue to a higher degree than cisplatin. Consequently, NP-Pt can be considered as an effective inhibitor of glioblastoma tumour cell proliferation...

  6. Cooperative tumour cell membrane targeted phototherapy

    Science.gov (United States)

    Kim, Heegon; Lee, Junsung; Oh, Chanhee; Park, Ji-Ho

    2017-06-01

    The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane-selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer.

  7. Red blood cells inhibit tumour cell adhesion to the peritoneum.

    Science.gov (United States)

    van Rossen, M E; Stoop, M P; Hofland, L J; van Koetsveld, P M; Bonthuis, F; Jeekel, J; Marquet, R L; van Eijck, C H

    1999-04-01

    Perioperative blood transfusion has been associated with increased tumour recurrence and poor prognosis in colorectal cancer. Blood loss in the peritoneal cavity might be a tumour-promoting factor for local recurrence. The aim of this study was to investigate whether blood in the peritoneal cavity affects local tumour recurrence. In an established in vivo rat model the effect of 1.5 ml syngeneic whole blood on tumour cell adhesion and tumour growth was investigated. In the same model the effect of 1.5 ml pure red blood cell (RBC) concentrate and 1.5 ml RBC-derived substances on tumour cell adhesion was studied. In an established in vitro model the effect of increasing numbers of RBCs (0-250 bx 10(6)) on tumour cell adhesion and tumour growth was assessed. Both the presence of blood and RBC concentrate in the peritoneal cavity prevented tumour cell adhesion in vivo (overall P effect on tumour cell adhesion. In in vitro studies RBCs inhibited tumour cell adhesion but not tumour growth. RBC-derived factors prevent tumour cell adhesion to the peritoneum, and consequently tumour recurrence.

  8. Low tumour cell content in a lung tumour bank: implications for molecular characterisation.

    Science.gov (United States)

    Goh, Felicia; Duhig, Edwina E; Clarke, Belinda E; McCaul, Elizabeth; Passmore, Linda; Courtney, Deborah; Windsor, Morgan; Naidoo, Rishendren; Franz, Louise; Parsonson, Kylie; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

    2017-10-01

    Lung cancer encompasses multiple malignant epithelial tumour types, each with specific targetable, potentially actionable mutations, such that precision management mandates accurate tumour typing. Molecular characterisation studies require high tumour cell content and low necrosis content, yet lung cancers are frequently a heterogeneous mixture of tumour and stromal cells. We hypothesised that there may be systematic differences in tumour cell content according to histological subtype, and that this may have implications for tumour banks as a resource for comprehensive molecular characterisation studies in lung cancer. To investigate this, we estimated tumour cell and necrosis content of 4267 samples resected from 752 primary lung tumour specimens contributed to a lung tissue bank. We found that banked lung cancer samples had low tumour cell content (33%) generally, although it was higher in carcinoids (77.5%) than other lung cancer subtypes. Tumour cells comprise a variable and often small component of banked resected tumour samples, and are accompanied by stromal reaction, inflammation, fibrosis, and normal structures. This has implications for the adequacy of unselected tumour bank samples for diagnostic and molecular investigations, and further research is needed to determine whether tumour cell content has a significant impact on analytical results in studies using tissue from tumour bank resources. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  9. Neutrophil-induced transmigration of tumour cells treated with tumour-conditioned medium is facilitated by granulocyte-macrophage colony-stimulating factor.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    OBJECTIVE: To investigate the effect of different cytokines that are present in tumour-conditioned medium on human neutrophil (PMN)-induced tumour cell transmigration. DESIGN: Laboratory study. SETTING: University hospital, Ireland. MATERIAL: Isolated human PMN and cultured human breast tumour cell line, MDA-MB-231. Interventions: Human PMN treated with either tumour-conditioned medium or different media neutralised with monoclonal antibodies (MoAb), and MDA-MB-231 cells were plated on macrovascular and microvascular endothelial monolayers in collagen-coated transwells to assess migration of tumour cells. MAIN OUTCOME MEASURES: Cytokines present in tumour-conditioned medium, PMN cytocidal function and receptor expression, and tumour cell transmigration. RESULTS: tumour-conditioned medium contained high concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8), but not granulocyte colony-stimulating factor (G-CSF) and interleukin 3 (IL-3). Anti-GM-CSF MoAb significantly reduced PMN-induced transmigration of tumour cells treated with tumour-conditioned medium (p < 0.05), whereas anti-VEGF and anti-IL-8 MoAbs did not affect their migration. In addition, anti-GM-CSF MoAb, but not anti-VEGF or anti-IL-8 MoAb, reduced PMN CD11b and CD18 overexpression induced by tumour-conditioned medium (p < 0.05). CONCLUSION: These results indicate that the GM-CSF that is present in tumour-conditioned medium may be involved, at least in part, in alterations in PMN function mediated by the medium and subsequently PMN-induced transmigration of tumour cells.

  10. Tumour markers in germ cell tumours and thyroid cancer

    International Nuclear Information System (INIS)

    Mann, K.

    1988-01-01

    In patients with germ cell tumours of gonadal and extragonadal origin both markers, human chorionic gonadotropin (hCG) and alphafetoprotein (AFP) are madatory for diagnosis and control of treatment. In seminoma, we found preoperatively elevated levels of hCG(+hCG-β) in 42/349 patients (12%) up to 1200 mlU/ml using a polyclonal radioimmunoassay (1. IRP hCG standard 75/537). Lactatedehydrogenase can be useful in marker negative patients. Serum levels reflect tumour burden even if not highly specific. Presently, placental alkaline phosphatase is under discussion for seminoma. However, commercial kits are not available. As a relatively high secretion of hCG/β/hCG was found in gestational trophoblastic diseases, this parameters may be useful for differential diagnosis in pregnancy. In the follow-up of patients with differentiated thyroid carcinoma the determination of thyroglobulin (Tg) in combination with ultrasound of the thyroid and X-ray of the chest is sufficient. For Tg-determination thyroid hormone replacement therapy must be discontinued only in rare single cases with borderline levels, which need radioiodtesting additionally. Calcitonin is the most important marker in medullary thyroid carcinoma. Pentagastrin stimulated calcitonin as screening test is necessary, if multiple endocrine adenomatosis or the familial forms are suspected. In single cases benefit came from new scintigraphic methods such as 131 I-metaiodo-benzylguanidine or 201 thallium-chloride. (orig./MG) [de

  11. Tumour markers in germ cell tumours and thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mann, K.

    1988-02-01

    In patients with germ cell tumours of gonadal and extragonadal origin both markers, human chorionic gonadotropin (hCG) and alphafetoprotein (AFP) are madatory for diagnosis and control of treatment. In seminoma, we found preoperatively elevated levels of hCG(+hCG-..beta..) in 42/349 patients (12%) up to 1200 mlU/ml using a polyclonal radioimmunoassay (1. IRP hCG standard 75/537). Lactatedehydrogenase can be useful in marker negative patients. Serum levels reflect tumour burden even if not highly specific. Presently, placental alkaline phosphatase is under discussion for seminoma. However, commercial kits are not available. As a relatively high secretion of hCG/..beta../hCG was found in gestational trophoblastic diseases, this parameters may be useful for differential diagnosis in pregnancy. In the follow-up of patients with differentiated thyroid carcinoma the determination of thyroglobulin (Tg) in combination with ultrasound of the thyroid and X-ray of the chest is sufficient. For Tg-determination thyroid hormone replacement therapy must be discontinued only in rare single cases with borderline levels, which need radioiodtesting additionally. Calcitonin is the most important marker in medullary thyroid carcinoma. Pentagastrin stimulated calcitonin as screening test is necessary, if multiple endocrine adenomatosis or the familial forms are suspected. In single cases benefit came from new scintigraphic methods such as /sup 131/I-metaiodo-benzylguanidine or /sup 201/thallium-chloride.

  12. Granular cell tumour of the larynx - A case report | Appiah ...

    African Journals Online (AJOL)

    Granular cell tumour of the larynx - A case report. P Appiah-Thompson, KK Baidoo. Abstract. Granular cell tumours (GCTs) are benign tumours rarely found in the larynx even though they are common in the head and neck region. The laryngeal tumour may be asymptomatic but typically patients present with hoarseness of ...

  13. Primary pleuro-pulmonary malignant germ cell tumours.

    Directory of Open Access Journals (Sweden)

    Vaideeswar P

    2002-01-01

    Full Text Available Lungs and pleura are rare sites for malignant germ-cell tumours. Two cases, pure yolk-sac tumour and yolk sac-sac tumour/embryonal carcinoma are described in young males who presented with rapid progression of respiratory symptoms. The malignant mixed germ cell tumour occurred in the right lung, while the yolk-sac tumour had a pseudomesotheliomatous growth pattern suggesting a pleural origin. Alpha-foetoprotein was immunohistochemically demonstrated in both.

  14. Granular cell tumour of the neurohypophysis: a rare sellar tumour with specific radiological and operative features.

    LENUS (Irish Health Repository)

    Aquilina, K

    2012-02-03

    Symptomatic granular cell tumours of the neurohypophysis are rare sellar lesions. Preoperative prediction of the diagnosis on the basis of radiological appearance is useful as these tumours carry specific surgical difficulties. This is possible when the tumour arises from the pituitary stalk, rostral to a normal pituitary gland. This has not been emphasized previously.

  15. Total hip arthroplasty for giant cell tumour.

    Directory of Open Access Journals (Sweden)

    Kulkarni S

    1996-07-01

    Full Text Available A 32 month follow up of an uncommon case of a Giant Cell Tumour affecting the proximal end of femur is presented. Following a wide excision, the hip was reconstructed using Charnley type of low friction total hip arthroplasty. At a 32 month review, there was no recurrence and the function was good.

  16. Childhood ovarian juvenile granulosa cell tumour

    African Journals Online (AJOL)

    Prof Ezechukwu

    2012-05-12

    May 12, 2012 ... 19 years and below should have surgery and close moni- toring for tumour recurrence only.4, 10 Others have used stem cell transplantation.5 Newer agents that block an- giogenesis are being studied; two are being tried currently; sunitinib and bevacizumab.5 Hormone based treatments like paclitaxel and ...

  17. Granular cell tumour of the urinary bladder

    Directory of Open Access Journals (Sweden)

    Christoph von Klot

    2012-04-01

    Full Text Available With only 16 cases reported in the literature, the mostly benign granular cell tumour of the urinary bladder is exceptionally rare. We present the case of a 68-year old patient with one of these lesions demonstrating our histological findings including several immunohistochemical stainings used to differentiate between other more common entities.

  18. Giant cell tumour of the proximal radius.

    Science.gov (United States)

    Singh, A P; Mahajan, S; Singh, A P

    2009-11-01

    A 52-year-old Indian woman presented with a progressively increasing swelling and pain in the right elbow for the past eight months, which was not associated with trauma or constitutional symptoms. The patient was diagnosed to have Campanacci grade III giant cell tumour of the proximal radius, and was treated with above elbow amputation. The patient has not shown any recurrence after five years of follow-up. The case was reported because of its rarity and the unusual site of occurrence of the tumour.

  19. MRI of intracranial germ cell tumours

    International Nuclear Information System (INIS)

    Sumida, M.; Uozumi, T.; Kiya, K.; Mukada, K.; Arita, K.; Kurisu, K.; Sugiyama, K.; Onda, J.; Satoh, H.; Ikawa, F.; Migita, K.

    1995-01-01

    We reviewed MRI findings in proven intracranial germ cell tumours in 22 cases, 12 of whom received Gd-DTPA. On T1-weighted images, the signal intensity of the tumour parenchyma was moderately low in 19 cases and isointense in 3; on T2-weighted images, it was high in all cases. Regions of different intensity thought to be cysts were found in 17 (77 %): 7 of 12 patients with germinoma (58 %) and in all other cases. Of the 13 patients with pineal lesions T1-weighted sagittal images showed the aqueduct to be obstructed in 5, stenotic in 7 and normal in 1. Strong contrast enhancement was observed in all 12 cases. Of the 14 patients with suprasellar lesions, 5 were found to have an intrasellar extension, and in 3 of these, the normal pituitary gland, which could be distinguished from the tumour, was displaced anteriorly. Ten patients (45 %) had multiple lesions. (orig.)

  20. Physical Guidance of Cell Migration

    Science.gov (United States)

    Losert, Wolfgang

    Cells migrate as individuals or groups, to perform critical functions in life from organ development to wound healing and the immune response. While directed migration of cells is often mediated by chemical or physical gradients, our recent work has demonstrated that the physical properties of the microenvironment can also control and guide migration. I will describe how an underlying wave-like process of the actin scaffolding drives persistent migration, and how such actin waves are nucleated and guided by the texture of the microenvironment. Based on this observation we design textures capable of guiding cells in a single preferred direction using local asymmetries in nano/microtopography on subcellular scales, or altering migration in other ways. This phenomenon is observed both for the pseudopod-dominated migration of Dictyostelium cells and for the lamellipod-driven migration of human neutrophils. The conservation of this mechanism across cell types suggests that actin-wave-based guidance is important in biology and physiology.

  1. Primary liver tumour of intermediate (hepatocyte-bile duct cell) phenotype: a progenitor cell tumour?

    Science.gov (United States)

    Robrechts, C; De Vos, R; Van den Heuvel, M; Van Cutsem, E; Van Damme, B; Desmet, V; Roskams, T

    1998-08-01

    A 57-year-old female patient presented with painless obstructive jaundice and mild mesogastric pain; she was in good general condition on admission. Abdominal ultrasonography revealed diffuse tumoral invasion of the liver, suggesting diffuse metastases. A liver biopsy showed a tumour with a trabecular growth pattern, composed of uniform relatively small cells, very suggestive of an endocrine carcinoma. Additional immunohistochemical stains, however, did not show any endocrine differentiation, but showed positivity for both hepatocyte-type cytokeratins (cytokeratin 8 and 18) and bile duct-type cytokeratins (cytokeratin 7 and 19). In addition, parathyroid hormone-related peptide, shown to be a good marker for cholangiocarcinoma, was immunoreactive. Electron microscopy revealed tumour cells with an intermediate phenotype: the cells clearly showed hepatocyte features on one hand and bile duct cell features on the other hand. Nine days after admission, the patient died due to liver failure and hepatic encephalopathy. Autopsy excluded another primary tumour site. Overall, this tumour was a primary liver tumour with an intermediate phenotype and with a very rapid clinical course. The intermediate (between hepatocyte and bile duct cell) phenotype suggests an immature progenitor cell origin, which is concordant with a rapid clinical course. This type of tumour has not been described previously and provides additional evidence for the existence of progenitor cells in human liver.

  2. Comparison of tumour age response to radiation for cells derived from tissue culture or solid tumours

    International Nuclear Information System (INIS)

    Keng, P.C.; Siemann, D.W.; Rochester Univ., NY; Rochester Univ., NY; Wheeler, K.T.

    1984-01-01

    Direct comparison of the cell age response of 9L and KHT tumour cells derived either from tissue culture or solid tumours was achieved. Cells from dissociated KHT and 9L tumours (the latter implanted either subcutaneously or intracerebrally) and cells from tissue culture were separated into homogenous sized populations by centrifugal elutriation. In both tumour models these homogeneous sized populations correspond to populations enriched at different stages of the cell cycle. The survival of these elutriated cell populations was measured after a single dose of Cs-137 gamma rays. For cells isolated from 9L solid tumours, there was little variation in radiosensitivity throughout the cell cycle; however, a very small but significant increase in resistance was found in late G 1 cells. This lack of a large variation in radiosensitivity through the cell cycle for 9L cells from solid tumours also was seen in 9L cells growing in monolayer tissue culture. When similar experiments were performed using the KHT sarcoma tumour model, the results showed that KHT cells in vitro exhibited a fairly conventional increase in radioresistance in both mid G 1 and late S. However, the cell age response of KHT cells from solid tumours was different; particularly in the late S and G 2 + M phases. (author)

  3. Substrate curvature regulates cell migration.

    Science.gov (United States)

    He, Xiuxiu; Jiang, Yi

    2017-05-23

    Cell migration is essential in many aspects of biology. Many basic migration processes, including adhesion, membrane protrusion and tension, cytoskeletal polymerization, and contraction, have to act in concert to regulate cell migration. At the same time, substrate topography modulates these processes. In this work, we study how substrate curvature at micrometer scale regulates cell motility. We have developed a 3D mechanical model of single cell migration and simulated migration on curved substrates with different curvatures. The simulation results show that cell migration is more persistent on concave surfaces than on convex surfaces. We have further calculated analytically the cell shape and protrusion force for cells on curved substrates. We have shown that while cells spread out more on convex surfaces than on concave ones, the protrusion force magnitude in the direction of migration is larger on concave surfaces than on convex ones. These results offer a novel biomechanical explanation to substrate curvature regulation of cell migration: geometric constrains bias the direction of the protrusion force and facilitates persistent migration on concave surfaces.

  4. Improved classification, diagnosis and prognosis of canine round cell tumours

    NARCIS (Netherlands)

    Cangul, Taci

    2001-01-01

    As the name suggests, canine round cell tumour (RCTs) are composed of cells with a round morphology. There is some discrepancy amongst authors as to which tumours belong to this category, but most designate lymphomas, melanomas, plasmacytomas, transmissible venereal tumours (TVTs), histiocytomas,

  5. Malignant Giant Cell Tumour of Bone with Axillary Metastasis

    African Journals Online (AJOL)

    2002-06-06

    Jun 6, 2002 ... SUMMARY. Giant Cell Tumour of bone is a typically benign and solitary tumour. However, multiple lesions have been described and 5-10% of lesions may be malignant. We present a case of a malignant giant cell tumour of the distal radius with metastasis to the ipsilateral axilla (an uncommon location).

  6. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation.

    Science.gov (United States)

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-11-23

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer.

  7. Germ cell tumours in neonates and infants: a distinct subgroup?

    NARCIS (Netherlands)

    Veltman, I.M.; Schepens, M.T.M.; Looijenga, L.H.J.; Strong, L.C.; Geurts van Kessel, A.H.M.

    2003-01-01

    Human germ cell tumours (GCTs) constitute a heterogeneous group of tumours that can be classified into four major subgroups. One of these subgroups encompasses (immature) teratomas and yolk sac tumours of patients under the age of 5 years. In this paper we review the various clinical, histological

  8. GRANULAR CELL TUMOUR OF THE LARYNX – A CASE REPORT

    African Journals Online (AJOL)

    2015-12-01

    Dec 1, 2015 ... SUMMARY. Granular cell tumours (GCTs) are benign tumours rarely found in the larynx even though they are common in the head and neck region. The laryngeal tumour may be asymptomatic but typically patients present with hoarseness of voice, stridor, haemoptysis and dysphagia. The lesion can mimic ...

  9. The inhibitory influence of adipose tissue-derived mesenchymal stem cell environment and Wnt antagonism on breast tumour cell lines.

    Science.gov (United States)

    Visweswaran, Malini; Arfuso, Frank; Dilley, Rodney J; Newsholme, Philip; Dharmarajan, Arun

    2018-02-01

    Tumours exhibit a heterogeneous mix of cell types that reciprocally regulate their growth in the tumour stroma, considerably affecting the progression of the disease. Both adipose-derived mesenchymal stem cells and Wnt signalling pathway are vital in driving breast tumour growth. Hence, we examined the effect of secreted factors released by adipose-derived mesenchymal stem cells, and further explored the anti-tumour property of the Wnt antagonist secreted frizzled-related protein 4 (sFRP4) on MCF-7 and MDA-MB-231 breast tumour cells. We observed that conditioned medium and extracellular matrix derived from adipose-derived mesenchymal stem cells inhibited tumour viability. The inhibitory effect of the conditioned medium was retained within its low molecular weight and non-protein component. The conditioned medium also induced apoptosis accompanied by a decrease in the mitochondrial membrane potential in tumour cells, Furthermore, it downregulated the protein expression of active β-catenin and Cyclin D1, which are major target proteins of the Wnt signalling pathway, and reduced the expression of anti-apoptotic protein Bcl-xL. The combination of conditioned medium and sFRP4 further potentiated the effects, depending on the tumour cell line and experimental assay. We conclude that factors derived from conditioned medium of adipose-derived mesenchymal stem cells and sFRP4 significantly decreased the tumour cell viability and migration rates (MCF-7), accompanied with an enhanced apoptotic activity through inhibition of canonical Wnt signalling. Besides giving an insight to possible paracrine interactions and influence of signalling pathways, reflective of a breast tumour microenvironment, this study emphasises the utilization of cell free-secreted factors and Wnt antagonists to improve conventional anti-cancer strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. The kinetics of cell proliferation in Wilms' tumours

    International Nuclear Information System (INIS)

    Willnow, U.

    1979-01-01

    The proliferation kinetics of 11 Wilms' tumours (9 primary tumours, 2 lung metastases) were studies by an autoradiographic in vitro method using simple labelling with 3H-thymidine and double labelling with 3H- and 14C-thymidine. The results were in accordance with clinical experience of rapid tumour growth. The 3H-thymidine labelling index ranges between 22.4 and 46.3%, the mean cell cycle time between 11.2 and 22.1 hr, the DNA synthesis time between 8.5 and 13.8 hr, and the mitosis time between 0.3 and 1.5 hr. The growth fraction, which can be determined only approximately with in vitro methods, showed an average value of 0.5. The growth of 2 lung metastases did not differ from the pattern of proliferation of the primary Wilms' tumours. The proliferative activity of Wilms' tumours reaches the magnitude of rapidly proliferating experimental animal tumours. Since X-rays and most cytostatics show specific activity dependent upon the phase of the cell cycle or the proliferative behaviour, cytokinetic data of individual tumours allow the formulation of an index, which represents a general measure of the sensitivity of tumour cells to chemotherapy and radiation. For Wilms' tumours this Cytokinetic Therapy Index ranges between 0.62 and about 1. This is in a region of high sensitivity. The fundamental importance of proliferation kinetics for the treatment of malignant individual solid tumours in children is discussed. (author)

  11. The influence of platelet membranes on tumour cell behaviour.

    Science.gov (United States)

    Coupland, L A; Hindmarsh, E J; Gardiner, E E; Parish, C R

    2017-06-01

    The significant role of platelets in the protection of tumour cells from immune attack and shear forces and the promotion of tumour cell extravasation from the bloodstream in the process of haematogenous metastasis have been extensively studied. The role of platelets, and in particular platelet membranes, in the promotion of a more metastatic phenotype in tumour cells is a more recent and, therefore, less well-recognised area of research. This review article summarises studies that have focused on the impact of tumour cell interactions with platelets and platelet membranes on tumour cell behaviour in vitro and in vivo. Furthermore, the gene expression changes that occur within tumour cells following contact with platelet membranes are also extensively reviewed. Overall, the interaction of platelet membranes with tumour cells results in a more invasive phenotype and the promotion of epithelial to mesenchymal transition with our own genetic studies revealing that matrix metalloproteinase-1, plasminogen activator inhibitor-1 and interleukin-8 are globally upregulated in a range of tumour cell lines.

  12. Insulin resistance in vascular endothelial cells promotes intestinal tumour formation

    DEFF Research Database (Denmark)

    Wang, X; Häring, M-F; Rathjen, Thomas

    2017-01-01

    The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterised by hyperinsulinaemia and insulin resistance. Because hyperinsulinaemia itself is an independent risk factor for cancer development, we examined tissue...... did not change intestinal tumour number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumour stroma might explain the association between tumour formation and insulin resistance. To this end, we generated Apc(Min/+) mice with loss of insulin receptors...... and increased the frequency of neutrophils in tumours. We conclude that although insulin is mitogenic for intestinal tumour cells in vitro, impaired insulin action in the tumour microenvironment may be more important in conditions where hyperinsulinaemia is secondary to insulin resistance. Insulin resistance...

  13. Single-cell Raman spectroscopy of irradiated tumour cells

    Science.gov (United States)

    Matthews, Quinn

    This work describes the development and application of a novel combination of single-cell Raman spectroscopy (RS), automated data processing, and principal component analysis (PCA) for investigating radiation induced biochemical responses in human tumour cells. The developed techniques are first validated for the analysis of large data sets (˜200 spectra) obtained from single cells. The effectiveness and robustness of the automated data processing methods is demonstrated, and potential pitfalls that may arise during the implementation of such methods are identified. The techniques are first applied to investigate the inherent sources of spectral variability between single cells of a human prostate tumour cell line (DU145) cultured in vitro. PCA is used to identify spectral differences that correlate with cell cycle progression and the changing confluency of a cell culture during the first 3-4 days after sub-culturing. Spectral variability arising from cell cycle progression is (i) expressed as varying intensities of protein and nucleic acid features relative to lipid features, (ii) well correlated with known biochemical changes in cells as they progress through the cell cycle, and (iii) shown to be the most significant source of inherent spectral variability between cells. This characterization provides a foundation for interpreting spectral variability in subsequent studies. The techniques are then applied to study the effects of ionizing radiation on human tumour cells. DU145 cells are cultured in vitro and irradiated to doses between 15 and 50 Gy with single fractions of 6 MV photons from a medical linear accelerator. Raman spectra are acquired from irradiated and unirradiated cells, up to 5 days post-irradiation. PCA is used to distinguish radiation induced spectral changes from inherent sources of spectral variability, such as those arising from cell cycle. Radiation induced spectral changes are found to correlate with both the irradiated dose and the

  14. Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

    Directory of Open Access Journals (Sweden)

    Kinga Majchrzak

    Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

  15. Tumour cell expansion in bladder epithelium

    NARCIS (Netherlands)

    J.M.J. Rebel (Annemarie)

    1995-01-01

    textabstractBladder cancer is common in western society. The major problem of patients with superficial bladder cancer is the high recurrence rate and multifocality of these tumours. In 70 % of the patients superficial bladder cancer recurs after local resection of the tumour within 15 years. The

  16. Genetic predisposition to testicular germ-cell tumours

    NARCIS (Netherlands)

    Lutke-Holzik, MF; Rapley, EA; Hoekstra, HJ; Sleijfer, DT; Nolte, IM; Sijmons, RH

    Testicular germ-cell tumours (TGCT) are the most common neoplasm in young men. Various studies have suggested the existence of an inherited predisposition to development of these tumours. Genome-wide screens subsequently provided evidence of a TGCT susceptibility gene on chromosome Xq27 (TGCT1) that

  17. Anti-tumour action of 64Cu-bleomycin on Ehrlich ascites tumour cells in vivo

    International Nuclear Information System (INIS)

    Maki, Hirotoshi; Kawai, Kenichi; Akaboshi, Mitsuhiko

    1979-01-01

    The anti-tumor action of the complex of Bleomycin (BLM) with high specific-radioactivity 64 Cu on Ehrlich ascites tumour (EAT) was studied in vivo. The 64 Cu-BLM was administered into intraperitoneal cavity of mice from 1 to 4 days after inoculation of EAT cells. The effect of 64 Cu-BLM to suppress the tumour growth as demonstrated by prolonging life span was observed. The amounts of 64 Cu-BLM (800 μCi-8 mg/Kg) were administered at 4, 8 and 16 times separately. Then, the shorter the time interval and the less the amounts of drugs at a time, the higher the suppressing effect for the tumour growth was. It was confirmed that anti-tumour action of 64 Cu-BLM was in all the cases higher than that of BLM alone. (author)

  18. Selection of viable cell subpopulations from murine tumours using FACS

    International Nuclear Information System (INIS)

    Chaplin, D.J.; Durand, R.E.; Olive, P.L.

    1985-01-01

    The authors developed a technique which enables isolation of viable tumour cells subpopulation as a function of their distance from the blood supply. The basis for this separation procedure is that the fluorochrome, Hoechst 33342, as a result of its high avidity for cellular DNA, exhibits a marked diffusion/consumption gradient when it has to pass through several cell layers. As a result intravenous injection of Hoechst 33342 into tumour bearing animals, results in a heterogeneous straining pattern within the tumour with cells close to blood vessels being brightly fluorescent while those more distant are less intensely stained. Since these differences in staining intensity persist after tumour disaggregation, cells can be sorted into subpopulations on the basis of their fluorescence intensity using a fluorescence activated cell sorter. This technique offers the unique possibility of identifying the location of those cell subpopulations resistant to treatment with either radiation or chemotherapeutic drugs

  19. Insulin promotes cell migration by regulating PSA-NCAM

    International Nuclear Information System (INIS)

    Monzo, Hector J.; Coppieters, Natacha; Park, Thomas I.H.; Dieriks, Birger V.; Faull, Richard L.M.; Dragunow, Mike; Curtis, Maurice A.

    2017-01-01

    Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of αv-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that αv-integrin plays a key role in the PSA-NCAM turnover process. αv-integrin knockdown stopped PSA-NCAM from being endocytosed, and αv-integrin/PSA-NCAM clusters co-labelled intracellularly with Rab5, altogether indicating a role for αv-integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of αv-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. - Highlights: • Insulin modulates PSA-NCAM turnover through upregulation of p-FAK. • P-FAK modulates αv-integrin/PSA-NCAM clustering. • αv-integrin acts as a carrier for PSA-NCAM endocytosis. • Cell migration is promoted by cell surface PSA. • Insulin promotes PSA-dependent migration in vitro.

  20. Insulin promotes cell migration by regulating PSA-NCAM

    Energy Technology Data Exchange (ETDEWEB)

    Monzo, Hector J.; Coppieters, Natacha [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Park, Thomas I.H. [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Dieriks, Birger V.; Faull, Richard L.M. [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Dragunow, Mike [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Curtis, Maurice A., E-mail: m.curtis@auckland.ac.nz [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand)

    2017-06-01

    Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of αv-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that αv-integrin plays a key role in the PSA-NCAM turnover process. αv-integrin knockdown stopped PSA-NCAM from being endocytosed, and αv-integrin/PSA-NCAM clusters co-labelled intracellularly with Rab5, altogether indicating a role for αv-integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of αv-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. - Highlights: • Insulin modulates PSA-NCAM turnover through upregulation of p-FAK. • P-FAK modulates αv-integrin/PSA-NCAM clustering. • αv-integrin acts as a carrier for PSA-NCAM endocytosis. • Cell migration is promoted by cell surface PSA. • Insulin promotes PSA-dependent migration in vitro.

  1. Giant Cell Tumour of the Distal Ulna: A Rare Presentation

    Directory of Open Access Journals (Sweden)

    Ruben Jaya Kumar

    2011-07-01

    Full Text Available Giant-cell tumour (GCT of bone, a primary yet locally aggressive benign tumour, commonly affects patients between the ages of 20 and 40 years, with the peak incidence occurring in the third decade. Women are affected slightly more than men. The distal end of the ulna is an extremely uncommon site for primary bone tumours in general and giant cell tumours in particular. Wide resection of the distal ulna is the recommended treatment for GCT in such locations. Radio-ulna convergence and dorsal displacement of the ulna stump are known complications following ulna resection proximal to the insertion of the pronator quadratus. This leads to reduction in grip power and forearm rotatory motion. Stabilization of the ulna stump with extensor carpi ulnaris (ECU tendon after wide resection of the tumour has been described in the literature. We report a case of GCT of distal end of ulna treated with wide resection and stabilization with ECU tendon.

  2. following Wide Resection of Giant Cell Tumour of Distal Ulna

    Directory of Open Access Journals (Sweden)

    Elango Mariappan

    2013-01-01

    Full Text Available Giant cell tumour of the bone (GCT is a rare locally aggressive primary bone tumour with an incidence of 3% to 5% of all primary bone tumours. The most common location for this tumour is the long bone metaepiphysis especially of the distal femur, proximal tibia, distal radius, and the proximal humerus. Involvement of distal ulna is rare accounting for 0.45% to 3.2%. Considering local aggressive nature and high recurrence, wide resection is the treatment recommended. Instability of ulnar stump and ulnar translation of the carpals are known complications following resection of distal ulna. To overcome these problems, we attempted a newer technique of distal ulna reconstruction using proximal fibula and TFCC reconstruction using palmaris longus tendon following wide resection of giant cell tumour of distal ulna in a 44-year-old male. This technique of distal radioulnar joint reconstruction has excellent functional results with no evidence of recurrence after one-year followup.

  3. Mesenchymal stem cells promote cell invasion and migration and autophagy-induced epithelial-mesenchymal transition in A549 lung adenocarcinoma cells.

    Science.gov (United States)

    Luo, Dan; Hu, Shiyuan; Tang, Chunlan; Liu, Guoxiang

    2018-03-01

    Mesenchymal stem cells (MSCs) are recruited into the tumour microenvironment and promote tumour growth and metastasis. Tumour microenvironment-induced autophagy is considered to suppress primary tumour formation by impairing migration and invasion. Whether these recruited MSCs regulate tumour autophagy and whether autophagy affects tumour growth are controversial. Our data showed that MSCs promote autophagy activation, reactive oxygen species production, and epithelial-mesenchymal transition (EMT) as well as increased migration and invasion in A549 cells. Decreased expression of E-cadherin and increased expression of vimentin and Snail were observed in A549 cells cocultured with MSCs. Conversely, MSC coculture-mediated autophagy positively promoted tumour EMT. Autophagy inhibition suppressed MSC coculture-mediated EMT and reduced A549 cell migration and invasion slightly. Furthermore, the migratory and invasive abilities of A549 cells were additional increased when autophagy was further enhanced by rapamycin treatment. Taken together, this work suggests that microenvironments containing MSCs can promote autophagy activation for enhancing EMT; MSCs also increase the migratory and invasive abilities of A549 lung adenocarcinoma cells. Mesenchymal stem cell-containing microenvironments and MSC-induced autophagy signalling may be potential targets for blocking lung cancer cell migration and invasion. Copyright © 2018 John Wiley & Sons, Ltd.

  4. Immunohistochemical detection of tumour cell proliferation and intratumoural microvessel density in canine malignant mammary tumours

    Directory of Open Access Journals (Sweden)

    Sennazli Gulbin

    2015-06-01

    Full Text Available The objective of this study was to investigate the correlation between different histological types and grades of canine malignant mammary tumours, tumour cell proliferation and their angiogenic activity using immunohistochemical markers. Mammary tissue samples from 47 bitches with mammary cancer were evaluated. The expression of cellular proliferation marker Ki-67 and endothelial marker Von Willebrand’s factor (vWF were immunohistochemically demonstrated. The tumours with the highest Ki-67 and vWF expressions were found to share similar histomorphological features. Simple solid carcinoma had the highest levels of Ki-67, vWF, and higher histological grade while complex carcinomas, osteosarcomas, and carcinosarcomas had the lowest ones. The differences between the expressions of Ki-67 and vWF in different tumour types were considered to be of great importance in determination of biological behaviour and prognosis of these tumours. This study is one of the few studies that evaluate these differences among the subtypes of malignant canine mammary tumours

  5. STRIPAK components determine mode of cancer cell migration and metastasis

    DEFF Research Database (Denmark)

    Madsen, Chris D; Hooper, Steven; Tozluoglu, Melda

    2015-01-01

    and MST4 kinases, which promote the co-localization of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we......The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3...... demonstrate that co-localization of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours migration in confined environments similar to those observed in vivo. We further show that FAM40B mutations found in human tumours uncouple it from PP2A and enable...

  6. Connexin membrane materials as potent inhibitors of breast cancer cell migration.

    Science.gov (United States)

    Ferrati, Silvia; Gadok, Avinash K; Brunaugh, Ashlee D; Zhao, Chi; Heersema, Lara A; Smyth, Hugh D C; Stachowiak, Jeanne C

    2017-08-01

    Gap junction (GJ) channels facilitate cell-cell communication through the exchange of chemical and mechanical signals, ensuring proper tissue development and homeostasis. The complex, disease stage-dependent role of connexins in breast cancer progression has been extensively studied over the past two decades. In the early stages of breast cancer, substantial evidence supports the role of GJ channels, formed by connexins at the interfaces between neighbouring cells, as suppressors of cell migration and proliferation. These findings suggest that materials that reintroduce connexins into the tumour cell environment have the potential to inhibit cell migration. Here, we report that exposure of highly metastatic MDA-MB-231 breast tumour cells to connexin-rich biovesicle materials potently suppresses cell migration. Specifically, these biovesicles, which can form GJ interfaces with cells, were extracted from the plasma membrane of donor cells engineered to express a high concentration of functional connexin 43 channels. These connexin-rich membrane materials dramatically reduced cell migration in both a transwell migration assay and a scratch closure assay. Collectively, these results suggest that using membrane materials to reintroduce connexins into the tumour cell environment provides a novel approach for combating cell migration and invasion. © 2017 The Author(s).

  7. Immunisation of colorectal cancer patients with autologous tumour cells

    DEFF Research Database (Denmark)

    Diederichsen, Axel Cosmus Pyndt; Stenholm, A C; Kronborg, O

    1998-01-01

    . There was an inverse relation between survival and HLA class II expression. This highlights an essential problem, in the absence of CD80 expression the expression of HLA class II may induce anergy. In future attempts to develop improved vaccines this problem should be addressed.......Patients with colorectal cancer were entered into a clinical phase I trial of immunotherapy with an autologous tumour cell/bacillus Calmette-Guerin (BCG) vaccine. We attempted to describe the possible effects and side effects of the immunisation, and further to investigate whether expression...... of immune-response-related surface molecules on the tumour cells in the vaccine correlated with survival. The first and second vaccine comprised of 107 irradiated tumour cells mixed with BCG, the third of irradiated tumour cells only. Thirty-nine patients were considered, but only 6 patients fulfilled...

  8. Ovarian sex-cord stromal tumours and small cell tumours: Pathological, genetic and management aspects.

    Science.gov (United States)

    Boussios, Stergios; Moschetta, Michele; Zarkavelis, George; Papadaki, Alexandra; Kefas, Aristides; Tatsi, Konstantina

    2017-12-01

    Non-epithelial ovarian cancers (NEOC) constitute a group of uncommon malignancies and their treatment is still a challenging task. Collectively, these tumours account for about 10% of all ovarian cancers and occur in all age groups from childhood to old-age. They include malignancies of germ cell origin, sex cord-stromal cell origin, and a variety of extremely rare ovarian cancers, such as small-cell carcinomas and sarcomas. Each of these classifications encompasses multiple histologic subtypes. It is imperative that these rare tumours are managed with accurate diagnosis, staging, and treatment, to optimise the outcome. The aetiology and molecular origins of each sub-group of NEOC remain largely unresolved, and international cooperation to promote high quality translational research is crucial. Much effort has been made into researching the molecular mechanisms underlying epithelial ovarian cancers, but far less is known about the genetic changes in NEOC. In this article, it is provided an overview of the current knowledge on the incidence, clinical presentation, pathology, genetics, therapeutic interventions, survival and prognostic factors of adult and juvenile granulosa cell tumours (GrCT), Sertoli-Leydig Cell tumours (SLCT) and small cell carcinoma of the ovary. We also consider future potential therapeutic targets in these rare cancers. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Tumour metastasis as an adaptation of tumour cells to fulfil their phosphorus requirements.

    Science.gov (United States)

    de Carvalho, Carla C C R; Caramujo, Maria José

    2012-05-01

    Inorganic phosphate (Pi) is a vital component of nucleotides, membrane phospholipids, and phosphorylated intermediates in cellular signalling. The Growth Rate Hypothesis (GRH) states that fast growing organisms should be richer in phosphorus (relatively low C:P and N:P cell content) than slow developing organisms as a result of high ribosome biogenesis. Cells that proliferate rapidly, such as cancer cells, require a high amount of ribosomes and other P-rich RNA components that are necessary to manufacture proteins. The GRH hypothesis may be applied to cancer predicting that tumour cells are richer in phosphorus than the surrounding tissue, and that they resort to metastasis in order to meet their nutrient demands. Considering that the cells most P-deprived should be located in the inner parts of the tumour we propose that changes in the membrane of these cells favour the detachment of the more peripheral cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Alpha particles induce expression of immunogenic markers on tumour cells

    International Nuclear Information System (INIS)

    Gorin, J.B.; Gouard, S.; Cherel, M.; Davodeau, F.; Gaschet, J.; Morgenstern, A.; Bruchertseifer, F.

    2013-01-01

    The full text of the publication follows. Radioimmunotherapy (RIT) is an approach aiming at targeting the radioelements to tumours, usually through the use of antibodies specific for tumour antigens. The radiations emitted by the radioelements then induce direct killing of the targeted cells as well as indirect killing through bystander effect. Interestingly, it has been shown that ionizing radiations, in some settings of external radiotherapy, can foster an immune response directed against tumour cells. Our research team is dedicated to the development of alpha RIT, i.e RIT using alpha particle emitters, we therefore decided to study the effects of such particles on tumour cells in regards to their immunogenicity. First, we studied the effects of bismuth 213, an alpha emitter, on cellular death and autophagy in six different tumour cell lines. Then, we measured the expression of 'danger' signals and MHC molecules at the cell surface to determine whether irradiation with 213 Bi could cause the tumour cells to be recognized by the immune system. Finally a co-culture of dendritic cells with irradiated tumour cells was performed to test whether it would induce dendritic cells to mature. No apoptosis was detected within 48 hours after irradiation in any cell line, however half of them exhibited signs of autophagy. No increase in membrane expression of 'danger' signals was observed after treatment with 213 Bi, but we showed an increase in expression of MHC class I and II for some cell lines. Moreover, the co-culture experiment indicated that the immunogenicity of a human adenocarcinoma cell line (LS 174T) was enhanced in vitro after irradiation with alpha rays. These preliminary data suggest that alpha particles could be of interest in raising an immune response associated to RIT. (authors)

  11. Giant Mediastinal Germ Cell Tumour: An Enigma of Surgical Consideration

    Directory of Open Access Journals (Sweden)

    Firdaus Hayati

    2016-01-01

    Full Text Available We present a case of 16-year-old male, who was referred from private centre for dyspnoea, fatigue, and orthopnea. The chest radiograph revealed complete opacification of left chest which was confirmed by computed tomography as a large left mediastinal mass measuring 14 × 15 × 18 cm. The diagnostic needle core biopsy revealed mixed germ cell tumour with possible combination of embryonal carcinoma, yolk sac, and teratoma. After 4 cycles of neoadjuvant BEP regime, there was initial response of tumour markers but not tumour bulk. Instead of classic median sternotomy or clamshell incision, posterolateral approach with piecemeal manner was chosen. Histology confirmed mixed germ cell tumour with residual teratomatous component without yolk sac or embryonal carcinoma component. Weighing 3.5 kg, it is one of the largest mediastinal germ cell tumours ever reported. We describe this rare and gigantic intrathoracic tumour and discuss the spectrum of surgical approach and treatment of this exceptional tumour.

  12. Immunotherapy with irradiated tumour cells and BCG in experimental osteosarcoma

    International Nuclear Information System (INIS)

    Larsson, S.-E.; Lorentzon, R.; Boquist, L.

    1981-01-01

    The effects of immunotherapy with irradiated tumour cells and BCG were studied in a non-metastasizing variety of the Dunn osteosarcoma transplantable in mice. Experimental animals which had been preimmunized with three injections of 0.7 to 1.4 x 10 6 irradiated tumour cells each 1 to 3 weeks before administration of 1 x 10 6 living tumour cells, showed a tumour incidence of 23 per cent. This was significantly (P<0.005) lower than the 92 per cent tumour incidence in the control animals. Non-specific immunotherapy with BCG given subcutaneously at a dose of 1.0 mg of dry-weight bacterial mass three times at 3-weeks intervals was found to have no protective effect against the osteosarcoma. The tumour incidence was 90 per cent for BCG-treated and 94 per cent for control animals. The osteosarcomas were studied light and electron microscopically and also with regard to the histochemical alkaline phosphatase activity. No structural difference was found between the tumours of the various groups. The demonstrated immunotherapeutic response is in contrast o the low degree of immunogenicity of the osteosarcoma, which we will report elsewhere. (author)

  13. Quantifying Collective Cell Migration during Cancer Progression

    Science.gov (United States)

    Lee, Rachel; Stuelten, Christina; Nordstrom, Kerstin; Parent, Carole; Losert, Wolfgang

    2014-03-01

    As tumors become more malignant, cells invade the surrounding tissue and migrate throughout the body to form secondary, metastatic tumors. This metastatic process is initiated when cells leave the primary tumor, either individually or as groups of collectively migrating cells. The mechanisms regulating how groups of cells collectively migrate are not well characterized. Here we study the migration dynamics of epithelial sheets composed of many cells using quantitative image analysis techniques. By extracting motion information from time-lapse images of cell lines of varying malignancy, we are able to measure how migration dynamics change during cancer progression. We further investigate the role that cell-cell adhesion plays in these collective dynamics by analyzing the migration of cell lines with varying levels of E-cadherin (a cell-cell adhesion protein) expression.

  14. Two cases of breast carcinoma with osteoclastic giant cells: Are the osteoclastic giant cells pro-tumoural differentiation of macrophages?

    Directory of Open Access Journals (Sweden)

    Shishido-Hara Yukiko

    2010-08-01

    Full Text Available Abstract Breast carcinoma with osteoclastic giant cells (OGCs is characterized by multinucleated OGCs, and usually displays inflammatory hypervascular stroma. OGCs may derive from tumor-associated macrophages, but their nature remains controversial. We report two cases, in which OGCs appear in common microenvironment despite different tumoural histology. A 44-year-old woman (Case 1 had OGCs accompanying invasive ductal carcinoma, and an 83-year-old woman (Case 2 with carcinosarcoma. Immunohistochemically, in both cases, tumoural and non-tumoural cells strongly expressed VEGF and MMP12, which promote macrophage migration and angiogenesis. The Chalkley count on CD-31-stained sections revealed elevated angiogenesis in both cases. The OGCs expressed bone-osteoclast markers (MMP9, TRAP, cathepsin K and a histiocyte marker (CD68, but not an MHC class II antigen, HLA-DR. The results indicate a pathogenesis: regardless of tumoural histology, OGCs derive from macrophages, likely in response to hypervascular microenvironments with secretion of common cytokines. The OGCs have acquired bone-osteoclast-like characteristics, but lost antigen presentation abilities as an anti-cancer defense. Appearance of OGCs may not be anti-tumoural immunological reactions, but rather pro-tumoural differentiation of macrophage responding to hypervascular microenvironments induced by breast cancer.

  15. Characterization of Collective Cell Migration Dynamics

    Science.gov (United States)

    Lee, Rachel; Yue, Haicen; Rappel, Wouter-Jan; Losert, Wolfgang

    2015-03-01

    During cancer progression, tumor cells invade the surrounding tissue and migrate throughout the body, forming clinically dangerous secondary tumors. This metastatic process begins when cells leave the primary tumor, either as individual cells or collectively migrating groups. Here we present data on the migration dynamics of epithelial sheets composed of many cells. Using quantitative image analysis techniques, we are able to extract motion information from time-lapse images of cell lines with varying malignancy. Adapting metrics originally used to study fluid flows we are able to characterize the migration dynamics of these cell lines. By describing the migration dynamics in great detail, we are able to make a clear comparison of our results to a simulation of collective cell migration. Specifically, we explore whether leader cells are required to describe our expanding sheets of cells and whether the answer depends on individual cell activity.

  16. Testicular germ cell tumours in dogs are predominantly of spermatocytic seminoma type and are frequently associated with somatic cell tumours

    DEFF Research Database (Denmark)

    Bush, J M; Gardiner, D W; Palmer, J S

    2011-01-01

    Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated and characte......Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated...... in canine TGCT. None of the canine TGCT evaluated demonstrated the presence of carcinoma in situ cells, a standard feature of human classical seminomas, suggesting that classical seminomas either do not occur in dogs or are rare in occurrence. Canine spermatocytic seminomas may provide a useful model...

  17. Gene expression of circulating tumour cells and its correlation with tumour stage in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Bölke E

    2009-09-01

    Full Text Available Abstract Background Breast cancer (BC represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting. Materials and methods Circulating tumour cells (CTC of 63 BC patients were isolated from peripheral blood (PB through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes ga733.2, muc-1, c-erbB2, mgb-1, spdef and c-erbB2 were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls. Results Significant correlations with tumour stages were found in single gene analyses of ga733.2, muc-1 and in multi-gene analyses of ga733.2/muc-1/mgb1/spdef. Furthermore, a significant correlation of Ca 15-3 and all studied genes was also observed. Conclusion Herein, we demonstrated a positive correlation of a gene signature consisting of ga733.2, muc-1, mgb1 and spdef and advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with Ca 15-3 positive cases.

  18. Insulin promotes cell migration by regulating PSA-NCAM.

    Science.gov (United States)

    Monzo, Hector J; Coppieters, Natacha; Park, Thomas I H; Dieriks, Birger V; Faull, Richard L M; Dragunow, Mike; Curtis, Maurice A

    2017-06-01

    Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of αv-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that αv-integrin plays a key role in the PSA-NCAM turnover process. αv-integrin knockdown stopped PSA-NCAM from being endocytosed, and αv-integrin/PSA-NCAM clusters co-labelled intracellularly with Rab5, altogether indicating a role for αv-integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of αv-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Gli and hedgehog in cancer: tumours, embryos and stem cells.

    Science.gov (United States)

    Ruiz i Altaba, Ariel; Sánchez, Pilar; Dahmane, Nadia

    2002-05-01

    Do tumours arise from stem cells, or are they derived from more differentiated cells that, for some reason, begin to recapitulate developmental programmes? Inappropriate activation of the Sonic hedgehog-Gli signalling pathway occurs in several types of tumour, including those of the brain and the skin. Studies in these and other systems suggest that inappropriate function of the Gli transcription factors in stem or precursor cells might lead to the onset of a tumorigenic programme and that these factors are prime targets for anticancer therapies.

  20. Extramedullary Myeloid Cell Tumour Presenting As Leukaemia Cutis

    Directory of Open Access Journals (Sweden)

    Thappa Devinder Mohan

    2002-01-01

    Full Text Available We herewith report a case of extramedullary myeloid cell tumour presenting as leukaemia cutis for its rarity. It occurred in a 50 year old male patient who presented to us with a 40 days history of painless raised solid skin swellings over the trunk. Histopathological examination of the skin biopsy and bone marrow biopsy showed features suggestive of non-Hodgkin’s lymphoma. Immunophenotyping on skin biopsy specimens and bone marrow biopsy found tumour cells expressing CD43 and Tdt but were negative for CD3 and CD20. These features were consistent with extramedullary myeloid cell tumour involving skin and subcutis (cutaneous manifestation of acute myeloid leukaemia.

  1. Tuning Collective Cell Migration by Cell-Cell Junction Regulation.

    Science.gov (United States)

    Friedl, Peter; Mayor, Roberto

    2017-04-03

    Collective cell migration critically depends on cell-cell interactions coupled to a dynamic actin cytoskeleton. Important cell-cell adhesion receptor systems implicated in controlling collective movements include cadherins, immunoglobulin superfamily members (L1CAM, NCAM, ALCAM), Ephrin/Eph receptors, Slit/Robo, connexins and integrins, and an adaptive array of intracellular adapter and signaling proteins. Depending on molecular composition and signaling context, cell-cell junctions adapt their shape and stability, and this gradual junction plasticity enables different types of collective cell movements such as epithelial sheet and cluster migration, branching morphogenesis and sprouting, collective network migration, as well as coordinated individual-cell migration and streaming. Thereby, plasticity of cell-cell junction composition and turnover defines the type of collective movements in epithelial, mesenchymal, neuronal, and immune cells, and defines migration coordination, anchorage, and cell dissociation. We here review cell-cell adhesion systems and their functions in different types of collective cell migration as key regulators of collective plasticity. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  2. Do migrating cells need a nucleus?

    Science.gov (United States)

    Hawkins, Rhoda J

    2018-03-05

    How the nucleus affects cell polarity and migration is unclear. In this issue, Graham et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201706097) show that enucleated cells polarize and migrate in two but not three dimensions and propose that the nucleus is a necessary component of the molecular clutch regulating normal mechanical responses. © 2018 Hawkins.

  3. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells.

    Directory of Open Access Journals (Sweden)

    Nicolas Goudin

    Full Text Available Natural regulatory T (Treg cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy.

  4. Scrotal Involvement with Testicular Nonseminomatous Germ Cell Tumour

    Directory of Open Access Journals (Sweden)

    C. G. O’Leary

    2016-01-01

    Full Text Available A 37-year-old male presented with a traumatic injury to the scrotal region necessitating emergency surgery. Evacuation of a haematoma and bilateral orchidectomy were performed. A left sided nonseminomatous germ cell tumour (NSGCT, predominantly yolk sac, was identified. Microscopic margins were positive for tumour. Initial tumour markers revealed an AFP of 22,854 ng/mL, HCG of <1 mIU/mL, and LDH of 463 IU/L. Eight weeks after surgery, AFP levels remained elevated at 11,646 ng/mL. Computed tomography (CT scanning demonstrated left inguinal adenopathy, 1.5 cm in max dimension. On review, extensive evidence of scrotal involvement was evident. His tumour was staged as stage IIIC, poor risk NSGCT. He was treated with 4 cycles of bleomycin, etoposide, and cisplatin over a 12-week period. His tumour markers normalised after 3 cycles. There was a marked improvement noted clinically. Follow-up CT scans demonstrated complete resolution of his tumour. He later underwent further surgery to remove a small amount of remaining spermatic cord. Histology revealed no malignant tissue. The patient suffered many complications including testosterone deficiency, osteopenia, infertility, and psychological distress. Discussion. A small proportion of testicular cancer may present in an atypical manner. The scrotum and testicle have markedly different embryonic origins and therefore a distinct anatomic separation. As a result the scrotum is not a typical site of spread of testicular cancer. Case reports have been described that were managed in a similar manner with good outcomes. Therefore, even with significant scrotal involvement, if timely and appropriate treatment is administered, complete resolution of the tumour may be achieved.

  5. Clinical and genetic aspects of testicular germ cell tumours

    NARCIS (Netherlands)

    Holzik, Martijn F. Lutke; Sijmons, Rolf H.; Hoekstra-Weebers, Josette E. H. M.; Sleijfer, Dirk Th.; Hoekstra, Harald J.

    2008-01-01

    In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs). TGCT is the most common type of malignant disorder in men aged 15-40 years. Its incidence has increased sharply in recent years. Fortunately, survival of patients with TGCT has improved enormously, which

  6. Sacrococcygeal germ-cell tumours - the Red Cross War Memorial ...

    African Journals Online (AJOL)

    Patients. Twenty-seven patients with sacrococcygeal germ-cell tumours were treated in our hospital from 1980 to 1996. Design. A retrospective review of these patients' records was undertaken. Results. There were 19 female and 8 male patients. Seventeen (63%) presented in the neonatal period, 13 on the first day of life.

  7. Future use of mitocans against tumour-initiating cells?

    Czech Academy of Sciences Publication Activity Database

    Morrison, B.J.; Anděra, Ladislav; Reynolds, B.A.; Ralph, S.J.; Neužil, Jiří

    2009-01-01

    Roč. 53, č. 1 (2009), s. 147-153 ISSN 1613-4125 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mitocans * tumour-initiating cells * metastasis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.356, year: 2009

  8. Genetic analysis of neonatal and infantile germ cell tumours.

    NARCIS (Netherlands)

    Veltman, I.M.

    2006-01-01

    Human germ cell tumours (GCTs) can be classified into five distinct types, based on differences in anatomical location, histology, clinical outcome, age and genotype. The first type, the type I GCTs primarily occur in neonates and infants under the age of five years and include teratomas and yolk

  9. Proximal Osteoarticular Fibular Autograft for Giant Cell Tumour of ...

    African Journals Online (AJOL)

    Out of the various reconstructive procedures described, the option of non vascularised proximal fibular autograft has been widely used with satisfactory results. The case of a woman presenting with Campanacci grade 3 giant cell tumour treated by this method with a follow-up of 30 months is reported. Emphasis is placed on ...

  10. Mitochondria: An intriguing target for killing tumour-initiating cells

    Czech Academy of Sciences Publication Activity Database

    Yan, B.; Dong, L.; Neužil, Jiří

    2016-01-01

    Roč. 26, JAN 2016 (2016), s. 86-93 ISSN 1567-7249 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Tumour-initiating cell s * ALPHA-TOCOPHERYL SUCCINATE * Therapeutic resistance * Mitochondria Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.704, year: 2016

  11. Maximizing dendritic cell migration in cancer immunotherapy

    NARCIS (Netherlands)

    Verdijk, Pauline; Aarntzen, Erik H. J. G.; Punt, Cornelis J. A.; de Vries, I. Jolanda M.; Figdor, Carl G.

    2008-01-01

    The success of dendritic cell (DC)-based immunotherapy in inducing cellular immunity against tumors is highly dependent on accurate delivery and trafficking of the DC to T-cell-rich areas of secondary lymphoid tissues. To provide an overview of DC migration in vivo and how migration to peripheral

  12. Intracapillary HbO2 saturations in murine tumours and human tumour xenografts measured by cryospectrophotometry: relationship to tumour volume, tumour pH and fraction of radiobiologically hypoxic cells.

    Science.gov (United States)

    Rofstad, E K; Fenton, B M; Sutherland, R M

    1988-05-01

    Frequency distributions for intracapillary HbO2 saturation were determined for two murine tumour lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI) using a cryospectrophotometric method. The aim was to search for possible relationships between HbO2 saturation status and tumour volume, tumour pH and fraction of radiobiologically hypoxic cells. Tumour pH was measured by 31P NMR spectroscopy. Hypoxic fractions were determined from cell survival curves for tumours irradiated in vivo and assayed in vitro. Tumours in the volume range 100-4000 mm3 were studied and the majority of the vessels were found to have HbO2 saturations below 10%. The volume-dependence of the HbO2 frequency distributions differed significantly among the four tumour lines; HbO2 saturation status decreased with increasing tumour volume for the KHT, RIF-1 and MLS lines and was independent of tumour volume for the OWI line. The data indicated that the rate of decrease in HbO2 saturation status during tumour growth was related to the rate of development of necrosis. The volume-dependence of tumour pH was very similar to that of the HbO2 saturation status for all tumour lines. Significant correlations were therefore found between HbO2 saturation status and tumour pH, both within tumour lines and across the four tumour lines, reflecting that the volume-dependence of both parameters probably was a compulsory consequence of reduced oxygen supply conditions during tumour growth. Hypoxic fraction increased during tumour growth for the KHT, RIF-1 and MLS lines and was volume-independent for the OWI line, suggesting a relationship between HbO2 saturation status and hypoxic fraction within tumour lines. However, there was no correlation between these two parameters across the four tumour lines, indicating that the hypoxic fraction of a tumour is not determined only by the oxygen supply conditions; other parameters may also be important, e.g. oxygen diffusivity, rate of oxygen

  13. Tuning Collective Cell Migration by Cell-Cell Junction Regulation

    NARCIS (Netherlands)

    Friedl, P.; Mayor, R.

    2017-01-01

    Collective cell migration critically depends on cell-cell interactions coupled to a dynamic actin cytoskeleton. Important cell-cell adhesion receptor systems implicated in controlling collective movements include cadherins, immunoglobulin superfamily members (L1CAM, NCAM, ALCAM), Ephrin/Eph

  14. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.

    Science.gov (United States)

    Sousa, Cristovão M; Biancur, Douglas E; Wang, Xiaoxu; Halbrook, Christopher J; Sherman, Mara H; Zhang, Li; Kremer, Daniel; Hwang, Rosa F; Witkiewicz, Agnes K; Ying, Haoqiang; Asara, John M; Evans, Ronald M; Cantley, Lewis C; Lyssiotis, Costas A; Kimmelman, Alec C

    2016-08-25

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.

  15. Recurrent Giant cell tumour in distal Humerus: A Case report

    Directory of Open Access Journals (Sweden)

    Y Bhanu Rekha

    2013-07-01

    Full Text Available Introduction: Giant cell tumour of bone (GCT is a common benign primary bone tumour, seen commonly in the distal Femur, proximal Tibia and distal Radius. Very few cases of GCT are reported in distal humerus. We report an unusual presentation of recurrent Giant cell tumour in a 25 year old male in the medial condyle and epicondyle of left Humerus. Case Report: Patient presented elsewhere with lytic lesion of left elbow three years ago. As it is an uncommon site for tumors, it was misdiagnosed as tuberculous osteomyelitis and was inadequately curetted. Patient presented to us with recurrence of tumor one year after the primary surgery. We did en-bloc resection of the tumour, with judicious removal of partial trochlea. Though reconstruction was planned, it was found to be not necessary as the elbow was stable per-operatively. Patient regained near normal movements of the elbow with no instability. His Mayo Elbow Performance score improved from 30 to 85.There is no recurrence or metastasis of the tumor in the two-year follow-up. Conclusion: Though bone tumors are rare in distal Humerus, biopsy is needed to confirm the diagnosis of any lytic lesion in this region for proper management. Keywords: Recurrent Giant cell tumor, resection of GCT, GCT distal Humerus.

  16. Shifting the optimal stiffness for cell migration.

    Science.gov (United States)

    Bangasser, Benjamin L; Shamsan, Ghaidan A; Chan, Clarence E; Opoku, Kwaku N; Tüzel, Erkan; Schlichtmann, Benjamin W; Kasim, Jesse A; Fuller, Benjamin J; McCullough, Brannon R; Rosenfeld, Steven S; Odde, David J

    2017-05-22

    Cell migration, which is central to many biological processes including wound healing and cancer progression, is sensitive to environmental stiffness, and many cell types exhibit a stiffness optimum, at which migration is maximal. Here we present a cell migration simulator that predicts a stiffness optimum that can be shifted by altering the number of active molecular motors and clutches. This prediction is verified experimentally by comparing cell traction and F-actin retrograde flow for two cell types with differing amounts of active motors and clutches: embryonic chick forebrain neurons (ECFNs; optimum ∼1 kPa) and U251 glioma cells (optimum ∼100 kPa). In addition, the model predicts, and experiments confirm, that the stiffness optimum of U251 glioma cell migration, morphology and F-actin retrograde flow rate can be shifted to lower stiffness by simultaneous drug inhibition of myosin II motors and integrin-mediated adhesions.

  17. Glycolipids of human primary testicular germ cell tumours.

    Science.gov (United States)

    Olie, R. A.; Fenderson, B.; Daley, K.; Oosterhuis, J. W.; Murphy, J.; Looijenga, L. H.

    1996-01-01

    The glycolipid content of human non-seminomatous germ cell tumour cell lines correlates with their differentiation lineage. To analyse whether this reflects the situation in primary tumours, we studied five embryonal carcinomas, five yolk sac tumours and nine (mixed) non-seminomas, using thin-layer chromatography and carbohydrate immunostaining. We also analysed the glycolipid content of 19 seminomas to reveal their relationship with non-seminomas. Lactosylceramide (CDH) was detected in all embryonal carcinomas, but in fewer than half of the seminomas. Seminomas and embryonal carcinomas contained globoseries glycolipids, including globotriosylceramide (Gb3), globoside (Gb4), galactosy globoside (Gb5) and sialy1 galactosyl globoside (GL7). The lacto-series glycolipid Le(x) was found in all embryonal carcinomas, but only in one seminoma. Gangliosides GD3 and GT3 were detected in many seminomas, but rarely in embryonal carcinomas. Yolk sac tumours displayed a heterogeneous glycolipid profile. Compared with seminomas and pure embryonal carcinomas, differentiated non-seminomas had reduced levels of globo-series glycolipids, especially Gb3 and Gb5, whereas CDH, Le(x), GD3 and GT3 were found in the majority of cases. Thus, the glycolipid content of non-seminoma cell lines reflects the situation in primary tumours. Globo-series glycolipids are similarly expressed in seminomas and embryonal carcinomas. The expression of Gb3 and Gb5 is reduced in non-seminomas upon differentiation. Le(x) expression in non-seminomas, including embryonal carcinomas, allows discrimination from seminomas. Expression of gangliosides in seminomas might indicate their maturation from ganglioside-negative precursor cells. Reprogramming of these precursors would result in the formation of Le(x)-expressing embryonal carcinomas. Images Figure 1 Figure 2 PMID:8679447

  18. Tumour-cell killing by X-rays and immunity quantitated in a mouse model system

    International Nuclear Information System (INIS)

    Porteous, D.D.; Porteous, K.M.; Hughes, M.J.

    1979-01-01

    As part of an investigation of the interaction of X-rays and immune cytotoxicity in tumour control, an experimental mouse model system has been used in which quantitative anti-tumour immunity was raised in prospective recipients of tumour-cell suspensions exposed to varying doses of X-rays in vitro before injection. Findings reported here indicate that, whilst X-rays kill a proportion of cells, induced immunity deals with a fixed number dependent upon the immune status of the host, and that X-rays and anti-tumour immunity do not act synergistically in tumour-cell killing. The tumour used was the ascites sarcoma BP8. (author)

  19. Red blood cells inhibit tumour cell adhesion to the peritoneum

    NARCIS (Netherlands)

    M.E.E. van Rossen (Marie Elma); M.P.O. Stoop (M. P O); L.J. Hofland (Leo); P.M. van Koetsveld (Peter); F. Bonthuis (Fred); J. Jeekel (Hans); R.L. Marquet (Richard); C.H.J. van Eijck (Casper)

    1999-01-01

    textabstractBackground: Perioperative blood transfusion has been associated with increased tumour recurrence and poor prognosis in colorectal cancer. Blood loss in the peritoneal cavity might be a tumour-promoting factor for local recurrence. The aim of this study was to investigate whether blood in

  20. New evidence for the origin of intracranial germ cell tumours from primordial germ cells

    DEFF Research Database (Denmark)

    Hoei-Hansen, C E; Sehested, A; Juhler, M

    2006-01-01

    Primary intracranial germ cell tumours are rare neoplasms that occur in children and adolescents. This study examined both the biology and the origin of these tumours, as it has been hypothesized that they originate from a totipotent primordial germ cell. We applied recent knowledge from gonadal...... germ cell tumours and analysed expression of a wide panel of stem cell-related proteins (C-KIT, OCT-3/4 (POU5F1), AP-2gamma (TFAP2C), and NANOG) and developmentally regulated germ cell-specific proteins (including MAGE-A4, NY-ESO-1, and TSPY). Expression at the protein level was analysed in 21 children...

  1. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration.

    Directory of Open Access Journals (Sweden)

    Sylvie Lachmann

    Full Text Available The mammalian protein kinase N (PKN family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

  2. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration.

    Science.gov (United States)

    Lachmann, Sylvie; Jevons, Amy; De Rycker, Manu; Casamassima, Adele; Radtke, Simone; Collazos, Alejandra; Parker, Peter J

    2011-01-01

    The mammalian protein kinase N (PKN) family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s) of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

  3. Human neutrophils facilitate tumor cell transendothelial migration.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

  4. Evaluation of GLUT-1 in the granular cell tumour and congenital granular cell epulis.

    Science.gov (United States)

    Souto, Giovanna Ribeiro; Caldeira, Patrícia Carlos; Johann, Aline Cristina Batista Rodrigues; Andrade Marigo, Helenicede; Souza, Suzana Cantanhede Orsini Machadode; Mesquita, Ricardo Alves

    2013-07-01

    The glucose transporter type 1 (GLUT-1) protein is a useful marker for perineurial cells. Because of the possible neuroectodermal histogenesis of the granular cell tumour and congenital granular cell epulis, the aim of this study was to assess the immunoexpression of GLUT-1 protein in granular cell tumour and congenital granular cell epulis to aid in clarifying their histogenesis. The protocol of this study was approved by the Committee of Bioethics in Research at Universidade Federal Minas Gerais. Six cases of granular cell tumour and three cases of congenital granular cell epulis were submitted to immunohistochemistry for GLUT-1 and S-100 using the streptavidin-biotin standard protocol. Five cases of granular cell tumour were located on the tongue and one case on the upper lip. All cases of congenital granular cell epulis were observed in the alveolar ridge of newborns. All lesions evaluated proved to be immunonegative for GLUT-1. S-100 was found to be positive in all granular cell tumours and negative in congenital granular cell epulis. Neither granular cell tumour nor congenital granular cell epulis is directly related to perineurial cells. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Detection of circulating tumour cells on mRNA levels with established breast cancer cell lines.

    Science.gov (United States)

    Zebisch, Michael; Kölbl, Alexandra C; Andergassen, Ulrich; Hutter, Stephan; Neugebauer, Julia; Engelstädter, Verena; Günthner-Biller, Maria; Jeschke, Udo; Friese, Klaus; Rack, Brigitte

    2013-03-01

    Circulating tumour cells were detected and quantified by real-time polymerase chain reaction (PCR) in peripheral blood, based on the fact that the expression of certain genes is upregulated in tumour tissues in comparison to surrounding blood cells. Calibration curves showing gene expression as functions of the number of tumour cells within a blood sample were prepared. Blood samples were therefore spiked with cells of breast cancer cell lines, RNA was extracted, transcribed to complementary DNA (cDNA) and used in real-time PCR reaction on the Cytokeratins (CK) 8, 18 and 19. Calibration curves were generated by Microsoft™ Excel®. Relative quantification curves of gene expression in different breast cancer cell lines showed no unitary tendencies. The oscillations in the relative quantification curves of gene expression suggested an occurrence of immunological effects, leading to an apparent agglutination of added tumour cells together with the blood cells of the sample. Thus, strategies to obtain evaluable results should be considered.

  6. Rho GTPases in collective cell migration

    NARCIS (Netherlands)

    Zegers, M.M.; Friedl, P.

    2014-01-01

    The family of Rho GTPases are intracellular signal transducers that link cell surface signals to multiple intracellular responses. They are best known for their role in regulating actin dynamics required for cell migration, but in addition control cell-cell adhesion, polarization, vesicle

  7. Giant Cell Tumour of Tendon Sheath Masquerading As Trigger Finger

    Directory of Open Access Journals (Sweden)

    N Rahimawati

    2010-11-01

    Full Text Available We report a case of a 59-year-old female who presented in the general orthopaedic clinic with triggering of her right middle finger. She did not respond to conventional treatment methods; subsequently she underwent surgical open release under local anaesthesia. Five months postoperatively, the patient presented with signs and symptoms of acute flexor tenosynovitis, and was thought to have a postoperative infection. Re-examination by a hand surgeon raised the possibility of a different aetiology. Based on clinical findings and response to initial treatment, giant cell tumour of the flexor tendon sheath was suspected and later confirmed following surgical biopsy. A high index of suspicion and knowledge of the variegated presentations of giant cell tumour in the hand are beneficial in these types of cases.

  8. Cytotoxic effects of radiation and docetaxel in human tumour cells

    Energy Technology Data Exchange (ETDEWEB)

    Dunne, A.L

    2000-12-01

    Data from both single institutions and from randomised multicentre trials have demonstrated that the combination of chemotherapy with radiotherapy can increase the survival of cancer patients. Treatment regimens consisting of taxanes (paclitaxel and docetaxel), a potent class of new chemotherapeutic agents, combined with radiotherapy have recently undergone preclincal investigation. Overall, these studies show that taxanes can enhance the radiation sensitivity of tumour cells. However, data on docetaxel is very limited and the mechanism of radiosensitisation by docetaxel remains largely unknown. The chief purpose of this thesis was to investigate the ability of docetaxel to radiosensitise human tumour cells and investigate potential mechanisms for radiosensitisation. The results reported here for docetaxel indicate that for the cell fines examined this drug does have a synergistic effect and is thus a radiosensitising agent. The degree of radiosensitisation seen seems to be largely dependent on drug concentration. A mechanism involving docetaxel potentiation of radiation-induced apoptosis is also suggested. The second purpose of this thesis is to investigate the potential usefulness of an apoptosis assay and the comet assay as biological indicators for cellular radiosensitivity. Many scientists and clinicans have highlighted the need for development of new rapid, predictive assays of radiation responses. If the radiosensitivity of tumours could be predicted, it may eventually allow the individualisation of patient treatment by radiotherapy. In summary, initial DNA damage measured using the comet assay was successful in predicting the radiosensitivity of colorectal tumour cells. The results suggest that the comet assay appears more suitable than the detection of apoptosis for the prediction of radiosensitivity. We conclude that the results obtained from this thesis will contribute to the current attempts to improve the radiotherapeutic management of cancer. (author)

  9. Entropy measures of collective cell migration

    Science.gov (United States)

    Whitby, Ariadne; Parrinello, Simona; Faisal, Aldo

    2015-03-01

    Collective cell migration is a critical process during tissue formation and repair. To this end there is a need to develop tools to quantitatively measure the dynamics of collective cell migration obtained from microscopy data. Drawing on statistical physics we use entropy of velocity fields derived from dense optic flow to quantitatively measure collective migration. Using peripheral nerve repair after injury as experimental system, we study how Schwann cells, guided by fibroblasts, migrate in cord-like structures across the cut, paving a highway for neurons. This process of emergence of organised behaviour is key for successful repair, yet the emergence of leader cells and transition from a random to ordered state is not understood. We find fibroblasts induce correlated directionality in migrating Schwann cells as measured by a decrease in the entropy of motion vector. We show our method is robust with respect to image resolution in time and space, giving a principled assessment of how various molecular mechanisms affect macroscopic features of collective cell migration. Finally, the generality of our method allows us to process both simulated cell movement and microscopic data, enabling principled fitting and comparison of in silico to in vitro. ICCS, Imperial College London & MRC Clinical Sciences Centre.

  10. Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine hemangiosarcoma.

    Science.gov (United States)

    Im, K S; Graef, A J; Breen, M; Lindblad-Toh, K; Modiano, J F; Kim, J-H

    2017-06-01

    The CXCR4/CXCL12 axis plays an important role in cell locomotion and metastasis in many cancers. In this study, we hypothesized that the CXCR4/CXCL12 axis promotes migration and invasion of canine hemangiosarcoma (HSA) cells. Transcriptomic analysis across 12 HSA cell lines and 58 HSA whole tumour tissues identified heterogeneous expression of CXCR4 and CXCL12, which was associated with cell movement. In vitro, CXCL12 promoted calcium mobilization, cell migration and invasion that were directly proportional to surface expression of CXCR4; furthermore, these responses proved sensitive to the CXCR4 antagonist, AMD3100, in HSA cell lines. These results indicate that CXCL12 potentiates migration and invasion of canine HSA cells through CXCR4 signalling. The direct relationship between these responses in HSA cells suggests that the CXCR4/CXCL12 axis contributes to HSA progression. © 2015 John Wiley & Sons Ltd.

  11. Isolated flavonoids against mammary tumour cells LM2.

    Science.gov (United States)

    Carli, Camila B de A; de Matos, Djamile C; Lopes, Flávia C M; Maia, Danielle C G; Dias, Maristela B; Sannomiya, Miriam; Rodrigues, Clenilson M; Andreo, Marcio A; Vilegas, Wagner; Colombo, Lucas L; Carlos, Iracilda Z

    2009-01-01

    The purpose of the present study was to investigate antitumour and anti-inflammatory activities of flavonoids isolated from Byrsonima crassa, Davilla elliptica and Mouriri pusa. The antitumour activity was measured by the MTT assay in murine mammary tumour cells (LM2) and the IC50 values of the flavonoids tested ranged from (31.5 +/- 2.97) to (203.1 +/- 5.9) microg/ml. The flavonoids 1 (myricetin-3-O-alpha-L-rhamnopyranoside) and 3 (quercetin-3-O-galactopyranoside) from D. elliptica were the most active ones against the tumour cells. The same samples were tested to determine the inhibition of the release of nitric oxide (NO) and of the tumour necrosis factor-alpha (TNF-alpha) in murine macrophages by the Griess and ELISA sandwich assay, respectively. Almost all the samples showed inhibitory activity to the release of NO but not of TNF-alpha. Of all substances tested, flavonoids 2 (quercetin) and 6 (myricetin) may show promising activity in the treatment of murine breast cancer by immunomodulatory and antiproliferative activities.

  12. ASIC proteins regulate smooth muscle cell migration.

    Science.gov (United States)

    Grifoni, Samira C; Jernigan, Nikki L; Hamilton, Gina; Drummond, Heather A

    2008-03-01

    The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated that Epithelial Na(+)Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration; however, the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence individual ASIC expression and determine the importance of ASIC proteins in wound healing and chemotaxis (PDGF-bb)-initiated migration. We found ASIC1, ASIC2, and ASIC3, but not ASIC4, expression in A10 cells. ASIC1, ASIC2, and ASIC3 siRNA molecules significantly suppressed expression of their respective proteins compared to non-targeting siRNA (RISC) transfected controls by 63%, 44%, and 55%, respectively. Wound healing was inhibited by 10, 20, and 26% compared to RISC controls following suppression of ASIC1, ASIC2, and ASIC3, respectively. Chemotactic migration was inhibited by 30% and 45%, respectively, following suppression of ASIC1 and ASIC3. ASIC2 suppression produced a small, but significant, increase in chemotactic migration (4%). Our data indicate that ASIC expression is required for normal migration and may suggest a novel role for ASIC proteins in cellular migration.

  13. Monocytes and macrophages, implications for breast cancer migration and stem cell-like activity and treatment

    Science.gov (United States)

    Ward, Rebecca; Sims, Andrew H.; Lee, Alexander; Lo, Christina; Wynne, Luke; Yusuf, Humza; Gregson, Hannah; Lisanti, Michael P.; Sotgia, Federica; Landberg, Göran; Lamb, Rebecca

    2015-01-01

    Macrophages are a major cellular constituent of the tumour stroma and contribute to breast cancer prognosis. The precise role and treatment strategies to target macrophages remain elusive. As macrophage infiltration is associated with poor prognosis and high grade tumours we used the THP-1 cell line to model monocyte-macrophage differentiation in co-culture with four breast cancer cell lines (MCF7, T47D, MDA-MB-231, MDA-MB-468) to model in vivo cellular interactions. Polarisation into M1 and M2 subtypes was confirmed by specific cell marker expression of ROS and HLA-DR, respectively. Co-culture with all types of macrophage increased migration of ER-positive breast cancer cell lines, while M2-macrophages increased mammosphere formation, compared to M1-macrophages, in all breast cancer cells lines. Treatment of cells with Zoledronate in co-culture reduced the “pro-tumourigenic” effects (increased mammospheres/migration) exerted by macrophages. Direct treatment of breast cancer cells in homotypic culture was unable to reduce migration or mammosphere formation. Macrophages promote “pro-tumourigenic” cellular characteristics of breast cancer cell migration and stem cell activity. Zoledronate targets macrophages within the microenvironment which in turn, reduces the “pro-tumourigenic” characteristics of breast cancer cells. Zoledronate offers an exciting new treatment strategy for both primary and metastatic breast cancer. PMID:26008983

  14. Is cell survival a determinant of the in situ response of 9L tumours

    International Nuclear Information System (INIS)

    Wheeler, K.T.; Wallen, C.A.

    1980-01-01

    The influence of growth rate, location, size and potential lethal damage (PLD) recovery on the cellular radiosensitivity and the tumour response was studied in 9L/Ro and 9L/SF rat tumours. The median day of death of rats bearing the intracerebral (i.c.) 9L/Ro tumours was 16-18 days; for i.c. 9L/SF tumours it was 23-25 days. The doubling time of 9L/Ro cells was slightly faster than for 9L/SF cells both in culture and in the brain. The cellular radiosensitivity of both i.c. tumour cell sublines was identical. However, subcutaneous (s.c.) 9L/Ro tumour cells were more resistant. There was no evidence of a substantial hypoxic fraction in either site. When i.c. 9L/Ro and 9L/SF tumours of similar size were treated with fractionated doses of BCNU, X-rays or combinations of the two, the responses of the two tumours were essentially identical. The rate of recovery from radiation-induced PLD was identical in the two sublines and the two sites. Increase in life-span of rats bearing i.c. 9L/Ro tumours appeared to be correlated with the tumour cell kill measured after completion of PLD recovery rather than with the tumour cell kill determined immediately after irradiation. (author)

  15. Prognostic value of the CD4+/ CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells

    DEFF Research Database (Denmark)

    Diederichsen, Axel Cosmus Pyndt; Hjelmborg, J v B; Christensen, Per B

    2003-01-01

    The purpose of this study was to clarify whether HLA-DR expression of colorectal tumour cells or the CD4+/CD8+ ratio of the tumour infiltrating lymphocytes is significantly associated with the prognosis of colorectal cancer. Using flow cytometry, we studied the tumour cell expression of the HLA...... class II in 70 enzymatically dissociated colorectal cancers and the phenotype of tumour infiltrating lymphocytes (TILs) in 41 cases. There was no trend in 5-year survival between three levels (low, medium, high) of HLA-DR expression on the tumour cells. Patients with low CD4+/CD8+ ratios had a better...... clinical course, with significantly higher 5-year survival, p=0.046, independent of the Dukes stage and age. Our results have implications for tumour immunology; colorectal cancer cells might be a target for cytotoxic T-lymphocytes, however the tumour cells are not able to initiate an immune response...

  16. Primary Cilia, Signaling Networks and Cell Migration

    DEFF Research Database (Denmark)

    Veland, Iben Rønn

    Primary cilia are microtubule-based, sensory organelles that emerge from the centrosomal mother centriole to project from the surface of most quiescent cells in the human body. Ciliary entry is a tightly controlled process, involving diffusion barriers and gating complexes that maintain a unique...... and cytoskeletal organization. Further, cell migration and polarization in are impaired in Invs MEFs. In two-dimensional cell migration, the centrosome is positioned between the nucleus and the leading edge with the primary cilium directed towards the direction of migration. PDGFRα is activated in the primary......, which leads to uncontrolled cell movements. Together, the results obtained from my PhD studies reflect the high level of complexity within signaling systems regulated by the primary cilium that control cellular processes during embryonic development and in tissue homeostasis. As such, this dissertation...

  17. Rho GTPases: masters of cell migration.

    Science.gov (United States)

    Sadok, Amine; Marshall, Chris J

    2014-01-01

    Since their discovery in the late eighties, the role of Rho GTPases in the regulation of cell migration has been extensively studied and has mainly focused on the hallmark family members Rho, Rac, and Cdc42. Recent technological advances in cell biology, such as Rho-family GTPase activity biosensors, studies in 3D, and unbiased RNAi-based screens, have revealed an increasingly complex role for Rho GTPases during cell migration, with many inter-connected functions and a strong dependency on the physical and chemical properties of the surrounding environment. This review aims to give an overview of recent studies on the role of Rho-family GTPase members in the modulation of cell migration in different environments, and discuss future directions.

  18. Maximizing dendritic cell migration in cancer immunotherapy.

    NARCIS (Netherlands)

    Verdijk, P.; Aarntzen, E.H.J.G.; Punt, C.J.A.; Vries, I.J.M. de; Figdor, C.G.

    2008-01-01

    BACKGROUND: The success of dendritic cell (DC)-based immunotherapy in inducing cellular immunity against tumors is highly dependent on accurate delivery and trafficking of the DC to T-cell-rich areas of secondary lymphoid tissues. OBJECTIVE: To provide an overview of DC migration in vivo and how

  19. Carcinoma in situ testis, the progenitor of testicular germ cell tumours

    DEFF Research Database (Denmark)

    Hoei-Hansen, C E; Rajpert-De Meyts, E; Daugaard, G

    2005-01-01

    Testicular germ cell tumours (TGCT), including seminomas, embryonal carcinomas, teratomas and yolk sac tumours, have a common precursor, the carcinoma in situ (CIS) cell. Recent gene expression studies displaying close similarity of CIS cells to embryonic stem cells support the longstanding theory...

  20. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity.

    Science.gov (United States)

    Marusyk, Andriy; Tabassum, Doris P; Altrock, Philipp M; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia

    2014-10-02

    Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

  1. Chromatin structure and epigenetics of tumour cells: A review

    Czech Academy of Sciences Publication Activity Database

    Bártová, Eva; Krejčí, Jana; Hájek, R.; Harničarová, Andrea; Kozubek, Stanislav

    2009-01-01

    Roč. 9, č. 1 (2009), s. 51-61 ISSN 1871-529X R&D Projects: GA AV ČR(CZ) 1QS500040508; GA ČR(CZ) GA204/06/0978 Grant - others:GA MŠk(CZ) LC06027; GA MŠk(CZ) LC535 Program:LC; LC Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : tumour cells * chromatin * radiation Subject RIV: BO - Biophysics

  2. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-04-26

    Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

  3. Histomorphological and immunohistochemical characterization of 172 cutaneous round cell tumours in dogs

    Directory of Open Access Journals (Sweden)

    Marina Rios Araújo

    2012-08-01

    Full Text Available This paper describes the use of a panel of antibodies (CD117, CD3, CD79a, CD45, cytokeratin, vimentin and E-cadherin on formalin-fixed, paraffin-embedded sections of canine cutaneous round cell tumours. Neoplastic tumours were diagnosed by histology and histochemical stains and included 107 mast cell tumours, 31 cutaneous histiocytomas, two localized histiocytic sarcomas, 21 cutaneous lymphomas, three plasma cell tumours, one transmissible venereal tumour and seven unclassified round cell tumours. The histologic diagnosis was modified in 39.5% of the total 172 neoplasms. The staining for CD45 and Ecadherin were variable, and therefore, the final diagnoses of cutaneous histiocytoma and localized histiocytic sarcoma were made based on histology in association with negative results for CD3, CD79a, CD117 and cytokeratin. The cellular origin of unclassified round cell tumours was defined in all cases. Cutaneous B-cell lymphoma and plasma cell tumours were CD79a-positive and could be distinguished from each other by the morphological characteristics. Mast cell tumours and T cell lymphoma were CD117 and CD3 positive, respectively. The positive staining for vimentin and the negative staining for CD3, CD79a, CD117 and cytokeratin favoured the diagnosis of transmissible venereal tumours. Thus, the final diagnosis of cutaneous round cell tumours should be based on the interpretation of immunohistochemical results together with the cellular morphology observed by histology. Therefore, more studies to optimize the specific markers in formalin-fixed, paraffinembedded tissues (especially for histiocytes are required for definitive diagnosis of round cell tumours in dogs.

  4. ASIC PROTEINS REGULATE SMOOTH MUSCLE CELL MIGRATION

    OpenAIRE

    Grifoni, Samira C.; Jernigan, Nikki L.; Hamilton, Gina; Drummond, Heather A.

    2007-01-01

    The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated Epithelial Na+ Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration, however the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence indi...

  5. Galectin-3 coats the membrane of breast cells and makes a signature of tumours

    KAUST Repository

    Simone, Giuseppina

    2014-01-01

    Galectin-3, β-galactoside-binding lectin, coats the membrane of most cancer cells and is involved in metastasis and endothelium recognition as well as in evading immune surveillance through killing of activated T cells. To flag galectin as a biomarker of tumours and metastasis, it is pivotal to understand the role of this protein in different tumours and at different stages. Breast tumours have an anomalous behaviour of the galectin-3 compared to other tumour cells. Herein, FACS sorting and galactoside based assays were used to investigate the role of galectin-3 in metastasis and metastatisation of breast cancer cells. Breast galectin fingerprint at the FACS displayed a higher amount in healthy cells, compared to metastatic cells. The microfluidic assay was able to isolate tumour and metastatic cells more than healthy breast cells. Investigation was performed on samples from patients with breast tumours at stage I and stage III whilst MCF7 and EPH-4 cells were used to perform preliminary investigations. The readout of the conditioned medium (from culturing of stage I cells) fingerprint by FACS evidenced high expression of free galectin. Analysis of the results established that the galectin coating the membrane, by galactoside recognition of the breast cells, and engaged by the cells to form protein-carbohydrate complexes inside the microfluidic assay, resembled the tumour signature of tumours in breast cells whilst the galectin free is independent of those mechanisms. © 2014 The Royal Society of Chemistry.

  6. Saturated and mono-unsaturated lysophosphatidylcholine metabolism in tumour cells: a potential therapeutic target for preventing metastases.

    Science.gov (United States)

    Raynor, Anna; Jantscheff, Peter; Ross, Thomas; Schlesinger, Martin; Wilde, Maurice; Haasis, Sina; Dreckmann, Tim; Bendas, Gerd; Massing, Ulrich

    2015-07-11

    Metastasis is the leading cause of mortality in malignant diseases. Patients with metastasis often show reduced Lysophosphatidylcholine (LysoPC) plasma levels and treatment of metastatic tumour cells with saturated LysoPC species reduced their metastatic potential in vivo in mouse experiments. To provide a first insight into the interplay of tumour cells and LysoPC, the interactions of ten solid epithelial tumour cell lines and six leukaemic cell lines with saturated and mono-unsaturated LysoPC species were explored. LysoPC metabolism by the different tumour cells was investigated by a combination of cell culture assays, GC and MS techniques. Functional consequences of changed membrane properties were followed microscopically by detecting lateral lipid diffusion or cellular migration. Experimental metastasis studies in mice were performed after pretreatment of B16.F10 melanoma cells with LysoPC and FFA, respectively. In contrast to the leukaemic cells, all solid tumour cells show a very fast extracellular degradation of the LysoPC species to free fatty acids (FFA) and glycerophosphocholine. We provide evidence that the formerly LysoPC bound FFA were rapidly incorporated into the cellular phospholipids, thereby changing the FA-compositions accordingly. A massive increase of the neutral lipid amount was observed, inducing the formation of lipid droplets. Saturated LysoPC and to a lesser extent also mono-unsaturated LysoPC increased the cell membrane rigidity, which is assumed to alter cellular functions involved in metastasis. According to that, saturated and mono-unsaturated LysoPC as well as the respective FFA reduced the metastatic potential of B16.F10 cells in mice. Application of high doses of liposomes mainly consisting of saturated PC was shown to be a suitable way to strongly increase the plasma level of saturated LysoPC in mice. These data show that solid tumours display a high activity to hydrolyse LysoPC followed by a very rapid uptake of the resulting FFA

  7. Plasticity of Cell Migration In Vivo and In Silico

    NARCIS (Netherlands)

    Boekhorst, V. Te; Preziosi, L.; Friedl, P.

    2016-01-01

    Cell migration results from stepwise mechanical and chemical interactions between cells and their extracellular environment. Mechanistic principles that determine single-cell and collective migration modes and their interconversions depend upon the polarization, adhesion, deformability,

  8. Plasticity of cell migration: a multiscale tuning model.

    NARCIS (Netherlands)

    Friedl, P.H.A.; Wolf, K. van der

    2010-01-01

    Cell migration underlies tissue formation, maintenance, and regeneration as well as pathological conditions such as cancer invasion. Structural and molecular determinants of both tissue environment and cell behavior define whether cells migrate individually (through amoeboid or mesenchymal modes) or

  9. Transport of calcium ions by Ehrlich ascites-tumour cells.

    Science.gov (United States)

    Landry, Y; Lehninger, A L

    1976-01-01

    Ehrlich ascites-tumour cells accumulate Ca2+ when incubated aerobically with succinate, phosphate and rotenone, as revealed by isotopic and atomic-absorption measurements. Ca2+ does not stimulate oxygen consumption by carefully prepared Ehrlich cells, but des so when the cells are placed in a hypo-osmotic medium. Neither glutamate nor malate support Ca2+ uptake in 'intact' Ehrlich cells, nor does the endogenous NAD-linked respiration. Ca2+ uptake is completely dependent on mitochondrial energy-coupling mechansims. It was an unexpected finding that maximal Ca2+ uptake supported by succinate requires rotenone, which blocks oxidation of enogenous NAD-linked substrates. Phosphate functions as co-anion for entry of Ca2+. Ca2+ uptake is also supported by extra-cellular ATP; no other nucleoside 5'-di- or tri-phosphate was active. The accumulation of Ca2+ apparently takes place in the mitochondria, since oligomycin and atractyloside inhibit ATP-supported Ca2+ uptake. Glycolysis does not support Ca2+ uptake. Neither free mitochondria released from disrupted cells nor permeability-damaged cells capable of absorbing Trypan Blue were responsible for any large fraction of the total observed energy-coupled Ca2+ uptake. The observations reported also indicate that electron flow through energy-conserving site 1 promotes Ca2+ release from Ehrlich cells and that extra-cellular ATP increase permeability of the cell membrane, allowing both ATP and Ca2+ to enter the cells more readily. PMID:988829

  10. Laminin α5-derived peptides modulate the properties of metastatic breast tumour cells.

    Science.gov (United States)

    Kusuma, Nicole; Anderson, Robin L; Pouliot, Normand

    2011-12-01

    The basement membrane protein laminin-511 has been implicated in breast cancer progression and metastasis. To identify peptides from LM-511 that modulate the metastatic properties of breast tumours, we screened laminin alpha 5 chain-derived peptides for their ability to promote adhesion of metastatic mammary carcinoma cells. Two selected adhesive peptides, α5A13b (FHVAYVLIKF) from the LN domain and A5G27 (RLVSYNGIIFFLK) from the LG-globular domain, were further characterised for their inhibitory properties against LM-511 activities in vitro and metastasis in vivo. In vitro, these peptides strongly inhibited LM-511-dependent adhesion and migration of highly metastatic 4T1.2 mammary carcinoma cells. In addition, A5G27 but not α5A13b significantly reduced breast tumour cell proliferation and inhibited laminin-511-induced matrix metalloproteinase-9 expression. Surprisingly, despite its potent inhibitory activity in vitro, A5G27 promoted rather than inhibited 4T1.2 experimental pulmonary metastasis in vivo, regardless of its route of administration. Adhesion of 4T1.2 cells to A5G27 was not inhibited by antibodies directed against α6, β1 or β3 integrins or CD44 but was significantly reduced in the presence of heparin suggesting a role for cell surface glycans. Treatment of the cells with α-L-fucosidase but not neuraminidase or heparinase II also partially inhibited cell adhesion to A5G27 and to LM-511 indicating that these interactions are mediated in part via terminal fucosyl residues. Overall, these results show that LMα5 peptides exhibit distinct functional properties in vitro and in vivo and suggest that interactions between the RLVSYNGIIFFLK sequence present in LM-511 and cell surface glycans may regulate LM-511 metastatic properties in vivo.

  11. Rapid and non-enzymatic in vitro retrieval of tumour cells from surgical specimens.

    Directory of Open Access Journals (Sweden)

    Brigitte Mack

    Full Text Available The study of tumourigenesis commonly involves the use of established cell lines or single cell suspensions of primary tumours. Standard methods for the generation of short-term tumour cell cultures include the disintegration of tissue based on enzymatic and mechanical stress. Here, we describe a simple and rapid method for the preparation of single cells from primary carcinomas, which is independent of enzymatic treatment and feeder cells. Tumour biopsies are processed to 1 mm(3 cubes termed explants, which are cultured 1-3 days on agarose-coated well plates in specified medium. Through incisions generated in the explants, single cells are retrieved and collected from the culture supernatant and can be used for further analysis including in vitro and in vivo studies. Collected cells retain tumour-forming capacity in xenotransplantation assays, mimic the phenotype of the primary tumour, and facilitate the generation of cell lines.

  12. Impact of jamming on collective cell migration

    Science.gov (United States)

    Nnetu, Kenechukwu David; Knorr, Melanie; Pawlizak, Steve; Fuhs, Thomas; Zink, Mareike; KäS, Josef A.

    2012-02-01

    Multi-cellular migration plays an important role in physiological processes such as embryogenesis, cancer metastasis and tissue repair. During migration, single cells undergo cycles of extension, adhesion and retraction resulting in morphological changes. In a confluent monolayer, there are inter-cellular interactions and crowding, however, the impact of these interactions on the dynamics and elasticity of the monolayer at the multi-cellular and single cell level is not well understood. Here we study the dynamics of a confluent epithelial monolayer by simultaneously measuring cell motion at the multi-cellular and single cell level for various cell densities and tensile elasticity. At the multi-cellular level, the system exhibited spatial kinetic transitions from isotropic to anisotropic migration on long times and the velocity of the monolayer decreased with increasing cell density. Moreover, the dynamics was spatially and temporally heterogeneous. Interestingly, the dynamics was also heterogeneous in wound-healing assays and the correlation length was fitted by compressed exponential. On the single cell scale, we observed transient caging effects with increasing cage rearrangement times as the system age due to an increase in density. Also, the density dependent elastic modulus of the monolayer scaled as a weak power law. Together, these findings suggest that caging effects at the single cell level initiates a slow and heterogeneous dynamics at the multi-cellular level which is similar to the glassy dynamics of deformable colloidal systems.

  13. Tumour-infiltrating lymphocytes mediate lysis of autologous squamous cell carcinomas of the head and neck

    DEFF Research Database (Denmark)

    Hald, Jeppe; Rasmussen, N; Claesson, Mogens Helweg

    1995-01-01

    Tumour-infiltrating lymphocytes (TIL) and tumours from six patients with squamous cell carcinomas of the head and neck (SCCHN) were investigated. The six tumours all expressed major histocompatibility complex (MHC) class I antigens both in vivo and as tumor cell lines grown in vitro. In addition,...... in a MHC-class-I-restricted fashion. Thus, the results of the present study document that carcinomas of the head and neck in some patients are infiltrated by cytotoxic T cell precursors potentially capable of rejecting the autologous tumour....

  14. Regional tumour glutamine supply affects chromatin and cell identity

    DEFF Research Database (Denmark)

    Højfeldt, Jonas W; Helin, Kristian

    2016-01-01

    Limited perfusion of solid tumours produces a nutrient-deprived tumour core microenvironment. Low glutamine levels in the tumour core are now shown to lead to reduced levels of α-ketoglutarate and decreased histone demethylase activity, thereby promoting a less differentiated and more therapy-res...

  15. Impact of mesenchymal stem cell secreted PAI-1 on colon cancer cell migration and proliferation.

    Science.gov (United States)

    Hogan, Niamh M; Joyce, Myles R; Murphy, J Mary; Barry, Frank P; O'Brien, Timothy; Kerin, Michael J; Dwyer, Roisin M

    2013-06-14

    Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cell (MSC) and colon cancer cell (CCC) interactions. Mesenchymal Stem Cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3-dimensional scaffolds. Conditioned media containing all secreted factors was harvested at day 1, 3 and 7. Chemokine secretion and expression were analyzed by Chemi-array, ELISA (Macrophage migration inhibitory factor (MIF), plasminogen activator inhibitor type 1 (PAI-1)) and RQ-PCR. Colon cancer cell migration and proliferation in response to recombinant PAI-1, MSCs and MSCs+antibody to PAI-1 was analyzed using Transwell inserts and an MTS proliferation assay respectively. Chemi-array revealed secretion of a wide range of factors by each cell population, including PAI-1 and MIF. ELISA analysis revealed Mesenchymal Stem Cells to secrete the highest levels of PAI-1 (MSC mean 10.6 ng/mL, CCC mean 1.01 ng/mL), while colon cancer cells were the principal source of MIF. MSC-secreted PAI-1 stimulated significant migration of both CCC lines, with an antibody to the chemokine shown to block this effect (67-88% blocking,). A cell-line dependant effect on CCC proliferation was shown for Mesenchymal Stem Cell-secreted PAI-1 with HCT-116 cells showing decreased proliferation at all concentrations, and HT29 cells showing increased proliferation in the presence of higher PAI-1 levels. This is the first study to identify PAI-1 as an important mediator of Mesenchymal Stem Cell/colon cancer cell interactions and highlights the significant functional impact of Mesenchymal Stem Cell-secreted PAI-1 on colon cancer cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Vascular niches for disseminated tumour cells in bone

    Directory of Open Access Journals (Sweden)

    Anjali P. Kusumbe

    2016-09-01

    Full Text Available The vasculature of the skeletal system regulates osteogenesis and hematopoiesis, in addition to its primary function as a transportation network. Recent studies suggest that the vasculature in bone regulates multiple steps involved in the metastatic cascade. Matrix and growth factor abundant vascular microenvironments in bone not only provide a fertile soil for the metastatic growth but also support the dormancy of Disseminated Tumour Cells (DTCs. Interestingly, vasculature also seems to direct the reactivation of dormant DTCs. Targeting such early steps of bone metastasis by directing therapies against vascular niches can lead to the development of effective therapeutic strategies that delay or even prevent the metastatic relapse. However, this would require a detailed understanding of the regulatory mechanisms that govern the interaction between endothelial cells and DTCs in the early stages of bone metastasis. This review aims to highlight the importance of vascular niches and outline their newly identified roles during bone metastasis.

  17. Modeling collective cell migration in geometric confinement

    Science.gov (United States)

    Tarle, Victoria; Gauquelin, Estelle; Vedula, S. R. K.; D'Alessandro, Joseph; Lim, C. T.; Ladoux, Benoit; Gov, Nir S.

    2017-06-01

    Monolayer expansion has generated great interest as a model system to study collective cell migration. During such an expansion the culture front often develops ‘fingers’, which we have recently modeled using a proposed feedback between the curvature of the monolayer’s leading edge and the outward motility of the edge cells. We show that this model is able to explain the puzzling observed increase of collective cellular migration speed of a monolayer expanding into thin stripes, as well as describe the behavior within different confining geometries that were recently observed in experiments. These comparisons give support to the model and emphasize the role played by the edge cells and the edge shape during collective cell motion.

  18. Sodium hyaluronate enhances colorectal tumour cell metastatic potential in vitro and in vivo.

    LENUS (Irish Health Repository)

    Tan, B

    2012-02-03

    BACKGROUND: Sodium hyaluronate has been used intraperitoneally to prevent postoperative adhesions. However, the effect of sodium hyaluronate on tumour growth and metastasis in vitro and in vivo is still unknown. METHODS: Human colorectal tumour cell lines SW480, SW620 and SW707 were treated with sodium hyaluronate (10-500 microg\\/ml) and carboxymethylcellulose (0.125-1 per cent), and tumour cell proliferation and motility were determined in vitro. For the in vivo experiments male BD IX rats were randomized to a sodium hyaluronate group (n = 11; intraperitoneal administration of 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml 0.4 per cent sodium hyaluronate) or a phosphate-buffered saline group (n = 11; 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml phosphate-buffered saline intraperitoneally). Four weeks later the intraperitoneal tumour load was visualized directly. RESULTS: In vitro sodium hyaluronate increased tumour cell proliferation and motility significantly. Sodium hyaluronate-induced tumour cell motility appeared to be CD44 receptor dependent, whereas sodium hyaluronate-induced tumour cell proliferation was CD44 receptor independent. In vivo there was a significantly higher total tumour nodule count in the peritoneal cavity of the sodium hyaluronate-treated group compared with the control (P = 0.016). CONCLUSION: Sodium hyaluronate enhances tumour metastatic potential in vitro and in vivo, which suggests that use of sodium hyaluronate to prevent adhesions in colorectal cancer surgery may also potentiate intraperitoneal tumour growth. Presented to the Patey Prize Session of the Surgical Research Society and the annual scientific meeting of the Association of Surgeons of Great Britain and Ireland, Brighton, UK, 4-7 May 1999

  19. Management of Islet Cell Tumours: A Single Hospital Experience.

    Science.gov (United States)

    Fu, Wenguang; Li, Jing; Wen, Jian; Lin, Gao; Wei, Zeng; Deng, Jiaqi; Li, Qiu; Lei, Zhengming

    2015-05-01

    Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs. Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed. Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma. The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia. Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

  20. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

    Directory of Open Access Journals (Sweden)

    Bérengère Gobin

    Full Text Available Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma, a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1. Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma and POS-1 (undifferentiated osteosarcoma. Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R, appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor

  1. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

    Science.gov (United States)

    Gobin, Bérengère; Moriceau, Gatien; Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients.

  2. Migration of cells in a social context

    DEFF Research Database (Denmark)

    Vedel, Søren; Tay, Savas; Johnston, Darius M

    2013-01-01

    In multicellular organisms and complex ecosystems, cells migrate in a social context. Whereas this is essential for the basic processes of life, the influence of neighboring cells on the individual remains poorly understood. Previous work on isolated cells has observed a stereotypical migratory...... behavior characterized by short-time directional persistence with long-time random movement. We discovered a much richer dynamic in the social context, with significant variations in directionality, displacement, and speed, which are all modulated by local cell density. We developed a mathematical model...

  3. Stem cell migration - Methods and protocols

    Directory of Open Access Journals (Sweden)

    Carlo Alberto Redi

    2012-03-01

    Full Text Available The trafficking of stem cells is something unconsciously clear to any biologists (e.g., developmental biologists and physicians (e.g., all those taking care of hematopoietic and bone diseases and traumas; neverthless it is a phenomenon coming out as a hot topic just in these last years. Likely, the difficulties to track stem cells migration in vivo and the understanding of the elusive homing signals matching the circulating stem cells properties that makes these cells to stop and to start multiplication and differentiation....

  4. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Diez Soraya

    2010-03-01

    Full Text Available Abstract Background Wnt-11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development. We previously reported that Wnt-11 expression is elevated in hormone-independent prostate cancer and that the progression of prostate cancer from androgen-dependent to androgen-independent proliferation correlates with a loss of mutual inhibition between Wnt-11- and androgen receptor-dependent signals. However, the prevalence of increased expression of Wnt-11 in patient tumours and the functions of Wnt-11 in prostate cancer cells were not known. Results Wnt-11 protein levels in prostate tumours were determined by immunohistochemical analysis of prostate tumour tissue arrays. Wnt-11 protein was elevated in 77/117 of tumours when compared with 27 benign prostatic hypertrophy specimens and was present in 4/4 bone metastases. In addition, there was a positive correlation between Wnt-11 expression and PSA levels above 10 ng/ml. Androgen-depleted LNCaP prostate cancer cells form neurites and express genes associated with neuroendocrine-like differentiation (NED, a feature of prostate tumours that have a poor prognosis. Since androgen-depletion increases expression of Wnt-11, we examined the role of Wnt-11 in NED. Ectopic expression of Wnt-11 induced expression of NSE and ASCL1, which are markers of NED, and this was prevented by inhibitors of cyclic AMP-dependent protein kinase, consistent with the known role of this kinase in NED. In contrast, Wnt-11 did not induce NSE expression in RWPE-1 cells, which are derived from benign prostate, suggesting that the role of Wnt-11 in NED is specific to prostate cancer. In addition, silencing of Wnt-11 expression in androgen-depleted LNCaP cells prevented NED and resulted in apoptosis. Silencing of Wnt-11 gene expression in androgen-independent PC3 cells also reduced expression of NSE and increased apoptosis. Finally, silencing of Wnt-11 reduced PC3 cell migration and ectopic

  5. L-lactate transport in Ehrlich ascites-tumour cells.

    Science.gov (United States)

    Spencer, T L; Lehninger, A L

    1976-01-01

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids. PMID:7237

  6. Cell migration during heart regeneration in zebrafish.

    Science.gov (United States)

    Tahara, Naoyuki; Brush, Michael; Kawakami, Yasuhiko

    2016-07-01

    Zebrafish possess the remarkable ability to regenerate injured hearts as adults, which contrasts the very limited ability in mammals. Although very limited, mammalian hearts do in fact have measurable levels of cardiomyocyte regeneration. Therefore, elucidating mechanisms of zebrafish heart regeneration would provide information of naturally occurring regeneration to potentially apply to mammalian studies, in addition to addressing this biologically interesting phenomenon in itself. Studies over the past 13 years have identified processes and mechanisms of heart regeneration in zebrafish. After heart injury, pre-existing cardiomyocytes dedifferentiate, enter the cell cycle, and repair the injured myocardium. This process requires interaction with epicardial cells, endocardial cells, and vascular endothelial cells. Epicardial cells envelope the heart, while endocardial cells make up the inner lining of the heart. They provide paracrine signals to cardiomyocytes to regenerate the injured myocardium, which is vascularized during heart regeneration. In addition, accumulating results suggest that local migration of these major cardiac cell types have roles in heart regeneration. In this review, we summarize the characteristics of various heart injury methods used in the research community and regeneration of the major cardiac cell types. Then, we discuss local migration of these cardiac cell types and immune cells during heart regeneration. Developmental Dynamics 245:774-787, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Cellular adhesome screen identifies critical modulators of focal adhesion dynamics, cellular traction forces and cell migration behaviour

    Science.gov (United States)

    Fokkelman, Michiel; Balcıoğlu, Hayri E.; Klip, Janna E.; Yan, Kuan; Verbeek, Fons J.; Danen, Erik H. J.; van de Water, Bob

    2016-01-01

    Cancer cells migrate from the primary tumour into surrounding tissue in order to form metastasis. Cell migration is a highly complex process, which requires continuous remodelling and re-organization of the cytoskeleton and cell-matrix adhesions. Here, we aimed to identify genes controlling aspects of tumour cell migration, including the dynamic organization of cell-matrix adhesions and cellular traction forces. In a siRNA screen targeting most cell adhesion-related genes we identified 200+ genes that regulate size and/or dynamics of cell-matrix adhesions in MCF7 breast cancer cells. In a subsequent secondary screen, the 64 most effective genes were evaluated for growth factor-induced cell migration and validated by tertiary RNAi pool deconvolution experiments. Four validated hits showed significantly enlarged adhesions accompanied by reduced cell migration upon siRNA-mediated knockdown. Furthermore, loss of PPP1R12B, HIPK3 or RAC2 caused cells to exert higher traction forces, as determined by traction force microscopy with elastomeric micropillar post arrays, and led to considerably reduced force turnover. Altogether, we identified genes that co-regulate cell-matrix adhesion dynamics and traction force turnover, thereby modulating overall motility behaviour. PMID:27531518

  8. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2015-12-01

    Full Text Available Adult stem cells (ASCs reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014. Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013. Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4cKO mice, we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4cKO mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014. Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155.

  9. Bortezomib and TRAIL : A perfect match for apoptotic elimination of tumour cells?

    NARCIS (Netherlands)

    de Wilt, L. H. A. M.; Kroon, J.; Jansen, G.; de Jong, S.; Peters, G. J.; Kruyt, F. A. E.

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively eradicates tumour cells via specific cell surface receptors and is intensively explored for use as a novel anticancer approach. To enhance the efficacy of TRAIL receptor agonists the proteasome inhibitor

  10. Roles of K+ channels in regulating tumour cell proliferation and apoptosis.

    Science.gov (United States)

    Wang, Zhiguo

    2004-06-01

    K+ channels are a most diverse class of ion channels in the cytoplasmic membrane and are distributed widely in a variety of cells including cancer cells. Cell proliferation and apoptosis (programmed cell death or cell suicide) are two counterparts that share the responsibility for maintaining normal tissue homeostasis. Evidence has been accumulating from fundamental studies indicating that tumour cells possess various types of K+ channels, and that these K+ channels play important roles in regulating tumour cell proliferation and apoptosis, i.e. facilitating unlimited growth and promoting apoptotic death of tumour cells. The potential implications of K+ channels as a pharmacological target for cancer therapy and a biomarker for diagnosis of carcinogenesis are attracting increasing interest. This review aims to provide a comprehensive overview of current status of research on K+ channels/currents in tumour cells. Focus is placed on the roles of K+ channels/currents in regulating tumour cell proliferation and apoptosis. The possible mechanisms by which K+ channels affect tumour cell growth and death are discussed. Speculations are also made on the potential implications of regulation of tumour cell proliferation and apoptosis by K+ channels. Copyright 2004 Springer-Verlag

  11. Paxillin: a crossroad in pathological cell migration

    Directory of Open Access Journals (Sweden)

    Ana María López-Colomé

    2017-02-01

    Full Text Available Abstract Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.

  12. Analysis of primary cilia in directional cell migration in fibroblasts

    DEFF Research Database (Denmark)

    Christensen, Søren Tvorup; Veland, Iben; Schwab, Albrecht

    2013-01-01

    summarize selected methods in analyzing ciliary function in directional cell migration, including immunofluorescence microscopy, scratch assay, and chemotaxis assay by micropipette addition of PDGFRα ligands to cultures of fibroblasts. These methods should be useful not only in studying cell migration...

  13. Testicular germ cell tumours and parental occupational exposure to pesticides

    DEFF Research Database (Denmark)

    Le Cornet, Charlotte; Fervers, Béatrice; Oksbjerg Dalton, Susanne

    2015-01-01

    controls per case were randomly selected from the general national populations, matched on year of birth. Information on parental occupation was collected through censuses or Pension Fund information and converted into a pesticide exposure index based on the Finnish National Job-Exposure Matrix. RESULTS......OBJECTIVES: A potential impact of exposure to endocrine disruptors, including pesticides, during intrauterine life, has been hypothesised in testicular germ cell tumour (TGCT) aetiology, but exposure assessment is challenging. This large-scale registry-based case-control study aimed to investigate......: A total of 9569 cases and 32 028 controls were included. No overall associations were found for either maternal or paternal exposures and TGCT risk in their sons, with ORs of 0.83 (95% CI 0.56 to 1.23) and of 1.03 (0.92 to 1.14), respectively. Country-specific estimates and stratification by birth cohorts...

  14. Epidermal Langerhans' cell induction of immunity against an ultraviolet-induced skin tumour

    International Nuclear Information System (INIS)

    Cavanagh, L.L.; Sluyter, R.; Henderson, K.G.; Barnetson, R.St.C.; Halliday, G.M.

    1996-01-01

    Lanerghans' cells (LC) have been shown experimentally to induce immune response against many antigens; however, their role in the initiation of anti-tumour immunity has received little attention. This study examined the ability of murine epidermal LC to induce immunity to an ultraviolet radiation (UV)-induced skin tumour. Freshly prepared epidermal cells (EC) were cultured for 2 or 20 hr with granulocyte-macrophage colony-stimulating factor (GM-CSF), pulsed with an extract of the UV-13-1 tumour, then used to immunize naive syngeneic mice. Delayed type hypersensitivity (DTH) was elicited 10 days after immunization by injection of UV-13-1 tumour cells into the ear pinna, and measured 24 hr later. EC cultured with GM-CSF for 2 hr induced anti-tumour DTH, as did EC cultured for 20 hr without GM-CSF. Conversely, EC cultured for 2 hr without GM-CSF, or EC cultured for 20 hr with GM-CSF were unable to induce a DTH. Induction of immunity required active presentation of tumour antigens by Ia + EC and was tumour specific. Thus Ia + epidermal cells are capable of inducing anti-tumour immunity to UV-induced skin tumours, but only when they contact antigen in particular states of maturation. (author)

  15. Two cases report of a malignant germ cell tumour of ovary and a granulosa cell tumour:Interest of tumoral immunochemistry in the identification and management.

    Directory of Open Access Journals (Sweden)

    Jean eBouquet De Jolinière

    2014-05-01

    Full Text Available Abstract Objective: In this article, we present two case reports. The first case was a malignant germ cell tumor of the right ovary in a 23 year old female and a case of a bilateral undifferentiated granulosa cell tumor in a 71 year old female. The aim of these reports is to illustrate the interest of the immuno-histochemical analysis to define the correct diagnosis, to better classify these ovarian tumours and improve their management. Methods: This study we report two cases. The first case concern a 23 years old woman (A with a mixed germ cell tumour of the right ovary (dysgerminoma (75%, yolk sac tumour (20%, and a mature teratoma (5%, and the second case (B a bilateral non differentiated and necrotic granulosa cell tumour of both ovaries concerning a 71 year old patient. The staging system used was according to both classifications, the one of International Federation of Gynaecology and Obstetrics (FIGO 1987 for ovarian cancer, and the one of TNM code 2009. Results: The immunostaining establish the malignancy and the immunochemistry contribute to confirm effectively the right diagnosis (Table 2 and 3. Conclusion: An immuno-histochemical analysis is mandatory for the choice of chemotherapy to obtain the better response of the disease and improve the survival prognosis. The efficiency of the chemotherapy authorizes a conservative surgery including a unilateral salpingo-oophorectomy preserving fertility (A. Concerning the non-dysgerminoma tumour (B, and after a surgical staging and debulking, chemotherapy was recommended. The type of tumour and its histological feature conditioned the choice of treatment. The benefit of the immunohistological analysis in this case allowed the right adjuvant treatment. Key words: germ cell tumours, dysgerminoma, teratoma, yolk sac, ovarian cell tumour, and immunohistochemistry.

  16. Adhesion dynamics and durotaxis in migrating cells

    Science.gov (United States)

    Harland, Ben; Walcott, Sam; Sun, Sean X.

    2011-02-01

    When tissue cells are plated on a flexible substrate, durotaxis, the directed migration of cells toward mechanically stiff regions, has been observed. Environmental mechanical signals are not only important in cell migration but also seem to influence all aspects of cell differentiation and development, including the metastatic process in cancer cells. Based on a theoretical model suggesting that this mechanosensation has a mechanical basis, we introduce a simple model of a cell by considering the contraction of F-actin bundles containing myosin motors (stress fibers) mediated by the movement of adhesions. We show that, when presented with a linear stiffness gradient, this simple model exhibits durotaxis. Interestingly, since stress fibers do not form on soft surfaces and since adhesion sliding occurs very slowly on hard surfaces, the model predicts that the expected cell velocity reaches a maximum at an intermediate stiffness. This prediction can be experimentally tested. We therefore argue that stiffness-dependent cellular adaptations (mechanosensation) and durotaxis are intimately related and may share a mechanical basis. We therefore identify the essential physical ingredients, which combined with additional biochemical mechanisms can explain durotaxis and mechanosensation in cells.

  17. 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.

  18. 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.

  19. Role of tumour initiating cells in the radiation resistance of osteosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Klymenko, Olena

    2014-02-26

    In the present study we confirm that mouse osteosarcoma (MOS) cells lines possess a subset of cells with Tumour Initiating Cells (TICs) properties. We found that isolated TICs are not inherently radioresistant compared to non-TICs. On the other hand, we found that the fraction of TICs correlates well with the radiosensitivity of MOS cell lines measured using clonogenic cell survival assay. We conclude from our study that the TICs contribute to the tumour radiation response due to their interaction with their tumour surrounding environmental (niche).

  20. Role of tumour initiating cells in the radiation resistance of osteosarcoma

    International Nuclear Information System (INIS)

    Klymenko, Olena

    2014-01-01

    In the present study we confirm that mouse osteosarcoma (MOS) cells lines possess a subset of cells with Tumour Initiating Cells (TICs) properties. We found that isolated TICs are not inherently radioresistant compared to non-TICs. On the other hand, we found that the fraction of TICs correlates well with the radiosensitivity of MOS cell lines measured using clonogenic cell survival assay. We conclude from our study that the TICs contribute to the tumour radiation response due to their interaction with their tumour surrounding environmental (niche).

  1. Detection and Characterization of Circulating Tumour Cells in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Liangxuan Zhang

    2016-06-01

    Full Text Available Multiple myeloma (MM remains an incurable disease despite recent therapeutic improvements. The ability to detect and characterize MM circulating tumour cells (CTCs in peripheral blood provides an alternative to replace or augment invasive bone marrow (BM biopsies with a simple blood draw, providing real-time, clinically relevant information leading to improved disease manage‐ ment and therapy selection. Here we have developed and qualified an enrichment-free, cell-based immunofluores‐ cence MM CTC assay that utilizes an automated digital pathology algorithm to distinguish MM CTCs from white blood cells (WBCs on the basis of CD138 and CD45 expression levels, as well as a number of morphological parameters. These MM CTCs were further characterized for expression of phospho-ribosomal protein S6 (pS6 as a readout for PI3K/AKT pathway activation. Clinical feasi‐ bility of the assay was established by testing blood samples from a small cohort of patients, where we detected popu‐ lations of both CD138pos and CD138neg MM CTCs. In this study, we developed an immunofluorescent cell-based assay to detect and characterize CTCs in MM.

  2. Substrate Curvature Regulates Cell Migration -A Computational Study

    Science.gov (United States)

    He, Xiuxiu; Jiang, Yi

    Cell migration in host microenvironment is essential to cancer etiology, progression and metastasis. Cellular processes of adhesion, cytoskeletal polymerization, contraction, and matrix remodeling act in concert to regulate cell migration, while local extracellular matrix architecture modulate these processes. In this work we study how stromal microenvironment with native and cell-derived curvature at micron-meter scale regulate cell motility pattern. We developed a 3D model of single cell migration on a curved substrate. Mathematical analysis of cell morphological adaption to the cell-substrate interface shows that cell migration on convex surfaces deforms more than on concave surfaces. Both analytical and simulation results show that curved surfaces regulate the cell motile force for cell's protruding front through force balance with focal adhesion and cell contraction. We also found that cell migration on concave substrates is more persistent. These results offer a novel biomechanical explanation to substrate curvature regulation of cell migration. NIH 1U01CA143069.

  3. Optical diagnostics of tumour cells at different stages of pathology development

    Science.gov (United States)

    Shcheglova, L. S.; Abramova, L. L.; Maryakhina, V. S.

    2013-11-01

    The differences in optical and biophysical properties between the cells of mammary gland tumour extracted from tumours of different diameter are described. It is shown that the spectral and spectrokinetic properties of fluorescent probes in the cells extracted from the tumours 1 - 3 cm in diameter are essentially different. Thus, the extinction coefficient of rhodamine 6G gradually increases with the pathology development. At the same time the rate of interaction of the triplet states of molecular probes with the oxygen, diluted in the tumour cells cytoplasm, decreases with the growth of the tumour capsule diameter. The observed regularities can be due to the changes in the cell structure, biochemical and biophysical properties. The reported data may be useful for developing optical methods of diagnostics of biotissue pathological conditions.

  4. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

    Directory of Open Access Journals (Sweden)

    Joanna Birch

    2016-10-01

    Full Text Available The cell's repertoire of transfer RNAs (tRNAs has been linked to cancer. Recently, the level of the initiator methionine tRNA (tRNAiMet in stromal fibroblasts has been shown to influence extracellular matrix (ECM secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression are elevated in metastases by comparison with primary tumours. Thus, specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis.

  5. The value of molecular genetic analysis in the diagnosis and prognosis of renal cell tumours.

    Science.gov (United States)

    Kovacs, G

    1994-01-01

    Renal cell tumours have a heterogeneous morphology, which may also be changed during tumour progression. Through the use of molecular cytogenetic techniques, it has become possible to divide renal cell tumours into genetically well-defined entities. Papillary renal cell tumours are characterized by loss of the Y chromosome and trisomy of chromosomes 3q, 7, 8, 12, 16, 17 and 20. Non-papillary renal cell carcinomas show a specific loss of chromosome 3p and trisomy of chromosome 5q sequences and frequent loss of chromosome 6q, 8p, 9 and 14q sequences. Chromophobe renal cell carcinomas are marked by a highly specific combination of loss of chromosomes 1, 2, 6, 10, 13, 17 and 21 and gross rearrangement of mitochondrial DNA. Subsets of renal oncocytomas show minimal karyotype alterations or translocation 11q13;? or loss of the Y chromosome and chromosome 1. There are some data suggesting that molecular genetic markers may be used not only for diagnosing of renal cell tumours but also for predicting the prognosis of tumour subtypes. Trisomy of chromosomes 7 and 17 and loss of the Y chromosome marks papillary renal cell adenomas, whereas additional trisomies such as those of chromosomes 3q, 8, 12, 16 and 20 are associated with papillary renal cell carcinomas. Although non-papillary renal cell tumours develop as a carcinoma, their clinical behaviour is in strong correlation with secondary karyotype changes such as loss of chromosomes 6q, 8p, 9 and 14q.

  6. Polystyrene nanoparticles facilitate the internalization of impermeable biomolecules in non-tumour and tumour cells from colon epithelium

    Energy Technology Data Exchange (ETDEWEB)

    Cabeza, Laura [University of Granada, Department of Human Anatomy and Embryology, Institute of Biopathology and Regenerative Medicine (IBIMER) (Spain); Cano-Cortés, Victoria; Rodríguez, María J. [University of Granada, Department of Pharmaceutical and Organic Chemistry (Spain); Vélez, Celia; Melguizo, Consolación, E-mail: melguizo@ugr.es [University of Granada, Department of Human Anatomy and Embryology, Institute of Biopathology and Regenerative Medicine (IBIMER) (Spain); Sánchez-Martín, Rosario M., E-mail: rmsanchez@ugr.es [University of Granada, Department of Pharmaceutical and Organic Chemistry (Spain); Prados, Jose [University of Granada, Department of Human Anatomy and Embryology, Institute of Biopathology and Regenerative Medicine (IBIMER) (Spain)

    2015-01-15

    Advanced colon cancer has a poor prognosis due to the limited effectiveness of current chemotherapies. Treatment failures may be avoided by the utilization of nanoparticles, which can enhance the effects of antitumor drugs, reduce their side effects and increase their directionality. Polystyrene nanoparticles have shown high biocompatibility and appropriate physicochemical properties and may represent a novel and more effective approach against colon cancer. In the present study, polystyrene nanoparticles were synthesized and fluorescently labelled, analyzing their cell internalization, intracellular localization and capacity to release transported molecules in tumour and non-tumour human colon cell lines (T84 and CCD-18). Flow cytometry and fluorescence microscopy studies demonstrated that polystyrene nanoparticles are an effective vehicle for the intracellular delivery of small molecules into colon epithelium cells. The percentage cell uptake was around 100 % in both T84 and CCD-18 cell lines after only 24 h of exposure and was cell confluence-independent. The polystyrene nanoparticles showed no cytotoxicity in either colon cell line. It was found that small molecules can be efficiently delivered into colon cells by using a disulphide bridge as release strategy. Analysis of the influence of the functionalization of the polystyrene nanoparticles surface on the internalization efficiency revealed some morphological changes in these cells. These results demonstrate that polystyrene nanoparticles may improve the transport of biomolecules into colon cells which could have a potential application in chemotherapeutic treatment against colon cancer.

  7. Early growth of tumour cells in lung tissue

    International Nuclear Information System (INIS)

    Poll, P.H.A.

    1981-01-01

    As the treatment of metastases is a very important problem in human and veterinary medicine (for instance osteosarcoma is notorious for its high deathrate due to this problem), proof was sought for the hypothesis that the doubling time of early metastases is shorter than that of tumor cells of an older age. This is of fundamental importance for the therapeutic problem: is a favourable effect to be expected from a limited dose of radiation on the lungs when metastases are still very small or even invisible. If the hypothesis holds true, it would be justified to treat patients, even though a small group of patients will be treated unnecessarily; clinical experience shows that some patients have not developed metastases without adjuvant treatment. The interest was directed at the very early (1-cell, 2-cell etc.) stages. Obviously these are not detectable in patients and therefore an experimental study with tumourcells in the lungs of mice was devised. The expectation is that the theoretical approach may produce an additional basis for the radiotherapeutic and chemotherapeutic treatment of patients, in whom the tumourload has been diminished by treatment of the primary tumour but where metastases, although frequently not detectable must be expected. (Auth.)

  8. Collective cell migration: Implications for wound healing and cancer invasion

    Directory of Open Access Journals (Sweden)

    Li Li

    2013-07-01

    Full Text Available During embryonic morphogenesis, wound repair and cancer invasion, cells often migrate collectively via tight cell-cell junctions, a process named collective migration. During such migration, cells move as coherent groups, large cell sheets, strands or tubes rather than individually. One unexpected finding regarding collective cell migration is that being a "multicellular structure" enables cells to better respond to chemical and physical cues, when compared with isolated cells. This is important because epithelial cells heal wounds via the migration of large sheets of cells with tight intercellular connections. Recent studies have gained some mechanistic insights that will benefit the clinical understanding of wound healing in general. In this review, we will briefly introduce the role of collective cell migration in wound healing, regeneration and cancer invasion and discuss its underlying mechanisms as well as implications for wound healing.

  9. Tumour suppressive function and modulation of programmed cell death 4 (PDCD4 in ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Na Wei

    Full Text Available BACKGROUND: Programmed cell death 4 (PDCD4, originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells. PRINCIPAL FINDINGS: We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G(1 stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN and inhibited protein kinase B (p-Akt. In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4. CONCLUSION: PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulation of PDCD4 degradation in ovarian cancer cells. In response to the stress condition, endogenous PDCD4 was able to shuttle between cell compartments to perform its diverted functions.

  10. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.

    Science.gov (United States)

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid

    2015-06-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. © The Author (2015). Published by Oxford University Press on

  11. Extrapulmonary colony formation after intravenous injection of tumour cells into heparin treated animals

    NARCIS (Netherlands)

    Maat, B.

    1978-01-01

    Recent data on extrapulmonary colony formation after heparin administration are inconclusive. A systemic study of this topic was undertaken with 4 experimental tumour systems and 2 distinct periods of reduced clotting capacity in rats and mice. I.v. injection of various numbers of tumour cells into

  12. Molecular cytogenetics of human germ cell tumours : i(12p) and related chromosomal anomalies

    NARCIS (Netherlands)

    Geurts van Kessel, A; Suijkerbuijk, R F; Sinke, R J; Looijenga, L; Oosterhuis, J W; de Jong, B

    1993-01-01

    Human testicular germ cell tumours (TGCTs) comprise a heterogeneous group of solid neoplasms. These tumours are characterized by a highly specific chromosomal anomaly, i.e. an isochromosome of the short arm of chromosome 12. At present, this i(12p) chromosome has been observed in about 80% of TGCTs.

  13. Monte Carlo based protocol for cell survival and tumour control probability in BNCT.

    Science.gov (United States)

    Ye, S J

    1999-02-01

    A mathematical model to calculate the theoretical cell survival probability (nominally, the cell survival fraction) is developed to evaluate preclinical treatment conditions for boron neutron capture therapy (BNCT). A treatment condition is characterized by the neutron beam spectra, single or bilateral exposure, and the choice of boron carrier drug (boronophenylalanine (BPA) or boron sulfhydryl hydride (BSH)). The cell survival probability defined from Poisson statistics is expressed with the cell-killing yield, the 10B(n,alpha)7Li reaction density, and the tolerable neutron fluence. The radiation transport calculation from the neutron source to tumours is carried out using Monte Carlo methods: (i) reactor-based BNCT facility modelling to yield the neutron beam library at an irradiation port; (ii) dosimetry to limit the neutron fluence below a tolerance dose (10.5 Gy-Eq); (iii) calculation of the 10B(n,alpha)7Li reaction density in tumours. A shallow surface tumour could be effectively treated by single exposure producing an average cell survival probability of 10(-3)-10(-5) for probable ranges of the cell-killing yield for the two drugs, while a deep tumour will require bilateral exposure to achieve comparable cell kills at depth. With very pure epithermal beams eliminating thermal, low epithermal and fast neutrons, the cell survival can be decreased by factors of 2-10 compared with the unmodified neutron spectrum. A dominant effect of cell-killing yield on tumour cell survival demonstrates the importance of choice of boron carrier drug. However, these calculations do not indicate an unambiguous preference for one drug, due to the large overlap of tumour cell survival in the probable ranges of the cell-killing yield for the two drugs. The cell survival value averaged over a bulky tumour volume is used to predict the overall BNCT therapeutic efficacy, using a simple model of tumour control probability (TCP).

  14. [18F]FDG PET monitoring of tumour response to chemotherapy: does [18F]FDG uptake correlate with the viable tumour cell fraction?

    International Nuclear Information System (INIS)

    Spaepen, Karoline; Stroobants, Sigrid; Dupont, Patrick; Bormans, Guy; Mortelmans, Luc; Balzarini, Jan; Verhoef, Gregor; Vandenberghe, Peter; De Wolf-Peeters, Christine

    2003-01-01

    Because metabolic changes induced by chemotherapy precede the morphological changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([ 18 F]FDG PET) is thought to predict response to therapy earlier and more accurately than other modalities. To be a reliable predictor of response, changes in tumour [ 18 F]FDG uptake should reflect changes in viable cell fraction, but little is known about the contribution of apoptotic and necrotic cancer cells and inflammatory tissue to the [ 18 F]FDG signal. In a tumour mouse model we investigated the relation between chemotherapy-induced changes in various tumoral components and tumour uptake and size. SCID mice were subcutaneously inoculated in the right thigh with 5 x 10 6 Daudi cells. When the tumour measured 15-20 mm, Endoxan was given intravenously. At different time points [1-15 days (d1-d15) after the injection of Endoxan], ex vivo autoradiography and histopathology were performed in two mice and [ 18 F]FDG uptake in the tumour and tumour size were correlated with the different cell fractions measured with flow cytometry in five mice. At d1/d3, similar reductions in [ 18 F]FDG uptake and viable tumoral cell fraction were observed and these reductions preceded changes in tumour size. By d8/d10, [ 18 F]FDG uptake had stabilised despite a further reduction in viable tumoral cell fraction. At these time points a major inflammatory response was observed. At d15, an increase in viable tumour cells was again observed and this was accurately predicted by an increase in [ 18 F]FDG uptake, while the tumour volume remained unchanged. In contrast with variations in tumour volume, [ 18 F]FDG is a good marker for chemotherapy response monitoring. However, optimal timing seems crucial since a transient increase in stromal reaction may result in overestimation of the fraction of viable cells. (orig.)

  15. Tumour-initiating cells vs. cancer "stem" cells and CD133: What's in the name?

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Stantic, M.; Zobalová, Renata; Chladová, Jaromíra; Wang, X. F.; Procházka, L.; Dong, L.; Anděra, Ladislav; Ralph, S.J.

    2007-01-01

    Roč. 255, č. 4 (2007), s. 855-859 ISSN 0006-291X Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : tumour-initiating cells * CD133 * resistance to treatment Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.749, year: 2007

  16. Impact of Mesenchymal Stem Cell secreted PAI-1 on colon cancer cell migration and proliferation

    International Nuclear Information System (INIS)

    Hogan, Niamh M.; Joyce, Myles R.; Murphy, J. Mary; Barry, Frank P.; O’Brien, Timothy; Kerin, Michael J.; Dwyer, Roisin M.

    2013-01-01

    Highlights: •MSCs were directly co-cultured with colorectal cancer (CRC) cells on 3D scaffolds. •MSCs influence CRC protein/gene expression, proliferation and migration. •We report a significant functional role of MSC-secreted PAI-1 in colon cancer. -- Abstract: Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cell (MSC) and colon cancer cell (CCC) interactions. Mesenchymal Stem Cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3-dimensional scaffolds. Conditioned media containing all secreted factors was harvested at day 1, 3 and 7. Chemokine secretion and expression were analyzed by Chemi-array, ELISA (Macrophage migration inhibitory factor (MIF), plasminogen activator inhibitor type 1 (PAI-1)) and RQ-PCR. Colon cancer cell migration and proliferation in response to recombinant PAI-1, MSCs and MSCs + antibody to PAI-1 was analyzed using Transwell inserts and an MTS proliferation assay respectively. Chemi-array revealed secretion of a wide range of factors by each cell population, including PAI-1and MIF. ELISA analysis revealed Mesenchymal Stem Cells to secrete the highest levels of PAI-1 (MSC mean 10.6 ng/mL, CCC mean 1.01 ng/mL), while colon cancer cells were the principal source of MIF. MSC-secreted PAI-1 stimulated significant migration of both CCC lines, with an antibody to the chemokine shown to block this effect (67–88% blocking,). A cell-line dependant effect on CCC proliferation was shown for Mesenchymal Stem Cell-secreted PAI-1 with HCT-116 cells showing decreased proliferation at all concentrations, and HT29 cells showing increased proliferation in the presence of higher PAI-1 levels. This is the first study to identify PAI-1 as an important mediator of Mesenchymal Stem Cell/colon cancer cell interactions and highlights the

  17. Gene expression of circulating tumour cells in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Bölke E

    2009-09-01

    Full Text Available Abstract Background The diagnostic tools to predict the prognosis in patients suffering from breast cancer (BC need further improvements. New technological achievements like the gene profiling of circulating tumour cells (CTC could help identify new prognostic markers in the clinical setting. Furthermore, gene expression patterns of CTC might provide important informations on the mechanisms of tumour cell metastasation. Materials and methods We performed realtime-PCR and multiplex-PCR analyses following immunomagnetic separation of CTC. Peripheral blood (PB samples of 63 patients with breast cancer of various stages were analyzed and compared to a control group of 14 healthy individuals. After reverse-transcription, we performed multiplex PCR using primers for the genes ga733.3, muc-1 and c-erbB2. Mammaglobin1, spdef and c-erbB2 were analyzed applying realtime-PCR. Results ga733.2 overexpression was found in 12.7% of breast cancer cases, muc-1 in 15.9%, mgb1 in 9.1% and spdef in 12.1%. In this study, c-erbB2 did not show any significant correlation to BC, possibly due to a highly ambient expression. Besides single gene analyses, gene profiles were additionally evaluated. Highly significant correlations to BC were found in single gene analyses of ga733.2 and muc-1 and in gene profile analyses of ga733.3*muc-1 and GA7 ga733.3*muc-1*mgb1*spdef. Conclusion Our study reveals that the single genes ga733.3, muc-1 and the gene profiles ga733.3*muc-1 and ga733.3*3muc-1*mgb1*spdef can serve as markers for the detection of CTC in BC. The multigene analyses found highly positive levels in BC patients. Our study indicates that not single gene analyses but subtle patterns of multiple genes lead to rising accuracy and low loss of specificity in detection of breast cancer cases.

  18. [Small cell neuroendocrine tumour of the bladder: with reference to a case and bibliographical revision].

    Science.gov (United States)

    Lahoz Tornos, A; Marrón Penón, Maria C; Pardo López, Maria L; Nogueras Gimeno, M A; Pujol Obis, E; Del Villar Sordo, V

    2006-09-01

    The small cell neuroendocrine tumour is an infrecuent neoplasia, with inmunohistochemistry being the key to diagnosis. We present a new case making reference to treatment and its evolution there after. The clinic, diagnosis and treatment of this tumour is described. Bibliographical revision follours. The neuroendocrine tumour of small cell is an infrecuent neoplasia, in which the inmunohistochemistry study is key in the diagnosis. The differential diagnosis includes the high degree diferentiation transitionals cells carcinoma and primary and secondary linfoma. The standard treatment is based on chemotherapy plus surgery.

  19. Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

    Science.gov (United States)

    Marei, Hadir; Carpy, Alejandro; Woroniuk, Anna; Vennin, Claire; White, Gavin; Timpson, Paul; Macek, Boris; Malliri, Angeliki

    2016-01-01

    The small GTPase Rac1 has been implicated in the formation and dissemination of tumours. Upon activation by guanine nucleotide exchange factors (GEFs), Rac1 associates with a variety of proteins in the cell thereby regulating various functions, including cell migration. However, activation of Rac1 can lead to opposing migratory phenotypes raising the possibility of exacerbating tumour progression when targeting Rac1 in a clinical setting. This calls for the identification of factors that influence Rac1-driven cell motility. Here we show that Tiam1 and P-Rex1, two Rac GEFs, promote Rac1 anti- and pro-migratory signalling cascades, respectively, through regulating the Rac1 interactome. In particular, we demonstrate that P-Rex1 stimulates migration through enhancing the interaction between Rac1 and the actin-remodelling protein flightless-1 homologue, to modulate cell contraction in a RhoA-ROCK-independent manner. PMID:26887924

  20. Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

    NARCIS (Netherlands)

    Arendt, Maja L; Melin, Malin; Tonomura, Noriko; Koltookian, Michele; Courtay-Cahen, Celine; Flindall, Netty; Bass, Joyce; Boerkamp, Kim|info:eu-repo/dai/nl/313929149; Megquir, Katherine; Youell, Lisa; Murphy, Sue; McCarthy, Colleen; London, Cheryl; Rutteman, Gerard R|info:eu-repo/dai/nl/074076663; Starkey, Mike; Lindblad-Toh, Kerstin

    2015-01-01

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease.

  1. Radiation-induced apoptosis and cell cycle checkpoints in human colorectal tumour cell lines

    International Nuclear Information System (INIS)

    Playle, L.C.

    2001-03-01

    The p53 tumour suppressor gene is mutated in 75% of colorectal carcinomas and is critical for DNA damage-induced G1 cell cycle arrest. Data presented in this thesis demonstrate that after treatment with Ionizing Radiation (IR), colorectal tumour cell lines with mutant p53 are unable to arrest at G1 and undergo cell cycle arrest at G2. The staurosporine derivative, UCN-01, was shown to abrogate the IR-induced G2 checkpoint in colorectal tumour cell lines. Furthermore, in some cell lines, abrogation of the G2 checkpoint was associated with radiosensitisation. Data presented in this study demonstrate that 2 out of 5 cell lines with mutant p53 were sensitised to IR by UCN-01. In order to determine whether radiosensitisation correlated with lack of functional p53, transfected derivatives of an adenoma-derived cell line were studied, in which endogenous wild type p53 was disrupted by expression of a dominant negative p53 mutant protein (and with a vector control). In both these cell lines UCN-01 abrogated the G2 arrest however this was not associated with radiosensitisation, indicating that radiosensitisation is a cell type-specific phenomenon. Although 2 colorectal carcinoma cell lines, with mutant p53, were sensitised to IR by UCN-01, the mechanisms of p53-independent IR-induced apoptosis in the colon are essentially unknown. The mitogen-activated protein kinase (MAPK) pathways (that is the JNK, p38 and ERK pathways) have been implicated in apoptosis in a range of cell systems and in IR-induced apoptosis in some cell types. Data presented in this study show that, although the MAPKs can be activated by the known activator anisomycin, there is no evidence of a role for MAPKs in IR-induced apoptosis in colorectal tumour cell lines, regardless of p53 status. In summary, some colorectal tumour cell lines with mutant p53 can be sensitised to IR-induced cell death by G2 checkpoint abrogation and this may be an important treatment strategy, however mechanisms of IR-induced p53

  2. Clara cell adhesion and migration to extracellular matrix

    Directory of Open Access Journals (Sweden)

    deMello Daphne

    2008-01-01

    Full Text Available Abstract Background Clara cells are the epithelial progenitor cell of the small airways, a location known to be important in many lung disorders. Although migration of alveolar type II and bronchiolar ciliated epithelial cells has been examined, the migratory response of Clara cells has received little attention. Methods Using a modification of existing procedures for Clara cell isolation, we examined mouse Clara cells and a mouse Clara-like cell line (C22 for adhesion to and migration toward matrix substrate gradients, to establish the nature and integrin dependence of migration in Clara cells. Results We observed that Clara cells adhere preferentially to fibronectin (Fn and type I collagen (Col I similar to previous reports. Migration of Clara cells can be directed by a fixed gradient of matrix substrates (haptotaxis. Migration of the C22 cell line was similar to the Clara cells so integrin dependence of migration was evaluated with this cell line. As determined by competition with an RGD containing-peptide, migration of C22 cells toward Fn and laminin (Lm 511 (formerly laminin 10 was significantly RGD integrin dependent, but migration toward Col I was RGD integrin independent, suggesting that Clara cells utilize different receptors for these different matrices. Conclusion Thus, Clara cells resemble alveolar type II and bronchiolar ciliated epithelial cells by showing integrin mediated pro-migratory changes to extracellular matrix components that are present in tissues after injury.

  3. Ultrastructural proof of polyomavirus in Merkel cell carcinoma tumour cells and its absence in small cell carcinoma of the lung.

    Directory of Open Access Journals (Sweden)

    Charlotte T A H Wetzels

    Full Text Available BACKGROUND: A new virus called the Merkel Cell Polyomavirus (MCPyV has recently been found in Merkel Cell Carcinoma (MCC. MCC is a rare aggressive small cell neuroendocrine carcinoma primarily derived from the skin, morphologically indistinguishable from small cell lung carcinoma (SCLC. So far the actual presence of the virus in MCC tumour cells on a morphological level has not been demonstrated, and the presence of MCPyV in other small cell neuroendocrine carcinomas has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: We investigated MCC tissue samples from five patients and SCLCs from ten patients for the presence of MCPyV-DNA by PCR and sequencing. Electron microscopy was used to search ultrastructurally for morphological presence of the virus in MCPyV-DNA positive samples. MCPyV was detected in two out of five primary MCCs. In one MCC patient MCPyV-DNA was detected in the primary tumour as well as in the metastasis, strongly suggesting integration of MCPyV in the cellular DNA of the tumour in this patient. In the primary MCC of another patient viral particles in tumour cell nuclei and cytoplasm were identified by electron microscopy, indicating active viral replication in the tumour cells. In none of the SCLCs MCPyV-DNA was detected. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest that MCPyV is an oncogenic polyomavirus in humans, and is potentially causally related to the development of MCC but not to the morphological similar SCLC.

  4. Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.

    Directory of Open Access Journals (Sweden)

    Thomas Kruewel

    Full Text Available BACKGROUND: The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibition of their hyperactivity represents a molecular rationale in the combat of cancerous diseases. Here we examined the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumour progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these experimental drugs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot analysis confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptor was observed while whole genome gene expression analysis evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK signalling to impact cytoskeleton dynamics, migration, invasion and metastasis. CONCLUSIONS/SIGNIFICANCE: Our experiments and recently published in vivo engraftment studies with various tumour cell lines revealed the dual kinase inhibitors to be efficient in their antitumour activity.

  5. Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Nardou Katya

    2008-06-01

    Full Text Available Abstract Background Histone deacetylase inhibitors (HDACi are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results We show here that the HDACi Sodium Butyrate (NaB, suberoylanilide hydroxamic acid (SAHA and Trichostatin A (TSA strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.

  6. Non-germ cell tumours arising in germ cell tumours (teratoma with malignant transformation) in men: CT and MR findings

    Energy Technology Data Exchange (ETDEWEB)

    Athanasiou, A. [Department of Radiology, Institut Gustave-Roussy, Villejuif (France); Department of Radiology, Institut Curie, Paris (France)], E-mail: alexandra.athanasiou@curie.net; Vanel, D. [Department of Radiology, Institut Gustave-Roussy, Villejuif (France); Department of Radiology, Istituti Ortopedici Rizzoli, Bologna (Italy); El Mesbahi, O. [Department of Medicine, Institut Gustave-Roussy, Villejuif (France); Theodore, C. [Department of Medicine, Institut Gustave-Roussy, Villejuif (France); Department of Oncology, Hopital Foch, Suresnes (France); Fizazi, K. [Department of Medicine, Institut Gustave-Roussy, Villejuif (France)

    2009-02-15

    Purpose: To describe the imaging findings of germ cell tumours (GCT) containing non-germ cell malignant components (also designated teratoma with malignant transformation or TMT). Patients and methods: The records of 14 male patients with GCT and a non-germ cell histological component TMT were retrospectively reviewed. All patients had computed tomography (CT) and/or magnetic resonance (MR) studies before and after initial surgery and chemotherapy, as well as during follow-up. Imaging findings were correlated with the response to treatment and with overall survival. Pathological evaluation, immunohistochemistry, serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) were also taken into consideration. Sarcoma was identified in 10 out of 14 patients, with rhabdomyosarcoma ranking first (n = 4), followed by osteosarcoma (n = 2), fusiform cell sarcoma (n = 1), undifferentiated sarcoma (n = 1), neurosarcoma (n = 1) and myxoid sarcoma (n = 1). Other histological types of malignant transformation included adenocarcinoma (n = 3) and bronchoalveolar carcinoma (n = 1). Overall, 9 patients relapsed at a median time of 84 months (range 60-168). Results: Non-GCT malignant transformation was identified in the retroperitoneum (5), testis (3), mediastinum (3), peritoneum (2) and lungs (1). The CT and MR imaging findings before treatment and after relapse were evaluated with emphasis on imaging features that could possibly imply the presence of malignant transformation (heterogeneously enhancing soft-tissue masses, ossified masses with calcified lymph nodes, diffuse epiploic thickening associated with ascites and peritoneal nodules, pulmonary alveolar infiltration with septal thickening). All but 1 patient with TMT presented with nodal and distant metastases. The prognosis was poor: within a median follow-up of 59 months (range 3-180), 4 out of 14 patients were alive. Conclusion: TMT is rare and associated with poorer survival compared to GCT. Imaging can be useful

  7. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study

    OpenAIRE

    Morrow, C. J.; Trapani, F.; Metcalf, R. L.; Bertolini, G.; Hodgkinson, C. L.; Khandelwal, G.; Kelly, P.; Galvin, M.; Carter, L.; Simpson, K. L.; Williamson, S.; Wirth, C.; Simms, N.; Frankliln, L.; Frese, K. K.

    2016-01-01

    Background Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, ?liquid biopsies? such as circulating tumour cells (CTCs) are minimally invasive...

  8. Tumour cell–derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth

    Directory of Open Access Journals (Sweden)

    Hiroaki Haga

    2015-01-01

    Full Text Available The contributions of mesenchymal stem cells (MSCs to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs. We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.

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

    DEFF Research Database (Denmark)

    D'Andrea, Filippo P; 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 vascularization. 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 400 mm(3). Radiation was given as a single fraction of 0-15 Gy and the degree...

  10. Giant cell tumour of proximal radius in a 48 years old lady.

    Science.gov (United States)

    Khan, Kashif Mahmood; Minhas, Muhammad Saeed; Khan, Mohsin Ali; Bhatti, Anisuddin

    2014-03-01

    Giant cell tumour is a locally aggressive tumour of long-bones of epiphyseal region commonly occurring in adults aged 20-40 years. Most common location is distal femur, proximal tibia and distal radius. Different treatment options being used are curettage with bone graft or bone cement, resection with arthrodesis, reconstruction, radiation and chemotherapy. We are reporting a case of giant cell tumour of proximal radius in a 48 years old lady. It is very rare and only 4 cases have been reported in literature. It was treated by wide margin resection without reconstruction.

  11. A model of the effects of cancer cell motility and cellular adhesion properties on tumour-immune dynamics.

    Science.gov (United States)

    Frascoli, Federico; Flood, Emelie; Kim, Peter S

    2017-06-01

    We present a three-dimensional model simulating the dynamics of an anti-cancer T-cell response against a small, avascular, early-stage tumour. Interactions at the tumour site are accounted for using an agent-based model (ABM), while immune cell dynamics in the lymph node are modelled as a system of delay differential equations (DDEs). We combine these separate approaches into a two-compartment hybrid ABM-DDE system to capture the T-cell response against the tumour. In the ABM at the tumour site, movement of tumour cells is modelled using effective physical forces with a specific focus on cell-to-cell adhesion properties and varying levels of tumour cell motility, thus taking into account the ability of cancer cells to spread and form clusters. We consider the effectiveness of the immune response over a range of parameters pertaining to tumour cell motility, cell-to-cell adhesion strength and growth rate. We also investigate the dependence of outcomes on the distribution of tumour cells. Low tumour cell motility is generally a good indicator for successful tumour eradication before relapse, while high motility leads, almost invariably, to relapse and tumour escape. In general, the effect of cell-to-cell adhesion on prognosis is dependent on the level of tumour cell motility, with an often unpredictable cross influence between adhesion and motility, which can lead to counterintuitive effects. In terms of overall tumour shape and structure, the spatial distribution of cancer cells in clusters of various sizes has shown to be strongly related to the likelihood of extinction. © The authors 2016. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

  12. Endometrial polypoid adenomyomatosis in a bitch with ovarian granulosa cell tumour and pyometra.

    Science.gov (United States)

    Zanghì, A; Catone, G; Marino, G; Quartuccio, M; Nicòtina, P A

    2007-01-01

    Endometrial polypoid adenomyomatosis in an 8-year-old German shepherd bitch is described. The lesion was associated with ovarian granulosa cell tumour and pyometra; grossly, it consisted of sessile or pedunculated processes with both epithelial and non-epithelial components, in which smooth muscle cells were predominant. The endometrium was diffusely atrophic and showed multifocal squamous metaplasia. The findings are discussed as possible consequences of the functioning ovarian tumour and pyometra, but an involvement of growth factors is also proposed.

  13. IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis.

    Science.gov (United States)

    Perimenis, Philippos; Galaris, Apostolos; Voulgari, Alexandra; Prassa, Margarita; Pintzas, Alexander

    2016-08-12

    High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs. In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols. It is shown that pre-treatment of SMAC-mimetics followed by their combined treatment with BRAF inhibitors can decrease cell viability, migration and can very efficiently sensitize colorectal tumour cells to apoptosis. Moreover, co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize resistant tumour cells to apoptosis synergistically, as shown by median effect analysis. Finally, Birinapant and AT-406 can synergise with BCL-2 inhibitor ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression. Proposed synergistic rational anticancer combined protocols of IAP antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further exploited in vivo, from precision tumour biology to precision medical oncology.

  14. Giant cell tumour in the foot of a skeletally immature girl: a case report.

    LENUS (Irish Health Repository)

    Baker, Joseph F

    2009-08-01

    We present a case of delayed diagnosis of a benign giant cell tumour (GCT) of the third metatarsal in a skeletally immature girl. The patient underwent en bloc excision of the tumour. The tumour had replaced the third metatarsal and had infiltrated the surrounding soft tissue and the second and fourth metatarsal bases. Deep, lateral and medial margins were all involved. A high index of suspicion is needed when evaluating any tumours of the foot, because the compact structure of the foot may delay diagnosis. Early detection is important for avoiding amputation, as the hindfoot and midfoot are classified as one compartment and radical resection is impossible to achieve. Tumours grow faster in the foot than in other bones. GCT in this location and age-group are rare and should be considered in the differential diagnosis of a destructive bony lesion in skeletally immature patients.

  15. Differential migration and proliferation of geometrical ensembles of cell clusters

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Girish; Chen, Bo; Co, Carlos C.; Ho, Chia-Chi, E-mail: hocc@email.uc.edu

    2011-06-10

    Differential cell migration and growth drives the organization of specific tissue forms and plays a critical role in embryonic development, tissue morphogenesis, and tumor invasion. Localized gradients of soluble factors and extracellular matrix have been shown to modulate cell migration and proliferation. Here we show that in addition to these factors, initial tissue geometry can feedback to generate differential proliferation, cell polarity, and migration patterns. We apply layer by layer polyelectrolyte assembly to confine multicellular organization and subsequently release cells to demonstrate the spatial patterns of cell migration and growth. The cell shapes, spreading areas, and cell-cell contacts are influenced strongly by the confining geometry. Cells within geometric ensembles are morphologically polarized. Symmetry breaking was observed for cells on the circular pattern and cells migrate toward the corners and in the direction parallel to the longest dimension of the geometric shapes. This migration pattern is disrupted when actomyosin based tension was inhibited. Cells near the edge or corner of geometric shapes proliferate while cells within do not. Regions of higher rate of cell migration corresponded to regions of concentrated growth. These findings demonstrate that multicellular organization can result in spatial patterns of migration and proliferation.

  16. Differential migration and proliferation of geometrical ensembles of cell clusters

    International Nuclear Information System (INIS)

    Kumar, Girish; Chen, Bo; Co, Carlos C.; Ho, Chia-Chi

    2011-01-01

    Differential cell migration and growth drives the organization of specific tissue forms and plays a critical role in embryonic development, tissue morphogenesis, and tumor invasion. Localized gradients of soluble factors and extracellular matrix have been shown to modulate cell migration and proliferation. Here we show that in addition to these factors, initial tissue geometry can feedback to generate differential proliferation, cell polarity, and migration patterns. We apply layer by layer polyelectrolyte assembly to confine multicellular organization and subsequently release cells to demonstrate the spatial patterns of cell migration and growth. The cell shapes, spreading areas, and cell-cell contacts are influenced strongly by the confining geometry. Cells within geometric ensembles are morphologically polarized. Symmetry breaking was observed for cells on the circular pattern and cells migrate toward the corners and in the direction parallel to the longest dimension of the geometric shapes. This migration pattern is disrupted when actomyosin based tension was inhibited. Cells near the edge or corner of geometric shapes proliferate while cells within do not. Regions of higher rate of cell migration corresponded to regions of concentrated growth. These findings demonstrate that multicellular organization can result in spatial patterns of migration and proliferation.

  17. Loss of ADAM9 expression impairs β1 integrin endocytosis, focal adhesion formation and cancer cell migration

    DEFF Research Database (Denmark)

    Mygind, Kasper J; Schwarz, Jeanette; Sahgal, Pranshu

    2018-01-01

    The transmembrane protease ADAM9 is frequently upregulated in human cancers, and it promotes tumour progression in mice.In vitro, ADAM9 regulates cancer cell adhesion and migration by interacting with integrins. However, how ADAM9 modulates integrin functions is not known. We here show that ADAM9......, and both internalization and subsequent degradation of β1 integrin are significantly decreased in ADAM9-silenced cells, with no effect on β1 integrin recycling. Accordingly, the formation of focal adhesions and actin stress fibres in ADAM9-silenced cells is altered, possibly explaining the reduction...... in cell adhesion and migration in these cells. Taken together, our data provide mechanistic insight into the ADAM9-integrin interaction, demonstrating that ADAM9 regulates β1 integrin endocytosis. Moreover, our findings indicate that the reduced migration of ADAM9-silenced cells is, at least in part...

  18. Mast cells and eosinophils in rat mammary gland tumours induced by N-Nitroso-N-methylurea

    Directory of Open Access Journals (Sweden)

    Kissová Viktória

    2015-09-01

    Full Text Available The aim of the study was to evaluate the distribution and number of mast cells and eosinophils in rat mammary gland tumours induced by N-Nitroso-N-methylurea. The highest density of mast cells was found in cystic papillary adenocarcinomas of grade II. Eosinophils were detected only in the cystic papillary adenocarcinoma of grades I and II, in non-invasive cribriform adenocarcinoma and comedo-type carcinoma. Mast cell populations were observed perivascularly in the tumour stroma, in the host tumour interface, as well as in necrotic areas of neoplasms. Mast cells were observed to be intact according to their morphological changes, collectively referred to as degranulation. The obtained results indicate that mast cells and eosinophils play an important role in tumour micro-environment formation. The increased density of these cells in experimentally-induced rat mammary gland tumours suggests a poor prognosis in these cancers. Our results also confirmed that rat mammary gland tumours are good models for the study of breast cancers.

  19. Computed tomography evaluation of mast cell tumours; Avaliacao por tomografia computadorizada dos mastocitomas

    Energy Technology Data Exchange (ETDEWEB)

    Lorigados, Carla Aparecida Batista; Matera, Julia Maria; Macedo, Thais; Pinto, Ana Carolina Brandao Fonseca, E-mail: clorigados@usp.br [Universidade de Sao Paulo (USP), SP (Brazil). Faculdade de Medicina Veterinaria e Zootecnia. Dept. de Cirurgia

    2012-07-01

    The mast cell tumours are common tumours of the canine skin. Computed tomography (CT) has assumed an important role in tumours evaluation and staging. The aim of this study was to evaluate the role of CT as a method of assessing characteristics of mast cell tumors. Ten dogs with mast cell tumor were evaluated. CT was performed before and after the intravenous injection of hydro soluble ionic iodine. Attenuation, contrast enhancement, cleavage with adjacent tissues and the unidimensional measurement of each lesion was determined in it maximum diameter, in transversal plane. Concerning the attenuation characteristic, 50% were homogeneous and 50% heterogeneous. The contrast enhancement was homogeneous in 50% of cases, heterogeneous in 40% and peripheral in 10%. Fifty percent of the tumours showed loss of plane of cleavage and 30% partial loss. This information can help in directing the patients that will be undergoing chemotherapy or surgery. (author)

  20. Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells

    Science.gov (United States)

    Franzetti, G-A; Laud-Duval, K; van der Ent, W; Brisac, A; Irondelle, M; Aubert, S; Dirksen, U; Bouvier, C; de Pinieux, G; Snaar-Jagalska, E; Chavrier, P; Delattre, O

    2017-01-01

    Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1high states, characterized by highly active cell proliferation, and EWSR1-FLI1low states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential. PMID:28135250

  1. Immunisation with 'naïve' syngeneic dendritic cells protects mice from tumour challenge.

    Science.gov (United States)

    Grimshaw, M J; Papazisis, K; Picco, G; Bohnenkamp, H; Noll, T; Taylor-Papadimitriou, J; Burchell, J

    2008-02-26

    Dendritic cells (DCs) 'pulsed' with an appropriate antigen may elicit an antitumour immune response in mouse models. However, while attempting to develop a DC immunotherapy protocol for the treatment of breast cancer based on the tumour-associated MUC1 glycoforms, we found that unpulsed DCs can affect tumour growth. Protection from RMA-MUC1 tumour challenge was achieved in C57Bl/6 MUC1 transgenic mice by immunising with syngeneic DCs pulsed with a MUC1 peptide. However, unpulsed DCs gave a similar level of protection, making it impossible to evaluate the effect of immunisation of mice with DCs pulsed with the specific peptide. Balb/C mice could also be protected from tumour challenge by immunisation with unpulsed DCs prior to challenge with murine mammary tumour cells (410.4) or these cells transfected with MUC1 (E3). Protection was achieved with as few as three injections of 50,000 naïve DCs per mouse per week, was not dependent on injection route, and was not specific to cell lines expressing human MUC1. However, the use of Rag2-knockout mice demonstrated that the adaptive immune response was required for tumour rejection. Injection of unpulsed DCs into mice bearing the E3 tumour slowed tumour growth. In vitro, production of IFN-gamma and IL-4 was increased in splenic cells isolated from mice immunised with DCs. Depleting CD4 T cells in vitro partially decreased cytokine production by splenocytes, but CD8 depletion had no effect. This paper shows that naïve syngeneic DCs may induce an antitumour immune response and has implications for DC immunotherapy preclinical and clinical trials.

  2. Directional Cell Migration in Response to Repeated Substratum Stretching

    Science.gov (United States)

    Okimura, Chika; Iwadate, Yoshiaki

    2017-10-01

    Crawling migration plays an essential role in a variety of biological phenomena, including development, wound healing, and immune system function. Migration properties such as anterior-posterior polarity, directionality, and velocity are regulated not only by the reception of a chemoattractant but also by sensing mechanical inputs from the external environment. In this review, we describe the mechanical response of migrating cells, particularly under repeated stretching of the elastic substratum, highlighting the fact that there appear to be two independent mechanosensing systems that generate the polarity needed for migration. Cells that have no stress fibers, such as Dictyostelium cells and neutrophil-like differentiated HL-60 cells, migrate perpendicular to the stretching direction via myosin II localization. Cells that do possess stress fibers, however, such as fish keratocytes, migrate parallel to the stretching via a stress-fiber-dependent process.

  3. Lutein Inhibits the Migration of Retinal Pigment Epithelial Cells via Cytosolic and Mitochondrial Akt Pathways (Lutein Inhibits RPE Cells Migration)

    Science.gov (United States)

    Su, Ching-Chieh; Chan, Chi-Ming; Chen, Han-Min; Wu, Chia-Chun; Hsiao, Chien-Yu; Lee, Pei-Lan; Lin, Victor Chia-Hsiang; Hung, Chi-Feng

    2014-01-01

    During the course of proliferative vitreoretinopathy (PVR), the retinal pigment epithelium (RPE) cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF) can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation. PMID:25110866

  4. Lutein Inhibits the Migration of Retinal Pigment Epithelial Cells via Cytosolic and Mitochondrial Akt Pathways (Lutein Inhibits RPE Cells Migration

    Directory of Open Access Journals (Sweden)

    Ching-Chieh Su

    2014-08-01

    Full Text Available During the course of proliferative vitreoretinopathy (PVR, the retinal pigment epithelium (RPE cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation.

  5. New approaches to targeted drug delivery to tumour cells

    International Nuclear Information System (INIS)

    Severin, E S

    2015-01-01

    Basic approaches to the design of targeted drugs for the treatment of human malignant tumours have been considered. The stages of the development of these approaches have been described in detail and theoretically substantiated, and basic experimental results have been reported. Considerable attention is paid to the general characteristic of nanopharmacological drugs and to the description of mechanisms of cellular interactions with nanodrugs. The potentialities and limitations of application of nanodrugs for cancer therapy and treatment of other diseases have been considered. The use of nanodrugs conjugated with vector molecules seems to be the most promising trend of targeted therapy of malignant tumours. The bibliography includes 122 references

  6. Renal cell carcinoma: stage, grade and histology migration over the last 15 years in a large Australian surgical series.

    Science.gov (United States)

    Doeuk, Norbert; Guo, Ding Y; Haddad, Richard; Lau, Howard; Woo, Henry H; Bariol, Simon; Drummond, Malcolm; Vladica, Philip; Brooks, Andrew; Patel, Manish I

    2011-05-01

    • To verify whether migration towards earlier-stage renal cell carcinoma (RCC), which has been observed in the USA over the last decade, also applies to Australia. • Between January 1993 and December 2007, 547 nephrectomies performed in public and private hospitals in western Sydney were analysed from a retrospectively collected database. • Data were divided into three consecutive time groups. • Tumour-node-metastasis (TNM) stage as well as patient demographics, size, grade and histology of tumours and proportion of benign tumours were also assessed. • In all, 499 nephrectomies were performed for RCC. The median age was 62 years, with a male:female ratio of 1.9 : 1. Similarly sized tumours were identified in each time group [group 1 (1993-1997), 54.8 mm; group 2 (1998-2002), 52.0 mm; group 3 (2003-2007), 52.2 mm, P= 0.6]. • Pathological stage II disease decreased from 18.1 to 11.1%, but stage III disease showed an increase from 13.9 to 21.5% over that time period (P= 0.02). • The proportion of stage I and stage IV disease has remained relatively the same. There has been a statistically significant upward histological migration for the papillary subtype from 1.3 to 10.2% (P= 0.01). • There has also been an increasing representation of Fuhrman grade III tumours over time, from 17.6 to 30.8%, and a decreasing proportion of Fuhrman grade I tumours from 16.2 to 7.1% (P= 0.03). • There was a decrease in the incidence of benign tumours originally thought to be malignant on preoperative investigations, from 10% in group 1 to 4% in group 3 (P= 0.03). • The recent US phenomenon of migration towards earlier-stage, smaller RCCs as well as increased representation of benign tumours was not observed in the present study. The results of the present study, however, show an upward histological migration for papillary RCCs and an increasing representation of more aggressive Fuhrman grade III tumours. © 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU

  7. Mechanical stretch modulates cell migration in the lungs.

    Science.gov (United States)

    López-Martínez, Cecilia; Huidobro, Covadonga; Albaiceta, Guillermo M; López-Alonso, Inés

    2018-01-01

    Cell migration is a core process to preserve homeostasis. Release of chemotactic signals induces changes in cell cytoskeleton to facilitate migration. This includes the rearrangement of cytoskeleton, genomic reprogramming and the modification of the surrounding extracellular matrix (ECM) to allow the motion of cells through. In the special case of repair after acute lung injury, cells must migrate while exposed to an increased mechanical stretch caused either by an increased work of breathing or positive-pressure ventilation. Interestingly, the cell response to this increased mechanical load can modify virtually all the mechanisms involved in cell migration. In this review we explore the interplay between stretch and the machinery responsible for cell migration. A translational approach to find new therapies in acute lung injury must take into account these interactions in order to develop effective treatments that promote lung repair.

  8. Adenomyoepithelial tumours and myoepithelial carcinomas of the breast – a spectrum of monophasic and biphasic tumours dominated by immature myoepithelial cells

    Directory of Open Access Journals (Sweden)

    Herbst Hermann

    2005-07-01

    Full Text Available Abstract Background Adenomyoepithelial tumours and myoepithelial carcinomas of the breast are primarily defined by the presence of neoplastic cells with a myoepithelial immunophenotype. Current classification schemes are based on purely descriptive features and an assessment of individual prognosis is still problematic. Methods A series of 27 adenomyoepithelial tumours of the breast was analysed immunohistochemically with antibodies directed against various cytokeratins, p63, smooth muscle alpha-actin (SMA and vimentin. Additionally, double immunofluorescence and comparative genomic hybridisation (CGH was performed. Results Immunohistochemically, all the tumours showed a constant expression of high molecular weight cytokeratins (Ck Ck5 and Ck14, p63, SMA and vimentin. With exception of one case diagnosed as myoepithelial carcinoma, all tested tumours expressed low molecular weight cytokeratin Ck18 in variable proportions of cells. Even in monophasic tumours lacking obvious glandular differentiation in conventional staining, a number of neoplastic cells still expressed those cytokeratins. Double immunofluorescence revealed tumour cells exclusively staining for Ck5/Ck14 in the presence of other cell populations that co-expressed high molecular weight Ck5/Ck14 as well as either low molecular weight Ck8/18 or SMA. Based on morphology, we assigned the series to three categories, benign, borderline and malignant. This classification was supported by a stepwise increase in cytogenetic alterations on CGH. Conclusion Adenomyoepithelial tumours comprise a spectrum of neoplasms consisting of an admixture of glandular and myoepithelial differentiation patterns. As a key component SMA-positive cells co-expressing cytokeratins could be identified. Although categorisation of adenomyoepithelial tumours in benign, borderline and malignant was supported by results of CGH, any assessment of prognosis requires to be firmly based on morphological grounds. At present

  9. Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo

    International Nuclear Information System (INIS)

    Anesti, Anna-Maria; Simpson, Guy R; Price, Toby; Pandha, Hardev S; Coffin, Robert S

    2010-01-01

    Delivery of small interfering RNA (siRNA) to tumours remains a major obstacle for the development of RNA interference (RNAi)-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV) OncoVEX GM-CSF , we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV. To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA) or artificial microRNA (miRNA) against the reporter genes green fluorescent protein (eGFP) and β-galactosidase (lacZ). These vectors were tested in non-tumour cell lines in vitro and tumour cells that are moderately susceptible to HSV infection both in vitro and in mice xenografts in vivo. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting. Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells in vitro and tumours in vivo, with the viruses expressing artificial miRNA being comprehensibly more effective. This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells in vitro and in vivo. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen in human clinical trials

  10. In vivo infiltration of mononuclear cells in squamous cell carcinoma of the head and neck correlates with the ability to expand tumour-infiltrating T cells in vitro and with the expression of MHC class I antigens on tumour cells

    DEFF Research Database (Denmark)

    Hald, J; Rasmussen, N; Claesson, Mogens Helweg

    1994-01-01

    -peptide-specific T cells in the patients. Eight out of ten expanded tumour-infiltrating lymphocyte (TIL) cultures showed T-cell-mediated cytotoxicity. "Promiscuous" cytotoxic T cell activity against the natural-killer-cell-sensitive K562 target cell line was observed in three out of ten TIL expansion...

  11. Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration

    Directory of Open Access Journals (Sweden)

    Jo Richardson

    2016-05-01

    Full Text Available Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

  12. Bilateral synchronous testicular germ cell tumours in a patient with ...

    African Journals Online (AJOL)

    were normally developed and the penis was well developed. The scrotal sacs were underdeveloped and empty. The results of haematological investigations, including kidney and .... testosterone propionate.4. In conclusion, synchronous bilateral testicular tumours in bilateral cryptorchidism are very rare. Seminoma is the ...

  13. Pancreatic cancer tumour initiating cells: the molecular regulation and therapeutic values

    OpenAIRE

    Ni, Xiaoling; Long, Jiang; Cen, Putao; Chen, Leon; Yang, Jingxuan; Li, Min

    2012-01-01

    Abstract Pancreatic cancer is an aggressive solid tumour characterized by its local invasion, early metastasis and resistance to standard chemotherapy or radiation therapy. Tumour initiating cells (TICs) are not only capable of self-renewal and differentiation, but also play an important role in multi-drug resistance, and thus become a popular topic in cancer research especially in pancreatic cancer. In this review, we summarize the current progress of TICs in tumourigenesis, various newly id...

  14. Granular Cell Tumour of the Bile Duct in Association with Intrahepatic Bile Duct Adenomas

    OpenAIRE

    Schweiger, F; Radhi, J; Coop, FW; Murphy, RW

    1994-01-01

    Granular cell tumour of the extrahepatic biliary tract is a rare benign lesion likely of neurogenic origin. Review of the previously reported cases indicates that almost all patients are female, and the majority is Black. Symptoms usually are those of biliary obstruction or cholecystitis. Surgical resection of the tumour is curative. Intrahepatic bile duct adenoma is another rare benign biliary neoplasm that does not manifest clinically but can be confused with metastatic carcinoma, cholangio...

  15. Evidence for a role of matrix metalloproteinases and their inhibitors in primordial germ cell migration.

    Science.gov (United States)

    Díez-Torre, A; Díaz-Núñez, M; Eguizábal, C; Silván, U; Aréchaga, J

    2013-09-01

    Understanding the mechanisms that enable migrating cells to reach their targets is of vital importance, as several pathologies, including cardiac defects and some tumours, are consequences of altered cell migration. With a view to evaluating if matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in the active migration of primordial germ cells (PGCs) from their place of origin in extra-embryonic sites towards their final destination in the developing gonads, we analysed the expression of mRNAs encoding nine MMPs and four TIMPs in migrating (E10.5) and post-migrating (E12.5) PGCs by means of quantitative polymerase chain reaction and the presence of MT1-MMP in the membrane of these cells. Our results show that PGCs express MMP-2, MMP-9, MMP-11, MT1-MMP, TIMP-1, TIMP-2 and TIMP-3 at both migrating and non-migrating stages. Comparing expression levels of MMP genes between E10.5 and E12.5 PGCs revealed higher expression in migrating PGCs of MT1- MMP (10.3-fold), MMP-2 (4.8-fold), MMP-11 (3.2-fold) and MMP-9 (2.1-fold). Similarly, the levels of TIMP gene expression were always higher in E12.5 genital ridge somatic cells: TIMP-3 (3.4-fold), TIMP-1 (2.4-fold) and TIMP-2 (1.8-fold). Moreover, the analysis at protein level showed the presence of MT1-MMP in the membrane of migrating PGCs whereas the expression of these metalloproteinase is not detected once the PGCs have reach the urogenital ridges and stop migrating. These results suggest that the change from the motile to non-motile phenotype that occurs during PGC maturation to gonocytes may be mediated in part by enhanced expression of MMPs in migrating PGCs together with higher expression of TIMPs in E12.5 genital ridges. © 2013 American Society of Andrology and European Academy of Andrology.

  16. Multi-Cellular Logistics of Collective Cell Migration

    Science.gov (United States)

    Yamao, Masataka; Naoki, Honda; Ishii, Shin

    2011-01-01

    During development, the formation of biological networks (such as organs and neuronal networks) is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic) blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes “collective migration,” whereas strong noise from non-migratory cells causes “dispersive migration.” Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems. PMID:22205934

  17. Multi-cellular logistics of collective cell migration.

    Directory of Open Access Journals (Sweden)

    Masataka Yamao

    Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

  18. Robotic Patterning a Superhydrophobic Surface for Collective Cell Migration Screening.

    Science.gov (United States)

    Pang, Yonggang; Yang, Jing; Hui, Zhixin; Grottkau, Brian E

    2018-04-01

    Collective cell migration, in which cells migrate as a group, is fundamental in many biological and pathological processes. There is increasing interest in studying the collective cell migration in high throughput. Cell scratching, insertion blocker, and gel-dissolving techniques are some methodologies used previously. However, these methods have the drawbacks of cell damage, substrate surface alteration, limitation in medium exchange, and solvent interference. The superhydrophobic surface, on which the water contact angle is greater than 150 degrees, has been recently utilized to generate patterned arrays. Independent cell culture areas can be generated on a substrate that functions the same as a conventional multiple well plate. However, so far there has been no report on superhydrophobic patterning for the study of cell migration. In this study, we report on the successful development of a robotically patterned superhydrophobic array for studying collective cell migration in high throughput. The array was developed on a rectangular single-well cell culture plate consisting of hydrophilic flat microwells separated by the superhydrophobic surface. The manufacturing process is robotic and includes patterning discrete protective masks to the substrate using 3D printing, robotic spray coating of silica nanoparticles, robotic mask removal, robotic mini silicone blocker patterning, automatic cell seeding, and liquid handling. Compared with a standard 96-well plate, our system increases the throughput by 2.25-fold and generates a cell-free area in each well non-destructively. Our system also demonstrates higher efficiency than conventional way of liquid handling using microwell plates, and shorter processing time than manual operating in migration assays. The superhydrophobic surface had no negative impact on cell viability. Using our system, we studied the collective migration of human umbilical vein endothelial cells and cancer cells using assays of endpoint

  19. Partial wrist arthrodesis versus arthroplasty for distal radius giant cell tumours.

    Science.gov (United States)

    Zhu, Zhongsheng; Zhang, Chunlin; Zhao, Shichang; Dong, Yang; Zeng, Bingfang

    2013-11-01

    The purpose of this study was to evaluate the clinical efficacy of using the proximal fibular graft for partial wrist arthrodesis or arthroplasty after the resection of giant cell tumours of the distal radius. Between February 2006 and August 2010, 14 patients (seven males, seven females; average age, 35.7 years) with grade II and III giant cell tumours of the distal radius were treated by tumour resection and autologous proximal fibular grafts to reconstruct the wrist in our hospital. Seven patients each were treated by wrist arthroplasty and partial wrist arthrodesis, and were followed up for 2.2-6.8 years (average, 3.9 years). All patients achieved primary healing. No tumour recurrence was observed during follow-up in any of the patients. No statistically significant difference in forearm rotation was observed between patients undergoing the two different treatments. However, wrist flexion-extension activities were significantly better and the wrist grip strengths were significantly worse in the arthroplasty group than in the arthrodesis group. The Musculoskeletal Tumour Society score did not significantly differ between the groups. Overall, joint arthroplasty remains a favourable treatment with regard to the functional outcome for giant cell tumours of the distal radius; however, some of these patients may have a weaker grip strength. In comparison, partial wrist fusion appears to provide a durable and stable wrist with good long-term functional outcome.

  20. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer

    International Nuclear Information System (INIS)

    Kang, Hua; Watkins, Gareth; Parr, Christian; Douglas-Jones, Anthony; Mansel, Robert E; Jiang, Wen G

    2005-01-01

    Stromal cell-derived factor (SDF)-1 (CXC chemokine ligand-12) is a member of the CXC subfamily of chemokines, which, through its cognate receptor (CXC chemokine receptor [CXCR]4), plays an important role in chemotaxis of cancer cells and in tumour metastasis. We conducted the present study to evaluate the effect of SDF-1 on the invasiveness and migration of breast cancer cells, and we analyzed the expression of SDF-1 and its relation to clinicopathological features and clinical outcomes in human breast cancer. Expression of SDF-1 mRNA in breast cancer, endothelial (HECV) and fibroblast (MRC5) cell lines and in human breast tissues were studied using RT-PCR. MDA-MB-231 cells were transfected with a SDF-1 expression vector, and their invasiveness and migration was tested in vitro. In addition, the expression of SDF-1 was investigated using immunohistochemistry and quantitative RT-PCR in samples of normal human mammary tissue (n = 32) and mammary tumour (n = 120). SDF-1 expression was identified in MRC5, MDA-MB-435s and MDA-MB-436 cell lines, but CXCR4 expression was detected in all cell lines and breast tissues. An autocrine loop was created following transfection of MDA-MB-231 (which was CXCR4 positive and SDF-1 negative) with a mammalian expression cassette encoding SDF-1 (MDA-MB-231SDF1 +/+ ) or with control plasmid pcDNA4/GFP (MDA-MB-231 +/- ). MDA-MB-231SDF1 +/+ cells exhibited significantly greater invasion and migration potential (in transfected cells versus in wild type and empty MDA-MB-231 +/- ; P < 0.01). In mammary tissues SDF-1 staining was primarily seen in stromal cells and weakly in mammary epithelial cells. Significantly higher levels of SDF-1 were seen in node-positive than in node-negative tumours (P = 0.05), in tumours that metastasized (P = 0.05), and tumours from patients who died (P = 0.03) than in tumours from patients who were disease free. It was most notable that levels of SDF-1 correlated significantly with overall survival (P = 0.001) and

  1. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion

    Energy Technology Data Exchange (ETDEWEB)

    Elmpt, Wouter van; Zegers, Catharina M.L.; Reymen, Bart; Even, Aniek J.G.; Oellers, Michel; Troost, Esther G.C.; Lambin, Philippe [Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Dingemans, Anne-Marie C. [Maastricht University Medical Centre, Department of Pulmonology, GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Wildberger, Joachim E.; Das, Marco [Maastricht University Medical Centre, Department of Radiology, GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre, Department of Nuclear Medicine, GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); University Hospital RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

    2016-02-15

    Multiple imaging techniques are nowadays available for clinical in-vivo visualization of tumour biology. FDG PET/CT identifies increased tumour metabolism, hypoxia PET visualizes tumour oxygenation and dynamic contrast-enhanced (DCE) CT characterizes vasculature and morphology. We explored the relationships among these biological features in patients with non-small-cell lung cancer (NSCLC) at both the patient level and the tumour subvolume level. A group of 14 NSCLC patients from two ongoing clinical trials (NCT01024829 and NCT01210378) were scanned using FDG PET/CT, HX4 PET/CT and DCE CT prior to chemoradiotherapy. Standardized uptake values (SUV) in the primary tumour were calculated for the FDG and hypoxia HX4 PET/CT scans. For hypoxia imaging, the hypoxic volume, fraction and tumour-to-blood ratio (TBR) were also defined. Blood flow and blood volume were obtained from DCE CT imaging. A tumour subvolume analysis was used to quantify the spatial overlap between subvolumes. At the patient level, negative correlations were observed between blood flow and the hypoxia parameters (TBR >1.2): hypoxic volume (-0.65, p = 0.014), hypoxic fraction (-0.60, p = 0.025) and TBR (-0.56, p = 0.042). At the tumour subvolume level, hypoxic and metabolically active subvolumes showed an overlap of 53 ± 36 %. Overlap between hypoxic sub-volumes and those with high blood flow and blood volume was smaller: 15 ± 17 % and 28 ± 28 %, respectively. Half of the patients showed a spatial mismatch (overlap <5 %) between increased blood flow and hypoxia. The biological imaging features defined in NSCLC tumours showed large interpatient and intratumour variability. There was overlap between hypoxic and metabolically active subvolumes in the majority of tumours, there was spatial mismatch between regions with high blood flow and those with increased hypoxia. (orig.)

  2. Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model

    NARCIS (Netherlands)

    Marques, I.J.; Weiss, F.U.; Vlecken, D.H.; Nitsche, C.; Bakkers, J.; Lagendijk, A.K.; Partecke, L.I.; Heidecke, C.D.; Lerch, M.M.; Bagowski, C.P.

    2009-01-01

    BACKGROUND: Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For

  3. Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy.

    Directory of Open Access Journals (Sweden)

    Veronica Rainone

    Full Text Available Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies.We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC, as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras. Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation.Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines.Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer.

  4. Quantitative analysis of cell migration using optical flow.

    Directory of Open Access Journals (Sweden)

    Katica Boric

    Full Text Available Neural crest cells exhibit dramatic migration behaviors as they populate their distant targets. Using a line of zebrafish expressing green fluorescent protein (sox10:EGFP in neural crest cells we developed an assay to analyze and quantify cell migration as a population, and use it here to characterize in detail the subtle defects in cell migration caused by ethanol exposure during early development. The challenge was to quantify changes in the in vivo migration of all Sox10:EGFP expressing cells in the visual field of time-lapse movies. To perform this analysis we used an Optical Flow algorithm for motion detection and combined the analysis with a fit to an affine transformation. Through this analysis we detected and quantified significant differences in the cell migrations of Sox10:EGFP positive cranial neural crest populations in ethanol treated versus untreated embryos. Specifically, treatment affected migration by increasing the left-right asymmetry of the migrating cells and by altering the direction of cell movements. Thus, by applying this novel computational analysis, we were able to quantify the movements of populations of cells, allowing us to detect subtle changes in cell behaviors. Because cranial neural crest cells contribute to the formation of the frontal mass these subtle differences may underlie commonly observed facial asymmetries in normal human populations.

  5. Collective dynamics of cell migration and cell rearrangements

    Science.gov (United States)

    Kabla, Alexandre

    Understanding multicellular processes such as embryo development or cancer metastasis requires to decipher the contributions of local cell autonomous behaviours and long range interactions with the tissue environment. A key question in this context concerns the emergence of large scale coordination in cell behaviours, a requirement for collective cell migration or convergent extension. I will present a few examples where physical and mechanical aspects play a significant role in driving tissue scale dynamics. Geometrical confinement is one of the key external factors influencing large scale coordination during collective migration. Using a combination of in vitro experiments and numerical simulations, we show that the velocity correlation length, measured in unconfined conditions, provides a convenient length scale to predict the dynamic response under confinement. The same length scale can also be used to quantify the influence range of directional cues within the cell population. Heterogeneity within motile cell populations is frequently associated with an increase in their invasive capability and appears to play an important role during cancer metastasis. Using in silico experiments, we studied the way cell invasion is influenced by both the degree of cell coordination and the amount of variability in the motile force of the invading cells. Results suggest that mechanical heterogeneity dramatically enhances the invasion rate through an emerging cooperative process between the stronger and weaker cells, accounting for a number of observed invasion phenotypes. Effective convergent extension requires on a consistent orientation of cell intercalation at the tissue scale, most often in relation with planar cell polarity mechanisms to define the primary axes of deformation. Using a novel modelling approach for cells mechanical interactions, we studied the dynamics of substrate free motile cell populations. Ongoing work shows in particular that nematic order emerges

  6. Collective cell migration in morphogenesis, regeneration and cancer.

    NARCIS (Netherlands)

    Friedl, P.H.A.; Gilmour, D.

    2009-01-01

    The collective migration of cells as a cohesive group is a hallmark of the tissue remodelling events that underlie embryonic morphogenesis, wound repair and cancer invasion. In such migration, cells move as sheets, strands, clusters or ducts rather than individually, and use similar actin- and

  7. Dictyostelium cells migrate similarly on surfaces of varying chemical composition.

    Science.gov (United States)

    McCann, Colin P; Rericha, Erin C; Wang, Chenlu; Losert, Wolfgang; Parent, Carole A

    2014-01-01

    During cell migration, cell-substrate binding is required for pseudopod anchoring to move the cell forward, yet the interactions with the substrate must be sufficiently weak to allow parts of the cell to de-adhere in a controlled manner during typical protrusion/retraction cycles. Mammalian cells actively control cell-substrate binding and respond to extracellular conditions with localized integrin-containing focal adhesions mediating mechanotransduction. We asked whether mechanotransduction also occurs during non-integrin mediated migration by examining the motion of the social amoeba Dictyostelium discoideum, which is thought to bind non-specifically to surfaces. We discovered that Dictyostelium cells are able to regulate forces generated by the actomyosin cortex to maintain optimal cell-surface contact area and adhesion on surfaces of various chemical composition and that individual cells migrate with similar speed and contact area on the different surfaces. In contrast, during collective migration, as observed in wound healing and metastasis, the balance between surface forces and protrusive forces is altered. We found that Dictyostelium collective migration dynamics are strongly affected when cells are plated on different surfaces. These results suggest that the presence of cell-cell contacts, which appear as Dictyostelium cells enter development, alter the mechanism cells use to migrate on surfaces of varying composition.

  8. Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems

    Directory of Open Access Journals (Sweden)

    Scott A. Nelson

    2012-11-01

    Nonsense mutations that result in the expression of truncated, N-terminal, fragments of the adenomatous polyposis coli (APC tumour suppressor protein are found in most sporadic and some hereditary colorectal cancers. These mutations can cause tumorigenesis by eliminating β-catenin-binding sites from APC, which leads to upregulation of β-catenin and thereby results in the induction of oncogenes such as MYC. Here we show that, in three distinct experimental model systems, expression of an N-terminal fragment of APC (N-APC results in loss of directionality, but not speed, of cell motility independently of changes in β-catenin regulation. We developed a system to culture and fluorescently label live pieces of gut tissue to record high-resolution three-dimensional time-lapse movies of cells in situ. This revealed an unexpected complexity of normal gut cell migration, a key process in gut epithelial maintenance, with cells moving with spatial and temporal discontinuity. Quantitative comparison of gut tissue from wild-type mice and APC heterozygotes (APCMin/+; multiple intestinal neoplasia model demonstrated that cells in precancerous epithelia lack directional preference when moving along the crypt-villus axis. This effect was reproduced in diverse experimental systems: in developing chicken embryos, mesoderm cells expressing N-APC failed to migrate normally; in amoeboid Dictyostelium, which lack endogenous APC, expressing an N-APC fragment maintained cell motility, but the cells failed to perform directional chemotaxis; and multicellular Dictyostelium slug aggregates similarly failed to perform phototaxis. We propose that N-terminal fragments of APC represent a gain-of-function mutation that causes cells within tissue to fail to migrate directionally in response to relevant guidance cues. Consistent with this idea, crypts in histologically normal tissues of APCMin/+ intestines are overpopulated with cells, suggesting that a lack of migration might cause cell

  9. Automated migration analysis based on cell texture: method & reliability

    Directory of Open Access Journals (Sweden)

    Chittenden Thomas W

    2005-03-01

    Full Text Available Abstract Background In this paper, we present and validate a way to measure automatically the extent of cell migration based on automated examination of a series of digital photographs. It was designed specifically to identify the impact of Second Hand Smoke (SHS on endothelial cell migration but has broader applications. The analysis has two stages: (1 preprocessing of image texture, and (2 migration analysis. Results The output is a graphic overlay that indicates the front lines of cell migration superimposed on each original image, with automated reporting of the distance traversed vs. time. Expert preference compares to manual placement of leading edge shows complete equivalence of automated vs. manual leading edge definition for cell migration measurement. Conclusion Our method is indistinguishable from careful manual determinations of cell front lines, with the advantages of full automation, objectivity, and speed.

  10. Ribosomal protein S6 phosphorylation and morphological changes in response to the tumour promoter 12-O-tetradecanoylphorbol 13-acetate in primary human tumour cells, established and transformed cell lines

    DEFF Research Database (Denmark)

    Rance, A J; Thönnes, M; Issinger, O G

    1985-01-01

    The phosphorylation of ribosomal protein S6 in fibroblasts, primary human tumour cells, established and SV40-transformed human cell lines was compared after the addition of 12-O-tetradecanoylphorbol 13-acetate (TPA). In fibroblasts and primary tumour cell cultures, stimulation of S6 phosphorylati...

  11. Expression of syndecan-4 and correlation with metastatic potential in testicular germ cell tumours.

    Science.gov (United States)

    Labropoulou, Vassiliki T; Skandalis, Spyros S; Ravazoula, Panagiota; Perimenis, Petros; Karamanos, Nikos K; Kalofonos, Haralabos P; Theocharis, Achilleas D

    2013-01-01

    Although syndecan-4 is implicated in cancer progression, there is no information for its role in testicular germ cell tumours (TGCTs). Thus, we examined the expression of syndecan-4 in patients with TGCTs and its correlation with the clinicopathological findings. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCTs. In seminomas, high percentage of tumour cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Stromal staining for syndecan-4 was found in seminomas and it was associated with nodal metastasis (P = 0.04), vascular/lymphatic invasion (P = 0.01), and disease stage (P = 0.04). Reduced tumour cell associated staining for syndecan-4 was observed in nonseminomatous germ cell tumours (NSGCTs) compared to seminomas. This loss of syndecan-4 was associated with nodal metastasis (P = 0.01), vascular/lymphatic invasion (P = 0.01), and disease stage (P = 0.01). Stromal staining for syndecan-4 in NSGCTs did not correlate with any of the clinicopathological variables. The stromal expression of syndecan-4 in TGCTs was correlated with microvessel density (P = 0.03). Our results indicate that syndecan-4 is differentially expressed in seminomas and NSGCTs and might be a useful marker. Stromal staining in seminomas and reduced levels of syndecan-4 in tumour cells in NSGCTs are related to metastatic potential, whereas stromal staining in TGCTs is associated with neovascularization.

  12. Expression of Syndecan-4 and Correlation with Metastatic Potential in Testicular Germ Cell Tumours

    Directory of Open Access Journals (Sweden)

    Vassiliki T. Labropoulou

    2013-01-01

    Full Text Available Although syndecan-4 is implicated in cancer progression, there is no information for its role in testicular germ cell tumours (TGCTs. Thus, we examined the expression of syndecan-4 in patients with TGCTs and its correlation with the clinicopathological findings. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCTs. In seminomas, high percentage of tumour cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Stromal staining for syndecan-4 was found in seminomas and it was associated with nodal metastasis (, vascular/lymphatic invasion (, and disease stage (. Reduced tumour cell associated staining for syndecan-4 was observed in nonseminomatous germ cell tumours (NSGCTs compared to seminomas. This loss of syndecan-4 was associated with nodal metastasis (, vascular/lymphatic invasion (, and disease stage (. Stromal staining for syndecan-4 in NSGCTs did not correlate with any of the clinicopathological variables. The stromal expression of syndecan-4 in TGCTs was correlated with microvessel density (. Our results indicate that syndecan-4 is differentially expressed in seminomas and NSGCTs and might be a useful marker. Stromal staining in seminomas and reduced levels of syndecan-4 in tumour cells in NSGCTs are related to metastatic potential, whereas stromal staining in TGCTs is associated with neovascularization.

  13. Effect of Static Magnetic Field on Cell Migration

    Science.gov (United States)

    Hashimoto, Yuichiro; Kawasumi, Masashi; Saito, Masao

    The effect of magnetic field on cell has long been investigated, but there are few quantitative investigations of the migration of cells. Cell-migration is important as one of the fundamental activities of the cell. This study proposes a method to evaluate quantitatively the cell-diffusion constant and the effect of static magnetic field on cell migration. The cell-lines are neuroblastoma (NG108-15), fibroblastoma (NIH/3T3) and osteoblastoma (MC3T3-E1). The static magnetic field of 30 mT or 120 mT is impressed by a permanent magnet in vertical or horizontal direction to the dish. It is shown that the cell-diffusion constant can represent the cell migration as the cell activity. It is found that the cell migration is enhanced by exposure to the magnetic field, depending on the kind of cell. It is conjectured that the effect of static magnetic field affects the cell migration, which is at the downstream of the information transmission.

  14. Dysregulated miR-183 inhibits migration in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Dwyer Roisin M

    2010-09-01

    Full Text Available Abstract Background The involvement of miRNAs in the regulation of fundamental cellular functions has placed them at the fore of ongoing investigations into the processes underlying carcinogenesis. MiRNA expression patterns have been shown to be dysregulated in numerous human malignancies, including breast cancer, suggesting their probable involvement as novel classes of oncogenes or tumour suppressor genes. The identification of differentially expressed miRNAs and elucidation of their functional roles may provide insight into the complex and diverse molecular mechanisms of tumorigenesis. MiR-183 is located on chromosome 7q32 and is part of a miRNA family which are dysregulated in numerous cancers. The aims of this study were to further examine the expression and functional role of miR-183 in breast cancer. Methods MiR-183 expression was quantitated in primary breast tumours, tumour associated normal tissue and breast cancer cell lines using RQ-PCR. Gain of function analysis was performed in breast cancer cells using pre-miR-183 and the effect of miR-183 overexpression on cell viability, proliferation, apoptosis and migration was examined. Customized Taqman Low Density Arrays (TLDA were used to identify dysregulated genes in breast cancer cells transfected with pre-miR-183. Results We demonstrate that miR-183 is dysregulated in breast cancer and expression correlates with estrogen receptor and HER2/neu receptor expression. Induced overexpression of miR-183 inhibited migration of breast cancer cells. This finding was substantiated by RQ-PCR of mRNA from cells overexpressing miR-183 which showed dysregulation of several migration and invasion related genes. Specifically, the VIL2-coding protein Ezrin was confirmed as a target of miR-183 and downregulation of this protein was confirmed with immunocytochemistry. Conclusions These findings indicate that miR-183 targets VIL2 and may play a central role in the regulation of migration and metastasis in

  15. Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells

    OpenAIRE

    Aparicio, Luis A; Castosa, Raquel; Haz-Conde, Mar; Rodríguez, Marta; Blanco, Moisés; Valladares, Manuel; Figueroa, Angélica

    2014-01-01

    Background Vinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investiga...

  16. Characteristics of meniscus progenitor cells migrated from injured meniscus.

    Science.gov (United States)

    Seol, Dongrim; Zhou, Cheng; Brouillette, Marc J; Song, Ino; Yu, Yin; Choe, Hyeong Hun; Lehman, Abigail D; Jang, Kee W; Fredericks, Douglas C; Laughlin, Barbara J; Martin, James A

    2017-09-01

    Serious meniscus injuries seldom heal and increase the risk for knee osteoarthritis; thus, there is a need to develop new reparative therapies. In that regard, stimulating tissue regeneration by autologous stem/progenitor cells has emerged as a promising new strategy. We showed previously that migratory chondrogenic progenitor cells (CPCs) were recruited to injured cartilage, where they showed a capability in situ tissue repair. Here, we tested the hypothesis that the meniscus contains a similar population of regenerative cells. Explant studies revealed that migrating cells were mainly confined to the red zone in normal menisci: However, these cells were capable of repopulating defects made in the white zone. In vivo, migrating cell numbers increased dramatically in damaged meniscus. Relative to non-migrating meniscus cells, migrating cells were more clonogenic, overexpressed progenitor cell markers, and included a larger side population. Gene expression profiling showed that the migrating population was more similar to CPCs than other meniscus cells. Finally, migrating cells equaled CPCs in chondrogenic potential, indicating a capacity for repair of the cartilaginous white zone of the meniscus. These findings demonstrate that, much as in articular cartilage, injuries to the meniscus mobilize an intrinsic progenitor cell population with strong reparative potential. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1966-1972, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  17. Silk Film Topography Directs Collective Epithelial Cell Migration

    Science.gov (United States)

    Rosenblatt, Mark I.

    2012-01-01

    The following study provides new insight into how surface topography dictates directed collective epithelial cell sheet growth through the guidance of individual cell movement. Collective cell behavior of migrating human corneal limbal-epithelial cell sheets were studied on highly biocompatible flat and micro-patterned silk film surfaces. The silk film edge topography guided the migratory direction of individual cells making up the collective epithelial sheet, which resulted in a 75% increase in total culture elongation. This was due to a 3-fold decrease in cell sheet migration rate efficiency for movement perpendicular to the topography edge. Individual cell migration direction is preferred in the parallel approach to the edge topography where localization of cytoskeletal proteins to the topography’s edge region is reduced, which results in the directed growth of the collective epithelial sheet. Findings indicate customized biomaterial surfaces may be created to direct both the migration rate and direction of tissue epithelialization. PMID:23185573

  18. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting

    Directory of Open Access Journals (Sweden)

    Sander A. A. Kooijmans

    2016-03-01

    Full Text Available Background: Extracellular vesicles (EVs are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. Methods: EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI anchor signal peptides derived from decay-accelerating factor (DAF. EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV–tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopy-coupled perfusion system. Results: V analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression, but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. Conclusions: We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules.

  19. Down-regulation of Fas-L in glioma cells by ribozyme reduces cell apoptosis, tumour-infiltrating cells, and liver damage but accelerates tumour formation in nude mice

    OpenAIRE

    Chio, C-C; Wang, Y-S; Chen, Y-L; Lin, S-J; Yang, B-C

    2001-01-01

    Fas-L (CD95L, APO-1L) expresses in a variety of tumours and has been proposed to play a role in tumour formation and metastasis. The contribution of Fas-L to tumour growth, however, is not conclusive especially in systems using cells with over-expressed Fas-L. In this study we down-regulated the expression o Fas-L in human glioma cells by a hammerhead ribozyme (Fas-Lribozyme) targeting against Fas-L mRNA. Fas-Lribozyme-carrying cells exhibited slightly enhanced growth rate and less degree of ...

  20. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-01-01

    Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.

  1. Tumour-infiltrating lymphocytes mediate lysis of autologous squamous cell carcinomas of the head and neck

    DEFF Research Database (Denmark)

    Hald, Jeppe; Rasmussen, N; Claesson, Mogens Helweg

    1995-01-01

    , the cancer cells either overexpressed the tumour-suppressor gene product p53 or harboured human papilloma virus 16/18 (HPV). The TIL were expanded in vitro in the presence of interleukin-2, immobilised anti-CD3 mAb and soluble anti-CD28 mAb. Expanded TIL cultures contained both CD4+ and CD8+ T cells...

  2. Radio metal (169Yb) uptake in normal and tumour cells in vitro. Influence of metabolic cell activity and complex structure

    International Nuclear Information System (INIS)

    Franke, W.G.; Kampf, G.

    1996-01-01

    Trivalent radio metal tracers have been used for tumour imaging and metastatic pain palliation. For better understanding their tumour accumulation, basic model studies of uptake of different 169 Yb complexes into cultured normal and tumour cells were performed. Whereas the uptake of 169 Yb citrate is strongly dependent on the metabolic activity and is not tumour-cell pacific, the uptake of 169 Yb complexed with amino carbonic acid (NTA, EDTA, DTPA) does not correlate to the metabolic activities. These complexes are taken up to a greater amount by the tumour cells (by a factor of about 2). Uptake of both complex types leads to a stable association to cellular compounds, 169 Yb is not releasable by the strong complexing agent DTPA. Protein binding of the 169 Yb complexes shows great influence on their cellular uptake. The bound proportion is no more available,for cellular uptake. The results indicate that i 0 uptake of 169 Yb citrate is an active cellular transport process which i not tumor-specific, ii) the 169 Yb amino carbonic acid complexes show a weak favouring by the tumour cells, iii) different from earlier acceptions the Yb complexes studied are not taken up by the cells in protein-bound form. The structure of the Yb complex is decisive for its protein binding and cellular uptake. (author). 13 refs., 6 figs

  3. CD117 immunoexpression in canine mast cell tumours: correlations with pathological variables and proliferation markers

    Directory of Open Access Journals (Sweden)

    Pires Maria A

    2007-08-01

    Full Text Available Abstract Background Cutaneous mast cell tumours are one of the most common neoplasms in dogs and show a highly variable biologic behaviour. Several prognosis tools have been proposed for canine mast cell tumours, including histological grading and cell proliferation markers. CD117 is a receptor tyrosine kinase thought to play a key role in human and canine mast cell neoplasms. Normal (membrane-associated and aberrant (cytoplasmic, focal or diffuse CD117 immunoexpression patterns have been identified in canine mast cell tumours. Cytoplasmic CD117 expression has been found to correlate with higher histological grade and with a worsened post-surgical prognosis. This study addresses the role of CD117 in canine mast cell tumours by studying the correlations between CD117 immunoexpression patterns, two proliferation markers (Ki67 and AgNORs histological grade, and several other pathological variables. Results Highly significant (p Conclusion These findings highlight the key role of CD117 in the biopathology of canine MCTs and confirm the relationship between aberrant CD117 expression and increased cell proliferation and higher histological grade. Further studies are needed to unravel the cellular mechanisms underlying focal and diffuse cytoplasmic CD117 staining patterns, and their respective biopathologic relevance.

  4. Epigenetic features of testicular germ cell tumours in relation to epigenetic characteristics of foetal germ cells

    DEFF Research Database (Denmark)

    Kristensen, Dina Graae; Skakkebæk, Niels E; Rajpert-De Meyts, Ewa

    2013-01-01

    Foetal development of germ cells is a unique biological process orchestrated by cellular specification, migration and niche development in concert with extensive epigenetic and transcriptional programs. Many of these processes take place early in foetal life and are hence very difficult to study ...

  5. Src Induces Podoplanin Expression to Promote Cell Migration*

    Science.gov (United States)

    Shen, Yongquan; Chen, Chen-Shan; Ichikawa, Hitoshi; Goldberg, Gary S.

    2010-01-01

    Nontransformed cells can force tumor cells to assume a normal morphology and phenotype by the process of contact normalization. Transformed cells must escape this process to become invasive and malignant. However, mechanisms underlying contact normalization have not been elucidated. Here, we have identified genes that are affected by contact normalization of Src-transformed cells. Tumor cells must migrate to become invasive and malignant. Src must phosphorylate the adaptor protein Cas (Crk-associated substrate) to promote tumor cell motility. We report here that Src utilizes Cas to induce podoplanin (Pdpn) expression to promote tumor cell migration. Pdpn is a membrane-bound extracellular glycoprotein that associates with endogenous ligands to promote tumor cell migration leading to cancer invasion and metastasis. In fact, Pdpn expression accounted for a major part of the increased migration seen in Src-transformed cells. Moreover, nontransformed cells suppressed Pdpn expression in adjacent Src-transformed cells. Of >39,000 genes, Pdpn was one of only 23 genes found to be induced by transforming Src activity and suppressed by contact normalization of Src-transformed cells. In addition, we found 16 genes suppressed by Src and induced by contact normalization. These genes encode growth factor receptors, adaptor proteins, and products that have not yet been annotated and may play important roles in tumor cell growth and migration. PMID:20123990

  6. Steroid hormones affect binding of the sigma ligand 11C-SA4503 in tumour cells and tumour-bearing rats

    International Nuclear Information System (INIS)

    Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Jong, Johan R. de; Vries, Erik F. de; Dierckx, Rudi A.; Waarde, Aren van; Ishiwata, Kiichi

    2009-01-01

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist 11 C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. 11 C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of 11 C-SA4503 to C6 cells was increased (∝50%) upon removal and decreased (∝60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC 50 progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of 11 C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of 11 C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

  7. Steroid hormones affect binding of the sigma ligand {sup 11}C-SA4503 in tumour cells and tumour-bearing rats

    Energy Technology Data Exchange (ETDEWEB)

    Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Jong, Johan R. de; Vries, Erik F. de; Dierckx, Rudi A.; Waarde, Aren van [University of Groningen, Nuclear Medicine and Molecular Imaging, University of Groningen Medical Center, Groningen (Netherlands); Ishiwata, Kiichi [Tokyo Metropolitan Institute of Gerontology, Positron Medical Center, Tokyo (Japan)

    2009-07-15

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist {sup 11}C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. {sup 11}C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of {sup 11}C-SA4503 to C6 cells was increased ({proportional_to}50%) upon removal and decreased ({proportional_to}60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC{sub 50} progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of {sup 11}C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of {sup 11}C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

  8. A biophysical approach to the optimisation of dendritic-tumour cell electrofusion

    International Nuclear Information System (INIS)

    Sukhorukov, Vladimir L.; Reuss, Randolph; Endter, Joerg M.; Fehrmann, Steffen; Katsen-Globa, Alisa; Gessner, Petra; Steinbach, Andrea; Mueller, Kilian J.; Karpas, Abraham; Zimmermann, Ulrich; Zimmermann, Heiko

    2006-01-01

    Electrofusion of tumour and dendritic cells (DCs) is a promising approach for production of DC-based anti-tumour vaccines. Although human DCs are well characterised immunologically, little is known about their biophysical properties, including dielectric and osmotic parameters, both of which are essential for the development of efficient electrofusion protocols. In the present study, human DCs from the peripheral blood along with a tumour cell line used as a model fusion partner were examined by means of time-resolved cell volumetry and electrorotation. Based on the biophysical cell data, the electrofusion protocol could be rapidly optimised with respect to the sugar composition of the fusion medium, duration of hypotonic treatment, frequency range for stable cell alignment, and field strengths of breakdown pulses triggering membrane fusion. The hypotonic electrofusion consistently gave a tumour-DC hybrid rate of up to 19%, as determined by counting dually labelled fluorescent hybrids in a microscope. This fusion rate is nearly twice as high as that usually reported in the literature for isotonic media. The experimental findings and biophysical approach presented here are generally useful for the development of efficient electrofusion protocols, especially for rare and valuable human cells

  9. Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

    DEFF Research Database (Denmark)

    Rudolph, Christiane; Melau, Cecilie; Nielsen, John E.

    2017-01-01

    BackgroundTesticular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype......, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were...... investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined. ResultsMMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR...

  10. A pilgrim's progress: Seeking meaning in primordial germ cell migration

    Directory of Open Access Journals (Sweden)

    Andrea V. Cantú

    2017-10-01

    Full Text Available Comparative studies of primordial germ cell (PGC development across organisms in many phyla reveal surprising diversity in the route of migration, timing and underlying molecular mechanisms, suggesting that the process of migration itself is conserved. However, beyond the perfunctory transport of cellular precursors to their later arising home of the gonads, does PGC migration serve a function? Here we propose that the process of migration plays an additional role in quality control, by eliminating PGCs incapable of completing migration as well as through mechanisms that favor PGCs capable of responding appropriately to migration cues. Focusing on PGCs in mice, we explore evidence for a selective capacity of migration, considering the tandem regulation of proliferation and migration, cell-intrinsic and extrinsic control, the potential for tumors derived from failed PGC migrants, the potential mechanisms by which migratory PGCs vary in their cellular behaviors, and corresponding effects on development. We discuss the implications of a selective role of PGC migration for in vitro gametogenesis.

  11. A pilgrim's progress: Seeking meaning in primordial germ cell migration.

    Science.gov (United States)

    Cantú, Andrea V; Laird, Diana J

    2017-10-01

    Comparative studies of primordial germ cell (PGC) development across organisms in many phyla reveal surprising diversity in the route of migration, timing and underlying molecular mechanisms, suggesting that the process of migration itself is conserved. However, beyond the perfunctory transport of cellular precursors to their later arising home of the gonads, does PGC migration serve a function? Here we propose that the process of migration plays an additional role in quality control, by eliminating PGCs incapable of completing migration as well as through mechanisms that favor PGCs capable of responding appropriately to migration cues. Focusing on PGCs in mice, we explore evidence for a selective capacity of migration, considering the tandem regulation of proliferation and migration, cell-intrinsic and extrinsic control, the potential for tumors derived from failed PGC migrants, the potential mechanisms by which migratory PGCs vary in their cellular behaviors, and corresponding effects on development. We discuss the implications of a selective role of PGC migration for in vitro gametogenesis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Embryonic cell-cell adhesion: a key player in collective neural crest migration.

    Science.gov (United States)

    Barriga, Elias H; Mayor, Roberto

    2015-01-01

    Cell migration is essential for morphogenesis, adult tissue remodeling, wound healing, and cancer cell migration. Cells can migrate as individuals or groups. When cells migrate in groups, cell-cell interactions are crucial in order to promote the coordinated behavior, essential for collective migration. Interestingly, recent evidence has shown that cell-cell interactions are also important for establishing and maintaining the directionality of these migratory events. We focus on neural crest cells, as they possess extraordinary migratory capabilities that allow them to migrate and colonize tissues all over the embryo. Neural crest cells undergo an epithelial-to-mesenchymal transition at the same time than perform directional collective migration. Cell-cell adhesion has been shown to be an important source of planar cell polarity and cell coordination during collective movement. We also review molecular mechanisms underlying cadherin turnover, showing how the modulation and dynamics of cell-cell adhesions are crucial in order to maintain tissue integrity and collective migration in vivo. We conclude that cell-cell adhesion during embryo development cannot be considered as simple passive resistance to force, but rather participates in signaling events that determine important cell behaviors required for cell migration. © 2015 Elsevier Inc. All rights reserved.

  13. The thioredoxin system in breast cancer cell invasion and migration

    Directory of Open Access Journals (Sweden)

    Maneet Bhatia

    2016-08-01

    Full Text Available Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1 in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1 expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.

  14. Intracellular pH gradients in migrating cells

    DEFF Research Database (Denmark)

    Martin, Christine; Pedersen, Stine Helene Falsig; Schwab, Albrecht

    2011-01-01

    Cell polarization along the axis of movement is required for migration. The localization of proteins and regulators of the migratory machinery to either the cell front or its rear results in a spatial asymmetry enabling cells to simultaneously coordinate cell protrusion and retraction. Protons...... might function as such unevenly distributed regulators as they modulate the interaction of focal adhesion proteins and components of the cytoskeleton in vitro. However, an intracellular pH (pH(i)) gradient reflecting a spatial asymmetry of protons has not been shown so far. One major regulator of p......H(i), the Na(+)/H(+) exchanger NHE1, is essential for cell migration and accumulates at the cell front. Here, we test the hypothesis that the uneven distribution of NHE1 activity creates a pH(i) gradient in migrating cells. Using the pH-sensitive fluorescent dye BCECF, pH(i) was measured in five cell lines (MV...

  15. Epidemiological study of paediatric germ cell tumours revealed the incidence and distribution that was expected, but a low mortality rate

    DEFF Research Database (Denmark)

    Evers, Madeline; Rechnitzer, Catherine; Graem, Niels

    2017-01-01

    Aim: Germ cell tumours (GCTs) are a rare heterogeneous tumour group derived from primordial germ cells, which can be benign or malignant and occur in the gonads or extragonadally. This study mapped the paediatric GCTs in Denmark from 1984 to 2013 to study the incidence and outcome. Methods: We id...

  16. Long-Term Live Cell Imaging of Cell Migration: Effects of Pathogenic Fungi on Human Epithelial Cell Migration.

    Science.gov (United States)

    Wöllert, Torsten; Langford, George M

    2016-01-01

    Long-term live cell imaging was used in this study to determine the responses of human epithelial cells to pathogenic biofilms formed by Candida albicans. Epithelial cells of the skin represent the front line of defense against invasive pathogens such as C. albicans but under certain circumstances, especially when the host's immune system is compromised, the skin barrier is breached. The mechanisms by which the fungal pathogen penetrates the skin and invade the deeper layers are not fully understood. In this study we used keratinocytes grown in culture as an in vitro model system to determine changes in host cell migration and the actin cytoskeleton in response to virulence factors produced by biofilms of pathogenic C. albicans. It is clear that changes in epithelial cell migration are part of the response to virulence factors secreted by biofilms of C. albicans and the actin cytoskeleton is the downstream effector that mediates cell migration. Our goal is to understand the mechanism by which virulence factors hijack the signaling pathways of the actin cytoskeleton to alter cell migration and thereby invade host tissues. To understand the dynamic changes of the actin cytoskeleton during infection, we used long-term live cell imaging to obtain spatial and temporal information of actin filament dynamics and to identify signal transduction pathways that regulate the actin cytoskeleton and its associated proteins. Long-term live cell imaging was achieved using a high resolution, multi-mode epifluorescence microscope equipped with specialized light sources, high-speed cameras with high sensitivity detectors, and specific biocompatible fluorescent markers. In addition to the multi-mode epifluorescence microscope, a spinning disk confocal long-term live cell imaging system (Olympus CV1000) equipped with a stage incubator to create a stable in vitro environment for long-term real-time and time-lapse microscopy was used. Detailed descriptions of these two long-term live

  17. Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome.

    Science.gov (United States)

    Walls, G V; Stevenson, M; Lines, K E; Newey, P J; Reed, A A C; Bowl, M R; Jeyabalan, J; Harding, B; Bradley, K J; Manek, S; Chen, J; Wang, P; Williams, B O; Teh, B T; Thakker, R V

    2017-07-13

    The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 (CDC73) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional (Cdc73 +/- ) and conditional parathyroid-specific (Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type (Cdc73 +/+ and Cdc73 +/+ /PTH-Cre) littermates. Survival of Cdc73 +/- mice, when compared to Cdc73 +/+ mice was reduced (Cdc73 +/- =80%; Cdc73 +/+ =90% at 18 months of age, Pfourfold higher than that in parathyroid glands of wild-type littermates (P<0.0001). Cdc73 +/- , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73 +/- mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73 +/- mice did not develop bone or renal tumours but female Cdc73 +/- mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73 +/- mice had increased proliferation rates that were 2-fold higher than in Cdc73 +/+ mice (P<0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.

  18. The evolution of carrying capacity in constrained and expanding tumour cell populations.

    Science.gov (United States)

    Gerlee, Philip; Anderson, Alexander R A

    2015-08-12

    Cancer cells are known to modify their micro-environment such that it can sustain a larger population, or, in ecological terms, they construct a niche which increases the carrying capacity of the population. It has however been argued that niche construction, which benefits all cells in the tumour, would be selected against since cheaters could reap the benefits without paying the cost. We have investigated the impact of niche specificity on tumour evolution using an individual based model of breast tumour growth, in which the carrying capacity of each cell consists of two components: an intrinsic, subclone-specific part and a contribution from all neighbouring cells. Analysis of the model shows that the ability of a mutant to invade a resident population depends strongly on the specificity. When specificity is low selection is mostly on growth rate, while high specificity shifts selection towards increased carrying capacity. Further, we show that the long-term evolution of the system can be predicted using adaptive dynamics. By comparing the results from a spatially structured versus well-mixed population we show that spatial structure restores selection for carrying capacity even at zero specificity, which poses a solution to the niche construction dilemma. Lastly, we show that an expanding population exhibits spatially variable selection pressure, where cells at the leading edge exhibit higher growth rate and lower carrying capacity than those at the centre of the tumour.

  19. The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines.

    Directory of Open Access Journals (Sweden)

    Amanda L Patchett

    Full Text Available The survival of the Tasmanian devil (Sarcophilus harrisii is threatened by devil facial tumour disease (DFTD. This transmissible cancer is usually fatal, and no successful treatments have been developed. In human studies, the small immunomodulatory molecule imiquimod is a successful immunotherapy, activating anti-tumour immunity via stimulation of toll-like receptor-7 (TLR7 signaling pathways. In addition, imiquimod is a potent inducer of apoptosis in human tumour cell lines via TLR7 independent mechanisms. Here we investigate the potential of imiquimod as a DFTD therapy through analysis of treated DFTD cell lines and Tasmanian devil fibroblasts. WST-8 proliferation assays and annexin V apoptosis assays were performed to monitor apoptosis, and changes to the expression of pro- and anti-apoptotic genes were analysed using qRT-PCR. Our results show that DFTD cell lines, but not Tasmanian devil fibroblasts, are sensitive to imiquimod-induced apoptosis in a time and concentration dependent manner. Induction of apoptosis was accompanied by down-regulation of the anti-apoptotic BCL2 and BCLXL genes, and up-regulation of the pro-apoptotic BIM gene. Continuous imiquimod treatment was required for these effects to occur. These results demonstrate that imiquimod can deregulate DFTD cell growth and survival in direct and targeted manner. In vivo, this may increase DFTD vulnerability to imiquimod-induced TLR7-mediated immune responses. Our findings have improved the current knowledge of imiquimod action in tumour cells for application to both DFTD and human cancer therapy.

  20. Newly-derived neuroblastoma cell lines propagated in serum-free media recapitulate the genotype and phenotype of primary neuroblastoma tumours

    NARCIS (Netherlands)

    Bate-Eya, Laurel T.; Ebus, Marli E.; Koster, Jan; den Hartog, Ilona J. M.; Zwijnenburg, Danny A.; Schild, Linda; van der Ploeg, Ida; Dolman, M. Emmy M.; Caron, Huib N.; Versteeg, Rogier; Molenaar, Jan J.

    2014-01-01

    Recently protocols have been devised for the culturing of cell lines from fresh tumours under serum-free conditions in defined neural stem cell medium. These cells, frequently called tumour initiating cells (TICs) closely retained characteristics of the tumours of origin. We report the isolation of

  1. The evaluation of in vitro effect of daunorubicin and tamoxifen in ehrlich ascites tumour (EAT) cells

    International Nuclear Information System (INIS)

    Topcul, M.; Topcul, F.; Oezalpan, A.

    2001-01-01

    In the most countries, breast cancer is still the most important cancer among women. It is known that Ehrlich Ascites Tumour is experimental breast cancer model in animal. The cells used in the study are hyper diploid line of Ehrlich Ascites Tumour (EAT) cells, initially provided to us from Institute of Pathology, Koln University. In the present study, an hyper diploid line which is estrogen receptor positive was used. An anthracycline-derived antibiotic, Daunorubicin (DNR, Cerubidine) is one of the clinically used anticancer drugs. DNR has been used alone or in combination with other cytotoxic agents against a variety of animal and human tumours. In vitro cell culture studies show that DNR enters the cell nuclei, inhibits nucleic acid synthesis, and arrest cell division. Tamoxifen (TAM, Nolvadex) is a semi-synthetical estrogen antagonist, used in the management of pre and post menopausal breast cancer. This drug bind to intracellular estrogen receptors, and prevents endogenous estrogens from binding to their own receptors. It is known that Ehrlich Ascites Tumour is experimental breast cancer model in animal. The cells used in the study are hyper diploid line of EAT cells initially provided to us from Institute of Pathology, Koln University. In the present study, an hyper diploid line which is Estrogen Receptor (+) was used. Estrogen Receptor levels were studied by the methods of Lippman and Huff and Raynaud et al. with minor modifications. Estrogen Receptor activity as demonstrated by dextran-coated charcoal technique is closely correlated with the clinical ability of Tamoxifen to inhibit tumour growth

  2. Cell Migration as a Therapeutic Target in Malignant Breast Cancer

    National Research Council Canada - National Science Library

    Plopper, George

    2002-01-01

    The objects of this project are to develop a high-throughput method for screening potential inhibitors of breast cancer cell migration, and to apply this method to identify signaling events mediating...

  3. Lack of relationship between TIMP-1 tumour cell immunoreactivity, treatment efficacy and prognosis in patients with advanced epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Steffensen, Karina Dahl; Waldstrøm, Marianne; Christensen, Rikke Kølby

    2010-01-01

    BACKGROUND: Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a natural inhibitor of the matrix metalloproteinases (MMPs) which are proteolytic enzymes involved in degradation of extracellular matrix thereby favoring tumour cell invasion and metastasis. TIMP-1 activity in tumour tissue may ther...... immunoreactivity in tumour tissue from patients with primary epithelial ovarian cancer did not correlate with patient survival or response to combination platinum/cyclophosphamide therapy.......BACKGROUND: Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a natural inhibitor of the matrix metalloproteinases (MMPs) which are proteolytic enzymes involved in degradation of extracellular matrix thereby favoring tumour cell invasion and metastasis. TIMP-1 activity in tumour tissue may...... therefore play an essential role in the progression of a malignant tumour.The primary aim of the present study was to evaluate TIMP-1 protein immunoreactivity in tissue from primary ovarian cancer patients and associate these findings with the course of the disease including response to treatment...

  4. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours

    International Nuclear Information System (INIS)

    Horsman, M.

    1996-01-01

    Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitize murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms. However, recent studies in mouse tumours have shown that these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The combined nicotinamide with hyperthermia proved that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically, with daily doses of up to 6 g, associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to

  5. Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells.

    Directory of Open Access Journals (Sweden)

    Aitziber Buqué

    Full Text Available Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non-squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance.

  6. SOX15 regulates proliferation and migration of endometrial cancer cells.

    Science.gov (United States)

    Rui, Xiaohui; Xu, Yun; Jiang, Xiping; Guo, Caixia; Jiang, Jingting

    2017-10-31

    The study aimed to investigate the effects of Sry-like high mobility group box 15 ( SOX15 ) on proliferation and migration of endometrial cancer (EC) cells. Immunohistochemistry (IHC) was applied to determine the expression of SOX15 in EC tissues and adjacent tissues. We used cell transfection method to construct the HEC-1-A and Ishikawa cell lines with stable overexpression and low expression SOX15 Reverse-transcription quantitative real-time PCR (RT-qPCR) and Western blot were performed to examine expression of SOX15 mRNA and SOX15 protein, respectively. By conducting a series of cell proliferation assay and migration assay, we analyzed the influence of SOX15 overexpression or low expression on EC cell proliferation and migration. The expression of SOX15 mRNA and protein in EC tissues was significantly lower than that in adjacent tissues. After lentivirus-transfecting SOX15 , the expression level of SOX15 mRNA and protein was significantly increased in cells of SOX15 group, and decreased in sh- SOX15 group. Overexpression of SOX15 could suppress cell proliferation, while down-regulation of SOX15 increased cell proliferation. Flow cytometry results indicated that overexpression of SOX15 induced the ratio of cell-cycle arrest in G 1 stage. In addition, Transwell migration assay results showed that SOX15 overexpression significantly inhibited cell migration, and also down-regulation of SOX15 promoted the migration. As a whole, SOX15 could regulate the proliferation and migration of EC cells and up- regulation of SOX15 could be valuable for EC treatment. © 2017 The Author(s).

  7. Influence of ipilimumab on expanded tumour derived T cells from patients with metastatic melanoma

    DEFF Research Database (Denmark)

    Bjørn, Jon; Lyngaa, Rikke Birgitte; Andersen, Rikke

    2017-01-01

    Introduction: Tumour infiltrating lymphocyte (TIL) based adoptive cell therapy (ACT) is a promising treatment for patients with advanced melanoma. Retrospective studies suggested an association between previous treatment with anti-CTLA-4 antibodies and long term survival after subsequent ACT. Thu...

  8. True precocious puberty following treatment of a Leydig cell tumour: two case reports and literature review

    Directory of Open Access Journals (Sweden)

    Alberto eVerrotti

    2015-11-01

    Full Text Available Leydig cell testicular tumours are a rare cause of precocious pseudopuberty in boys. Surgery is the main therapy and shows good overall prognosis. The physical signs of precocious puberty are expected to disappear shortly after surgical removal of the mass. We report two children, 7.5 and 7.7 year-old boys, who underwent testis-sparing surgery for a Leydig cell testicular tumour causing precocious pseudopuberty. During follow-up, after an immediate clinical and laboratory regression, both boys presented signs of precocious puberty and ultimately developed central precocious puberty. They were successfully treated with gonadotropin releasing hormone analogues. Only 6 other cases have been described regarding the development of central precocious puberty after successful treatment of a Leydig cell tumour causing precocious pseudo puberty. Gonadotropin-dependent precocious puberty should be considered in children treated for a Leydig cell tumour presenting persistent or recurrent physical signs of puberty activation. In such cases, therapy with gonadotropin releasing hormone analogues appears to be the most effective medical treatment.

  9. Dictyostelium Cells Migrate Similarly on Surfaces of Varying Chemical Composition

    OpenAIRE

    McCann, Colin P.; Rericha, Erin C.; Wang, Chenlu; Losert, Wolfgang; Parent, Carole A.

    2014-01-01

    During cell migration, cell-substrate binding is required for pseudopod anchoring to move the cell forward, yet the interactions with the substrate must be sufficiently weak to allow parts of the cell to de-adhere in a controlled manner during typical protrusion/retraction cycles. Mammalian cells actively control cell-substrate binding and respond to extracellular conditions with localized integrin-containing focal adhesions mediating mechanotransduction. We asked whether mechanotransduction ...

  10. Detection of chromosomal aberrations in seminomatous germ cell tumours using comparative genomic hybridization

    DEFF Research Database (Denmark)

    Ottesen, A M; Kirchhoff, M; Rajpert-De Meyts, Ewa

    1997-01-01

    Comparative genomic hybridization (CGH) was used to evaluate tissue specimens from 16 seminomas in order to elucidate the pathogenesis of germ cell tumours in males. A characteristic pattern of losses and gains within the entire genomes was detected in 94% of the seminomas by comparing the ratio...... of 12p and 21q appeared most consistently. Results from CGH analysis displayed no relationship to the clinical stages of the malignancy. Some rare aberrations appeared, however, only in clinical stage II and in tumours showing relapse in the contralateral testis following orchiectomy, although...

  11. Synchronous Multicentric Giant Cell Tumour of Distal Radius and Sacrum with Pulmonary Metastases

    Directory of Open Access Journals (Sweden)

    Varun Sharma Tandra

    2015-01-01

    Full Text Available Giant cell tumour (GCT is an uncommon primary bone tumour, and its multicentric presentation is exceedingly rare. We report a case of a 45-year-old female who presented to us with GCT of left distal radius. On the skeletal survey, osteolytic lesion was noted in her right sacral ala. Biopsy confirmed both lesions as GCT. Pulmonary metastasis was also present. Resection-reconstruction arthroplasty for distal radius and thorough curettage and bone grafting of the sacral lesion were done. Multicentric GCT involving distal radius and sacrum with primary sacral involvement is not reported so far to our knowledge.

  12. Nox1-dependent superoxide production controls colon adenocarcinoma cell migration.

    Science.gov (United States)

    Sadok, Amine; Bourgarel-Rey, Véronique; Gattacceca, Florence; Penel, Claude; Lehmann, Maxime; Kovacic, Hervé

    2008-01-01

    Reactive oxygen species are well-known mediators of various biological responses. Recently, new homologues of the catalytic subunit of NADPH oxidase have been discovered in non-phagocytic cells. These new homologues (Nox1-Nox5) produce low levels of superoxides compared to the phagocytic homologue Nox2/gp91phox. Using Nox1 siRNA, we show that Nox1-dependent superoxide production affects the migration of HT29-D4 colonic adenocarcinoma cells on collagen-I. Nox1 inhibition or down-regulation led to a decrease of superoxide production and alpha 2 beta 1 integrin membrane availability. An addition of arachidonic acid stimulated Nox1-dependent superoxide production and HT29-D4 cell migration. Pharmacological evidences using phospholipase A2, lipoxygenases and protein kinase C inhibitors show that upstream regulation of Nox1 relies on arachidonic acid metabolism. Inhibition of 12-lipoxygenase decreased basal and arachidonic acid induced Nox1-dependent superoxide production and cell migration. Migration and ROS production inhibited by a 12-lipoxygenase inhibitor were restored by the addition of 12(S)-HETE, a downstream product of 12-lipoxygenase. Protein kinase C delta inhibition by rottlerin (and also GO6983) prevented Nox1-dependent superoxide production and inhibited cell migration, while other protein kinase C inhibitors were ineffective. We conclude that Nox1 activation by arachidonic acid metabolism occurs through 12-lipoxygenase and protein kinase C delta, and controls cell migration by affecting integrin alpha 2 subunit turn-over.

  13. Association between tumour volume and recurrence of squamous cell carcinoma of the head and neck

    International Nuclear Information System (INIS)

    Kazmi, F.N.; Adil, A.; Ghaffar, S.; Ahmed, F.

    2012-01-01

    Objective: To evaluate the prognostic significance of computerized tomography derived tumour volume for squamous cell cancers of the head and neck, treated primarily by surgery. Methods: The retrospective review study comprised 72 patients with head and neck malignancies who were treated primarily by surgery at Aga Khan University Hospital, Karachi, with/without adjuvant. It was done from May 2007 to November 2008. Each patient was followed up for a minimum of one year to check for recurrence. For statistical analysis SPSS 17 was used. Frequencies, cross-tabulations with chi square tests to find associations, binary logistic regression analysis, Cox regression analysis and receiver operating characteristic curve tests were run on the data. Results: Overall, the median tumour volume for patients with recurrent disease was 52 cm/sup 3/ compared to 22 cm/sup 3/ for those who did not have a recurrence. It was found that large tumour volume was associated with a significantly higher chance of recurrence (p = 0.009). Laryngeal cancers with volumes greater than 46 cm/sup 3/ and oral cancers with volumes greater than 23.1 cm/sup 3/ were associated with poor prognosis. Conclusions: The primary tumour volume can represent an important prognostic factor for treatment outcome. Patients with larger primary tumour volumes should be treated more aggressively. (author)

  14. Aromatase inhibitors - a viable option for recurrent granulosa cell tumour of ovary: overview and case report

    International Nuclear Information System (INIS)

    Munem, A.A.; Bahrani, B.A.; Mehdi, I.

    2012-01-01

    Granulosa cell tumour of the ovary in adults is a rare tumour of low malignant potential affecting middle aged peri or post menopausal patients. These tumours are often diagnosed at an early stage, due to their hormonally active nature. They, however, have unique distinguishing histologic features and behaviour of frequent and late local or systemic relapses. The diagnosis can be challenging with unusual presentations. There is high association of endometrial carcinoma. Surgery is the mainstay of management in early low risk disease, while radiotherapy and systemic platinum based chemotherapy are employed in higher stage with poor prognostic indices. Survival is good in early stage disease. Recurrent, progressive, and treatment refractory disease is not infrequent and poses management challenge. Endocrine manipulation and hormone treatment are employed in few cases with equivocal results, as reported in literature. We present a case of recurrent and treatment refractory GCT in a postmenopausal patient, managed by aromatase inhibitor Anastrozole with reasonable efficacy. (author)

  15. Adnexal Tumours Of Skin

    Directory of Open Access Journals (Sweden)

    Parate Sanjay N

    1998-01-01

    Full Text Available A total 120 cases of epidermal appendage tumours of skin were analysed and classified according to the classification provided by WHO’. Epidermal appendage tumours accounted for 12.87% of all skin tumours, of which 29.17% were benign and 70.83% were malignant. Most of the tumours (75.83% were in the head and face region. The most common tumour was basal cell epithelioma (55%.

  16. Laser-photophoretic migration and fractionation of human blood cells.

    Science.gov (United States)

    Monjushiro, Hideaki; Tanahashi, Yuko; Watarai, Hitoshi

    2013-05-13

    Laser photophoretic migration behavior of human blood cells in saline solution was investigated under the irradiation of Nd:YAG laser beam (532 nm) in the absence and the presence of the flow in a fused silica capillary. Red blood cells (RBC) were migrated faster than white blood cells (WBC) and blood pellets to the direction of propagation of laser light. The observed photophoretic velocity of RBC was about 11 times faster than those of others. This was understood from the larger photophoretic efficiency of RBC than that of WBC, which was simulated based on the Mie scattering theory. Furthermore, it was found that, during the photophoretic migration, RBCs spontaneously orientated parallel to the migration direction so as to reduce the drag force. Finally, it was demonstrated that RBC and WBC were separated in a micro-channel flow system by the laser photophoresis. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Magnetic resonance imaging aspects of giant-cell tumours of bone

    International Nuclear Information System (INIS)

    Pereira, Helcio Mendoncça; Marchiori, Edson; Severo, Alessandro

    2014-01-01

    This study aimed to describe the magnetic resonance imaging (MRI) features of giant-cell tumours of bone. We analysed the clinical and MRI features of patients diagnosed with giant-cell tumours of bone confirmed by histopathology at our institution between 2010 and 2012. The peak incidence was between the second and third decades of life. There was no gender predominance. The most frequent locations were the knee and wrist. Pain and swelling were the prevailing symptoms. Fifty-one per cent of the patients were found to have associated secondary aneurysmal bone cysts on histopathology. On MRI, lesions demonstrated signal intensity equal to that of skeletal muscle on T1-weighted images and low signal intensity on T2-weighted images in 90% of cases. In gadolinium-enhanced T1-weighted images, 76.6% of cases demonstrated heterogeneous enhancement. We observed cystic components involving more than 50% of the lesion in 17 cases (56.6%). There was extra-osseous involvement in 13 cases (43.3%). MRI offers a valuable diagnostic tool for giant-cell tumours of bone. Contrast-enhanced MRI can distinguish between cystic and solid components of the tumour. MRI is also the imaging modality of choice for evaluation of soft-tissue involvement, offering a complete preoperative diagnosis.

  18. Giant cell tumour of tendon sheath and synovial membrane: A review of 26 cases.

    Science.gov (United States)

    Kant, Kumar Shashi; Manav, Ajoy Kumar; Kumar, Rakesh; Abhinav; Sinha, Vishvendra Kumar; Sharma, Akshat

    2017-11-01

    Aim of our study is to highlight the incidence and benign nature of Giant cell tumour of tendon sheath and need for complete removal, thus minimizing the chances of recurrence. A total of 26 cases of Giant cell tumour of tendon sheath operated in the department of Orthopaedics, Patna Medical College & Hospital, Patna from 2003 to 2010 were included in this study. The surgery was performed after clinical evaluation of the lesion and Fine Needle Aspiration Cytology (FNAC). The tumour underwent en bloc marginal excision. The patients were followed up for minimum two year. Our study population consisted of 18 females and 8 males. The mean age at the time of surgery was 38.3 years (range, 18-62 years). Twenty three cases were found in the 3rd and 4th decade. Twenty two cases involved upper extremity and only 4 cases in lower extremity. MRI was done in 2 cases where diagnosis was in doubt. Bony indentation on X-ray film was found in 7 cases and thorough curettage of cortical shell was done. All the cases were treated by marginal excision. Three cases developed post-operative stiffness but regained full range of movement with physiotherapy. Sensory impairment was seen in 3 cases. Recurrence occurred in 2 case and they were treated by repeat marginal excision. Meticulous en-masse marginal excision of the giant cell tumour of tendon sheath in blood less field using magnification is the treatment of choice.

  19. Stem cell factor supports migration in canine mesenchymal stem cells.

    Science.gov (United States)

    Enciso, Nathaly; Ostronoff, Luciana L K; Mejías, Guillermo; León, Leticia G; Fermín, María Luisa; Merino, Elena; Fragio, Cristina; Avedillo, Luis; Tejero, Concepción

    2018-03-01

    Adult Mesenchymal Stem Cells (MSC) are cells that can be defined as multipotent cells able to differentiate into diverse lineages, under appropriate conditions. These cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Initially discovered in bone marrow, MSC can now be isolated from a wide spectrum of adult and foetal tissues. Studies to evaluate the therapeutic potential of these cells are based on their ability to arrive to damaged tissues. In this paper we have done a comparative study analyzing proliferation, surface markers and OCT4, SOX9, RUNX2, PPARG genes expression in MSC cells from Bone marrow (BMMSC) and Adipose tissue (ASC). We also analyzed the role of Stem Cell Factor (SCF) on MSC proliferation and on ASCs metalloproteinases MMP-2, MMP-9 secretion. Healthy dogs were used as BMMSC donors, and ASC were collected from omentum during elective ovariohysterectomy surgery. Both cell types were cultured in IMDM medium with or without SCF, 10% Dog Serum (DS), and incubated at 38 °C with 5% CO2. Growth of BMMSCs and ASCs was exponential until 25-30 days. Flow citometry of MSCs revealed positive results for CD90 and negative for CD34, CD45 and MCH-II. Genes were evaluated by RT-PCR and metalloproteinases by zymografy. Our findings indicate morphological and immunological similarities as well as expression of genes from both origins on analyzed cells. Furthermore, SCF did not affect proliferation of MSCs, however it up-regulated MMP-2 and MMP-9 secretion in ASCs. These results suggest that metalloproteinases are possibly essential molecules pivoting migration.

  20. Cell Migration in Tissues: Explant Culture and Live Imaging.

    Science.gov (United States)

    Staneva, Ralitza; Barbazan, Jorge; Simon, Anthony; Vignjevic, Danijela Matic; Krndija, Denis

    2018-01-01

    Cell migration is a process that ensures correct cell localization and function in development and homeostasis. In disease such as cancer, cells acquire an upregulated migratory capacity that leads to their dissemination throughout the body. Live imaging of cell migration allows for better understanding of cell behaviors in development, adult tissue homeostasis and disease. We have optimized live imaging procedures to track cell migration in adult murine tissue explants derived from: (1) healthy gut; (2) primary intestinal carcinoma; and (3) the liver, a common metastatic site. To track epithelial cell migration in the gut, we generated an inducible fluorescent reporter mouse, enabling us to visualize and track individual cells in unperturbed gut epithelium. To image intratumoral cancer cells, we use a spontaneous intestinal cancer model based on the activation of Notch1 and deletion of p53 in the mouse intestinal epithelium, which gives rise to aggressive carcinoma. Interaction of cancer cells with a metastatic niche, the mouse liver, is addressed using a liver colonization model. In summary, we describe a method for long-term 3D imaging of tissue explants by two-photon excitation microscopy. Explant culturing and imaging can help understand dynamic behavior of cells in homeostasis and disease, and would be applicable to various tissues.

  1. Influence of femtosecond laser radiation on cells of the transplantable tumour Krebs-2

    International Nuclear Information System (INIS)

    Meshalkin, Yu P; Popova, N A; Nikolin, V P; Kaledin, V I; Kirpichnikov, A V; Pestryakov, Efim V

    2012-01-01

    The influence of femtosecond radiation of a titaniumsapphire laser on cells of the transplantable ascitic tumour Krebs-2 was studied. After in vitro irradiation by the pulsed fundamentalharmonic radiation with the wavelength 800 nm, pulse duration 30 fs, repetition rate 1 kHz, mean power 100 and 300 mW and exposure time 3 min, as well as by the second-harmonic radiation (40 nm, 50 fs, 120 mW), all cells were diffusely stained by the vital stain trypan blue, which may be an evidence of their death or abnormalities of membrane permeability. However, implantation of such cells to experimental animals led to formation of tumours at the transplantation site with the kinetics slightly different from the control one. In the group of mice to which the cells were inoculated after irradiation with second harmonic pulses of titanium-sapphire laser the inhibition of tumour growth was observed due to partial death of cells under the action of UV spectral components. To explain the mechanism of the observed phenomenon the possibility of pore formation (photoporation) in the cell membrane, described earlier in the papers on foreign DNA transfection into cells, is considered.

  2. Expression of core clock genes in colorectal tumour cells compared with normal mucosa

    DEFF Research Database (Denmark)

    Fonnes, S; Donatsky, A M; Gögenur, I

    2015-01-01

    AIM: Experimental studies have shown that some circadian core clock genes may act as tumour suppressors and have an important role in the response to oncological treatment. This study investigated the evidence regarding modified expression of core clock genes in colorectal cancer and its...... expression of colorectal cancer cells compared with healthy mucosa cells from specimens analysed by real-time or quantitative real-time polymer chain reaction. The expression of the core clock genes Period, Cryptochrome, Bmal1 and Clock in colorectal tumours were compared with healthy mucosa and correlated...... with clinicopathological features and survival. RESULTS: Seventy-four articles were identified and 11 studies were included. Overall, gene expression of Period was significantly decreased in colorectal cancer cells compared with healthy mucosa cells. This tendency was also seen in the gene expression of Clock. Other core...

  3. Profiling protein expression in circulating tumour cells using microfluidic western blotting.

    Science.gov (United States)

    Sinkala, Elly; Sollier-Christen, Elodie; Renier, Corinne; Rosàs-Canyelles, Elisabet; Che, James; Heirich, Kyra; Duncombe, Todd A; Vlassakis, Julea; Yamauchi, Kevin A; Huang, Haiyan; Jeffrey, Stefanie S; Herr, Amy E

    2017-03-23

    Circulating tumour cells (CTCs) are rare tumour cells found in the circulatory system of certain cancer patients. The clinical and functional significance of CTCs is still under investigation. Protein profiling of CTCs would complement the recent advances in enumeration, transcriptomic and genomic characterization of these rare cells and help define their characteristics. Here we describe a microfluidic western blot for an eight-plex protein panel for individual CTCs derived from estrogen receptor-positive (ER+) breast cancer patients. The precision handling and analysis reveals a capacity to assay sparingly available patient-derived CTCs, a biophysical CTC phenotype more lysis-resistant than breast cancer cell lines, a capacity to report protein expression on a per CTC basis and two statistically distinct GAPDH subpopulations within the patient-derived CTCs. Targeted single-CTC proteomics with the capacity for archivable, multiplexed protein analysis offers a unique, complementary taxonomy for understanding CTC biology and ascertaining clinical impact.

  4. The prognostic value of micrometastases and isolated tumour cells in histologically negative lymph nodes of patients with colorectal cancer: a systematic review and meta-analysis

    NARCIS (Netherlands)

    Sloothaak, D. A. M.; Sahami, S.; van der Zaag-Loonen, H. J.; van der Zaag, E. S.; Tanis, P. J.; Bemelman, W. A.; Buskens, C. J.

    2014-01-01

    Detection of occult tumour cells in lymph nodes of patients with stage I/II colorectal cancer is associated with decreased survival. However, according to recent guidelines, occult tumour cells should be categorised in micrometastases (MMs) and isolated tumour cells (ITCs). This meta-analysis

  5. MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells.

    Science.gov (United States)

    Cui, Yu-Xin; Bradbury, Robyn; Flamini, Valentina; Wu, Bo; Jordan, Nicola; Jiang, Wen G

    2017-06-27

    MicroRNA-7 (miR-7) has been observed as a potent tumour suppressor in multiple cancer types including breast cancer. The aim of this study was to investigate the response sensitivities of metastatic breast cancer cells to miR-7 and the roles of miR-7 in the interaction of endothelial cells and metastatic cancer cells. Expression profile of miRNAs in a breast cancer specimen cohort and breast cancer cells were determined using real-time quantitative miRNA assays. Effect of the altering expression of miR-7 on migration, invasion, proliferation, interaction and underlying molecular mechanism of breast cancer cells and endothelial cells was investigated after treatment with the synthesised mimic of miR-7. Luciferase activity analysis was performed to validate Wave-3 as a novel target of miR-7. miR-7 expression was negatively correlated with the stage, grade and survival of the breast cancer patients. There was also differential expression of miRNAs including miR-7 in the breast cancer cells. The synthesised mimic of miR-7 inhibits the motility and wound healing potential of breast cancer cells. The highly metastatic MDA-MB-231 cells are more sensitive to the miR-7 treatment than the poorly invasive MCF-7 cells. Treatment with miR-7 downregulated the expression of EGFR, IGF1R and Wave3 in MDA-MB-231 cells but not in MCF-7 cells. In addition, we further demonstrated that miR-7 inhibited the proliferation, migration and invasion of endothelial cells. And more importantly, miR-7 suppressed the homing and migration of endothelial cells to more aggressive tumour cell conditions. Given the dual inhibitory effect of miR-7 on metastatic breast cancer cells alone and the interaction of endothelial cells with the tumour-conditioned microenvironment, we suggest miR-7 may be a new therapeutic candidate for its capacity not only to prevent breast cancer cell spreading but also to inhibit tumour-associated angiogenesis in the metastatic breast cancer.

  6. Metabolism, migration and memory in cytotoxic T cells

    OpenAIRE

    FINLAY, DAVID

    2011-01-01

    PUBLISHED The transcriptional and metabolic programmes that control CD8(+) T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8(+) T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metab...

  7. Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells.

    Science.gov (United States)

    Stec, Małgorzata; Szatanek, Rafał; Baj-Krzyworzeka, Monika; Baran, Jarosław; Zembala, Maria; Barbasz, Jakub; Waligórska, Agnieszka; Dobrucki, Jurek W; Mytar, Bożenna; Szczepanik, Antoni; Siedlar, Maciej; Drabik, Grażyna; Urbanowicz, Barbara; Zembala, Marek

    2015-12-01

    Tumour cells release membrane micro(nano)fragments called tumour-derived microvesicles (TMV) that are believed to play an important role in cancer progression. TMV suppress/modify antitumour response of the host, but there is also some evidence for their direct interaction with cancer cells. In cancer patients TMV are present in body fluid and tumour microenvironment. The present study aimed at characterization of whole types/subpopulations, but not only exosomes, of TMV from newly established gastric cancer cell line (called GC1415) and to define their interactions with autologous cells. TMV were isolated from cell cultures supernatants by centrifugation at 50,000×g and their phenotype was determined by flow cytometry. The size of TMV was analysed by dynamic light scattering and nanoparticle tracking analysis, while morphology by transmission electron microscopy and atomic force microscopy. Interactions of TMV with cancer cells were visualized using fluorescence-activated cell sorter, confocal and atomic force microscopy, biological effects by xenografts in NOD SCID mice. Isolated TMV showed expression of CD44H, CD44v6 (hyaluronian receptors), CCR6 (chemokine receptor) and HER-2/neu molecules, exhibited different shapes and sizes (range 60-900 nm, highest frequency of particles with size range of 80-120 nm). TMV attached to autologous cancer cells within 2 h and then were internalized by them at 24 h. CD44H, CD44v6 and CCR6 molecules may play a role in attachment of TMV to cancer cells, while HER-2 associated with CD24 be involved in promoting cancer cells growth. Pre-exposure of cancer cells to TMV resulted in enhancement of tumour growth and cancer cell-induced angiogenesis in NOD SCID mice model. TMV interact directly with cancer cells serving as macro-messengers and molecular cargo transfer between gastric cancer cells resulting in enhancement of tumour growth. TMV should be considered in future as target of anticancer therapy.

  8. Steroid hormones affect binding of the sigma ligand C-11-SA4503 in tumour cells and tumour-bearing rats

    NARCIS (Netherlands)

    Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Ishiwata, Kiichi; de Jong, Johan R.; de Vries, Erik F.; Dierckx, Rudi A.; van Waarde, Aren

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined

  9. The prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is dependent on concurrent overexpression of Human Leucocyte Antigen-E in the tumour microenvironment

    NARCIS (Netherlands)

    Versluis, M. A. C.; Marchal, S.; Plat, A.; de Bock, G. H.; van Hall, T.; de Bruyn, M.; Hollema, H.; Nijman, H. W.

    2017-01-01

    Background: Human Leucocyte Antigen-E (HLA-E) has been reported as both a positive and negative prognostic marker in cancer. This apparent discrepancy may be due to opposing actions of HLA-E on tumour-infiltrating immune cells. Therefore, we evaluated HLA-E expression and survival in relation to the

  10. The prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is dependent on concurrent overexpression of Human Leucocyte Antigen-E in the tumour microenvironment

    NARCIS (Netherlands)

    Versluis, M A C; Marchal, S; Plat, A; Bock, G.H.; Hall, T.; de Bruyn, K.M.T.; Hollema, H.; Nijman, Hans W

    2017-01-01

    BACKGROUND: Human Leucocyte Antigen- E (HLA-E) has been reported as both a positive and negative prognostic marker in cancer. This apparent discrepancy may be due to opposing actions of HLA-E on tumour-infiltrating immune cells. Therefore, we evaluated HLA-E expression and survival in relation to

  11. Therapy of MHC Class I+ and Class I- HPV 16-Associated Tumours with Cytokines, Genetically Modified Tumour Vaccines and Dendritic Cells

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan; Šímová, Jana; Mikyšková, Romana; Vonka, V.

    2004-01-01

    Roč. 27, č. 4 (2004), s. 161D ISSN 0147-958X. [International Congress of Immunology /12./ and Annual Conference of FOCIS /4./. Montreal, 18.07.2004-23.07.2004] Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV 16 * tumour vaccines * dendritic cells Subject RIV: EC - Immunology Impact factor: 1.051, year: 2004

  12. Lethal Effect of Thermal Neutrons on Hypoxic Elirlich Ascites Tumour Cells in vitro

    OpenAIRE

    MITSUHIKO, AKABOSHI; KENICHI, KAWAI; HIROTOSHI, MAKI; Research Reactor Institute, Kyoto University; Research Reactor Institute, Kyoto University; Research Reactor Institute, Kyoto University

    1985-01-01

    Ehrlich ascites tumour cells were irradiated in vitro with thermal neutrons under aerobic and hypoxic conditions, and the survival of their reproductive capacity was assayed in vivo. Only a slight hypoxic protection was observed for thermal neutron irradiation with an oxygen enhancement ratio (OER) of 1.2, as compared with OER of 3.3 for ^Co-γ-rays. Absorbed dose of thermal neutrons was calculated by assuming that the energies of recoiled nuclei were completely absorbed within a cell nucleus....

  13. Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

    LENUS (Irish Health Repository)

    Whelan, M C

    2012-01-31

    Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

  14. Protrusive waves guide 3D cell migration along nanofibers

    Science.gov (United States)

    Guetta-Terrier, Charlotte; Monzo, Pascale; Zhu, Jie; Long, Hongyan; Venkatraman, Lakshmi; Zhou, Yue; Wang, PeiPei; Chew, Sing Yian; Mogilner, Alexander

    2015-01-01

    In vivo, cells migrate on complex three-dimensional (3D) fibrous matrices, which has made investigation of the key molecular and physical mechanisms that drive cell migration difficult. Using reductionist approaches based on 3D electrospun fibers, we report for various cell types that single-cell migration along fibronectin-coated nanofibers is associated with lateral actin-based waves. These cyclical waves have a fin-like shape and propagate up to several hundred micrometers from the cell body, extending the leading edge and promoting highly persistent directional movement. Cells generate these waves through balanced activation of the Rac1/N-WASP/Arp2/3 and Rho/formins pathways. The waves originate from one major adhesion site at leading end of the cell body, which is linked through actomyosin contractility to another site at the back of the cell, allowing force generation, matrix deformation and cell translocation. By combining experimental and modeling data, we demonstrate that cell migration in a fibrous environment requires the formation and propagation of dynamic, actin based fin-like protrusions. PMID:26553933

  15. Tumour infiltrating lymphocytes correlate with improved survival in patients with esophageal squamous cell carcinoma.

    Science.gov (United States)

    Jiang, Dongxian; Liu, Yalan; Wang, Hao; Wang, Haixing; Song, Qi; Sujie, Akesu; Huang, Jie; Xu, Yifan; Zeng, Haiying; Tan, Lijie; Hou, Yingyong; Xu, Chen

    2017-03-21

    We undertook a study of tumour infiltrating lymphocytes (TILs) in a large and relatively homogeneous group of patients with completely resected esophageal squamous cell carcinoma (ESCC). Hematoxylin and eosin-stained sections of 235 ESCC tumours were evaluated for density of TILs in intratumoural (iTIL) and stromal compartments (sTIL). Foxp3+, CD4+, and CD8+ T cells in tumoural and stromal areas were evaluated by immunohistochemistry. Of the 235 tumours, high sTIL (>10%), and iTIL (>10%) were observed in 101 (43.0%) and 98 (41.7%), respectively. The median follow-up period was 36.0 months (95% CI 29.929-42.071). Univariate analysis revealed that sTIL (>10%), iTIL (>20%), vessels involvement, lymph node metastasis, and clinical stage were significantly associated with postoperative outcome. In multivariate analysis, high sTIL (HR: 0.664, P = 0.019 for Disease free survival; HR: 0.608, P = 0.005 for Overall survival) was identified as independent better prognostic factor. Further analysis, sTIL was identified as independently prognostic factor in Stage III-IVa disease, which was not found in Stage I-II disease. Our study demonstrated that sTIL was associated with better ESCC patients' survival, especially in Stage III-IVa disease. Assessment of sTIL could be useful to discriminate biological behavior for ESCC patients.

  16. Mechanical guidance of collective cell migration and invasion

    Science.gov (United States)

    Trepat, Xavier

    A broad range of biological processes such as morphogenesis, tissue regeneration, and cancer invasion depend on the collective migration of epithelial cells. Guidance of collective cell migration is commonly attributed to soluble or immobilized chemical gradients. I will present novel mechanisms of collective cellular guidance that are physical in origin rather than chemical. Firstly, I will focus on how the mechanical interaction between the tumor and its stroma guides cancer cell invasion. I will show that cancer associated fibroblasts exert a physical force on cancer cells that enables their collective invasion. In the second part of my talk I will focus on durotaxis, the ability of cells to follow gradients of extracellular matrix stiffness. Durotaxis is well established as a single cell phenomenon but whether it can direct the motion of cell collectives is unknown. I will show that durotaxis emerges in cell collectives even if isolated constituent cells are unable to durotax. Collective durotaxis applies to a broad variety of epithelial cell types and requires the action of myosin motors and the integrity of cell-cell junctions. Collective durotaxis is more efficient than any previous report of single cell durotaxis; it thus emerges as robust mechanism to direct collective cell migration in development and disease.eplace this text with your abstract.

  17. Multidisciplinary approaches to understanding collective cell migration in developmental biology.

    Science.gov (United States)

    Schumacher, Linus J; Kulesa, Paul M; McLennan, Rebecca; Baker, Ruth E; Maini, Philip K

    2016-06-01

    Mathematical models are becoming increasingly integrated with experimental efforts in the study of biological systems. Collective cell migration in developmental biology is a particularly fruitful application area for the development of theoretical models to predict the behaviour of complex multicellular systems with many interacting parts. In this context, mathematical models provide a tool to assess the consistency of experimental observations with testable mechanistic hypotheses. In this review, we showcase examples from recent years of multidisciplinary investigations of neural crest cell migration. The neural crest model system has been used to study how collective migration of cell populations is shaped by cell-cell interactions, cell-environmental interactions and heterogeneity between cells. The wide range of emergent behaviours exhibited by neural crest cells in different embryonal locations and in different organisms helps us chart out the spectrum of collective cell migration. At the same time, this diversity in migratory characteristics highlights the need to reconcile or unify the array of currently hypothesized mechanisms through the next generation of experimental data and generalized theoretical descriptions. © 2016 The Authors.

  18. Low Doses of Curcuma longa Modulates Cell Migration and Cell-Cell Adhesion.

    Science.gov (United States)

    de Campos, Paloma Santos; Matte, Bibiana Franzen; Diel, Leonardo Francisco; Jesus, Luciano Henrique; Bernardi, Lisiane; Alves, Alessandro Menna; Rados, Pantelis Varvaki; Lamers, Marcelo Lazzaron

    2017-09-01

    Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC. Curcumin (2 μM) decreased cell proliferation in cell lines with mesenchymal characteristics, while cell death was detected only at 50 μM. We observed that highly migratory cells showed a decrease on migration speed and directionality when treated with 2 or 5 μM of curcumin (50% and 40%, respectively, p < 0.05). Using spheroids, we observed that curcumin dose dependently decreased cell-cell adhesion, especially on tumor-derived spheroids. Also, in a xenograft model with patient-derived OSCC cells, the administration of curcumin decreased tumor growth and aggressiveness when compared with untreated tumors, indicating the potential antitumor effect in oral cancer. These results suggest that lower doses of curcumin can influence several steps involved in tumorigenesis, including migration properties, suggesting a possible use in cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Seladin-1 and testicular germ cell tumours: new insights into cisplatin responsiveness.

    Science.gov (United States)

    Nuti, Francesca; Luciani, Paola; Marinari, Eliana; Erdei, Edit; Bak, Mihaly; Deledda, Cristiana; Rosati, Fabiana; Mazzinghi, Benedetta; Danza, Giovanna; Stoop, Hans; Looijenga, Leendert H J; Peri, Alessandro; Serio, Mario; Krausz, Csilla

    2009-12-01

    The molecular basis for the exquisite sensitivity of testicular germ cell tumours of adolescents and adults (TGCTs), ie seminomas and non-seminomatous germ cell tumours, to chemo/radiotherapy has not been fully clarified so far. It has been suggested that it may be dependent on factors involved in the regulation of apoptosis. Seladin-1 is a multi-functional protein involved in various biological processes, including apoptosis. The aim of our study was to assess the expression of seladin-1 in different histological types of TGCTs, known to have varying treatment sensitivity, in order to establish whether this protein may influence cisplatin responsiveness in vitro. Seladin-1 expression levels, both at the mRNA and at the protein level, were higher in the adjacent normal parenchyma than in the pathological counterparts. In tumoural tissues, the level of expression differed among TGCT histological types. The highest tumour-expression level was found in teratoma, whereas the lowest was detected in seminoma, corresponding to the different chemo/and radiosensitivities of these tumour types. In common with other cancers, in TGCT-derived cell lines seladin-1 showed anti-apoptotic properties through inhibition of caspase-3 activation. We confirmed our results using a non-seminomatous cell line model (NT2) before and after differentiation with retinoic acid. Significantly higher seladin-1 expression was observed in the differentiated derivatives (teratoma) and an inverse relationship was found between seladin-1 expression and the amount of cleaved caspase-3. Seladin-1 silencing or overexpression in this cell line supports involvement of seladin-1 in cisplatin responsiveness. Seladin-1 silencing was associated with greater cisplatin responsiveness demonstrated by decreased cell viability and increased expression of apoptotic markers. In contrast, overexpression of seladin-1 was associated with a higher survival rate and a clear anti-apoptotic effect. In conclusion, we have

  20. Loss of Gadkin Affects Dendritic Cell Migration In Vitro.

    Directory of Open Access Journals (Sweden)

    Hannah Schachtner

    Full Text Available Migration is crucial for the function of dendritic cells (DCs, which act as outposts of the immune system. Upon detection of pathogens, skin- and mucosa-resident DCs migrate to secondary lymphoid organs where they activate T cells. DC motility relies critically on the actin cytoskeleton, which is regulated by the actin-related protein 2/3 (ARP2/3 complex, a nucleator of branched actin networks. Consequently, loss of ARP2/3 stimulators and upstream Rho family GTPases dramatically impairs DC migration. However, nothing is known yet about the relevance of ARP2/3 inhibitors for DC migration. We previously demonstrated that the AP-1-associated adaptor protein Gadkin inhibits ARP2/3 by sequestering it on intracellular vesicles. Consistent with a role of Gadkin in DC physiology, we here report Gadkin expression in bone marrow-derived DCs and show that its protein level and posttranslational modification are regulated upon LPS-induced DC maturation. DCs derived from Gadkin-deficient mice were normal with regards to differentiation and maturation, but displayed increased actin polymerization. While the actin-dependent processes of macropinocytosis and cell spreading were not affected, loss of Gadkin significantly impaired DC migration in vitro, however, in vivo DC migration was unperturbed suggesting the presence of compensatory mechanisms.

  1. Laser-photophoretic migration and fractionation of human blood cells

    International Nuclear Information System (INIS)

    Monjushiro, Hideaki; Tanahashi, Yuko; Watarai, Hitoshi

    2013-01-01

    Graphical abstract: -- Highlights: •RBCs were migrated faster than WBCs and blood pellets by laser photophoresis. •Photophoretic efficiency of RBC and WBC was simulated by the Mie scattering theory. •Spontaneous orientation of RBC parallel to the migration direction was elucidated. •Laser photophoretic separation of RBC and WBC was possible in a tip flow system. -- Abstract: Laser photophoretic migration behavior of human blood cells in saline solution was investigated under the irradiation of Nd:YAG laser beam (532 nm) in the absence and the presence of the flow in a fused silica capillary. Red blood cells (RBC) were migrated faster than white blood cells (WBC) and blood pellets to the direction of propagation of laser light. The observed photophoretic velocity of RBC was about 11 times faster than those of others. This was understood from the larger photophoretic efficiency of RBC than that of WBC, which was simulated based on the Mie scattering theory. Furthermore, it was found that, during the photophoretic migration, RBCs spontaneously orientated parallel to the migration direction so as to reduce the drag force. Finally, it was demonstrated that RBC and WBC were separated in a micro-channel flow system by the laser photophoresis

  2. Laser-photophoretic migration and fractionation of human blood cells

    Energy Technology Data Exchange (ETDEWEB)

    Monjushiro, Hideaki; Tanahashi, Yuko; Watarai, Hitoshi, E-mail: watarai@chem.sci.osaka-u.ac.jp

    2013-05-13

    Graphical abstract: -- Highlights: •RBCs were migrated faster than WBCs and blood pellets by laser photophoresis. •Photophoretic efficiency of RBC and WBC was simulated by the Mie scattering theory. •Spontaneous orientation of RBC parallel to the migration direction was elucidated. •Laser photophoretic separation of RBC and WBC was possible in a tip flow system. -- Abstract: Laser photophoretic migration behavior of human blood cells in saline solution was investigated under the irradiation of Nd:YAG laser beam (532 nm) in the absence and the presence of the flow in a fused silica capillary. Red blood cells (RBC) were migrated faster than white blood cells (WBC) and blood pellets to the direction of propagation of laser light. The observed photophoretic velocity of RBC was about 11 times faster than those of others. This was understood from the larger photophoretic efficiency of RBC than that of WBC, which was simulated based on the Mie scattering theory. Furthermore, it was found that, during the photophoretic migration, RBCs spontaneously orientated parallel to the migration direction so as to reduce the drag force. Finally, it was demonstrated that RBC and WBC were separated in a micro-channel flow system by the laser photophoresis.

  3. How Tissue Mechanical Properties Affect Enteric Neural Crest Cell Migration

    Science.gov (United States)

    Chevalier, N. R.; Gazguez, E.; Bidault, L.; Guilbert, T.; Vias, C.; Vian, E.; Watanabe, Y.; Muller, L.; Germain, S.; Bondurand, N.; Dufour, S.; Fleury, V.

    2016-02-01

    Neural crest cells (NCCs) are a population of multipotent cells that migrate extensively during vertebrate development. Alterations to neural crest ontogenesis cause several diseases, including cancers and congenital defects, such as Hirschprung disease, which results from incomplete colonization of the colon by enteric NCCs (ENCCs). We investigated the influence of the stiffness and structure of the environment on ENCC migration in vitro and during colonization of the gastrointestinal tract in chicken and mouse embryos. We showed using tensile stretching and atomic force microscopy (AFM) that the mesenchyme of the gut was initially soft but gradually stiffened during the period of ENCC colonization. Second-harmonic generation (SHG) microscopy revealed that this stiffening was associated with a gradual organization and enrichment of collagen fibers in the developing gut. Ex-vivo 2D cell migration assays showed that ENCCs migrated on substrates with very low levels of stiffness. In 3D collagen gels, the speed of the ENCC migratory front decreased with increasing gel stiffness, whereas no correlation was found between porosity and ENCC migration behavior. Metalloprotease inhibition experiments showed that ENCCs actively degraded collagen in order to progress. These results shed light on the role of the mechanical properties of tissues in ENCC migration during development.

  4. Nanotopography guides and directs cell migration in amoeboid and epithelial cells

    Science.gov (United States)

    Lee, Rachel; Das, Satarupa; Hourwitz, Matthew; Sun, Xiaoyu; Parent, Carole; Fourkas, John; Losert, Wolfgang

    Cell migration plays a critical role in development, angiogenesis, immune response, wound healing, and cancer metastasis. In many cases, cells also move in the context of a matrix of collagen fibers, and the alignment of these fibers can both affect the migration phenotype and guide cells. Here we show that both fast and slow migrating cells - amoeboid HL-60 and epithelial MCF10A - are affected in similar ways by micro/nanostructures with dimensions similar to those of collagen fibers. Cell alignment enhances the efficiency of migration by increasing directional persistence.

  5. NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF

    Directory of Open Access Journals (Sweden)

    Mitchell E. Fane

    2017-02-01

    Full Text Available While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis.

  6. Vasculogenic Mimicry of HT1080 Tumour Cells In Vivo: Critical Role of HIF-1α-Neuropilin-1 Axis

    Science.gov (United States)

    Misra, Roli M.; Bajaj, Manmohan S.; Kale, Vaijayanti P.

    2012-01-01

    HT1080 - a human fibrosarcoma-derived cell line – forms aggressive angiogenic tumours in immuno-compromised mice. In spite of its extensive use as a model of tumour angiogenesis, the molecular event(s) initiating the angiogenic program in these cells are not known. Since hypoxia stimulates tumour angiogenesis, we examined the hypoxia-induced events evoked in these cells. In contrast to cells grown under normoxic conditions, hypoxia-primed (1% O2) HT1080 cells formed robust tubules on growth factor-reduced matrigel and formed significantly larger tumours in xenograft models in a chetomin-sensitive manner, indicating the role of HIF-1α-mediated transcription in these processes. Immuno-histochemical analyses of tumours formed by GFP-expressing HT1080 cells clearly showed that the tumour cells themselves expressed various angiogenic markers including Neuropilin-1 (NRP-1) and formed functional vessels containing red blood cells, thereby unambiguously demonstrating the vasculogenic mimicry of HT1080 cells in vivo. Experiments performed with the HT1080 cells stably transfected with plasmid constructs expressing shNRP-1 or full-length NRP-1 clearly established that the HIF1α-mediated up-regulation of NRP-1 played a deterministic role in the process. Hypoxia-exposure resulted in an up-regulation of c-Myc and OCT3/4 and a down-regulation of KLF4 mRNAs, suggesting their involvement in the tumour formation and angiogenesis. However, silencing of NRP-1 alone, though not affecting proliferation in culture, was sufficient to abrogate the tumour formation completely; clearly establishing that the hypoxia-mediated HIF-1α-dependent up-regulation of NRP-1 is a critical molecular event involved in the vasculogenic mimicry and tumor formation by HT1080 cells in vivo. PMID:23185562

  7. High glucose-mediated oxidative stress impairs cell migration.

    Directory of Open Access Journals (Sweden)

    Marcelo L Lamers

    Full Text Available Deficient wound healing in diabetic patients is very frequent, but the cellular and molecular causes are poorly defined. In this study, we evaluate the hypothesis that high glucose concentrations inhibit cell migration. Using CHO.K1 cells, NIH-3T3 fibroblasts, mouse embryonic fibroblasts and primary skin fibroblasts from control and diabetic rats cultured in 5 mM D-glucose (low glucose, LG, 25 mM D-glucose (high glucose, HG or 25 mM L-glucose medium (osmotic control--OC, we analyzed the migration speed, protrusion stability, cell polarity, adhesion maturation and the activity of the small Rho GTPase Rac1. We also analyzed the effects of reactive oxygen species by incubating cells with the antioxidant N-Acetyl-Cysteine (NAC. We observed that HG conditions inhibited cell migration when compared to LG or OC. This inhibition resulted from impaired cell polarity, protrusion destabilization and inhibition of adhesion maturation. Conversely, Rac1 activity, which promotes protrusion and blocks adhesion maturation, was increased in HG conditions, thus providing a mechanistic basis for the HG phenotype. Most of the HG effects were partially or completely rescued by treatment with NAC. These findings demonstrate that HG impairs cell migration due to an increase in oxidative stress that causes polarity loss, deficient adhesion and protrusion. These alterations arise, in large part, from increased Rac1 activity and may contribute to the poor wound healing observed in diabetic patients.

  8. Raman spectroscopy of single human tumour cells exposed to ionizing radiation in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Matthews, Q; Jirasek, A [Department of Physics and Astronomy, University of Victoria, Victoria BC V8W 3P6 (Canada); Brolo, AG [Department of Chemistry, University of Victoria, Victoria BC V8W 3V6 (Canada); Lum, J; Duan, X, E-mail: qmatthew@uvic.c, E-mail: jirasek@uvic.c [Deeley Research Centre, BC Cancer Agency-Vancouver Island Centre, Victoria BC V8R 6V5 (Canada)

    2011-01-07

    This work investigates the capability of Raman spectroscopy (RS) to study the effects of ionizing radiation on single human tumour cells. Prostate tumour cells (cell line DU145) are cultured in vitro and irradiated to doses between 15 and 50 Gy with single fractions of 6 MV photons. Single-cell Raman spectra are acquired from irradiated and unirradiated cultures up to 5 days post-irradiation. Principal component analysis is used to distinguish the uniquely radiation-induced spectral changes from inherent sources of spectral variability arising from cell cycle differences and other known factors. We observe uniquely radiation-induced spectral changes which are correlated with both the irradiated dose and the incubation time post-irradiation. The spectral changes induced by radiation arise from biochemical differences in lipids, nucleic acids, amino acids and conformational protein structures between irradiated and unirradiated cells. To our knowledge, this study is the first use of RS to observe radiation-induced biochemical differences in single cells, and is the first use of vibrational spectroscopy to observe uniquely radiation-induced biochemical differences in single cells independent of concurrent cell-cycle- or cell-death-related processes.

  9. The fourth front against cancer: The first clinical trials to test engineered viruses that attack tumour cells have yielded promising results for future cancer therapies

    OpenAIRE

    Hunter, Philip

    2011-01-01

    Engineered viruses that target and destroy tumour cells could become a fourth therapy option against cancer. The first clinical trials have demonstrated their ability to attack both solid tumours and metastases.

  10. Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration.

    Science.gov (United States)

    Richardson, Jo; Gauert, Anton; Briones Montecinos, Luis; Fanlo, Lucía; Alhashem, Zainalabdeen Mohmammed; Assar, Rodrigo; Marti, Elisa; Kabla, Alexandre; Härtel, Steffen; Linker, Claudia

    2016-05-31

    Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC) cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC) cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC) cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  11. Human papillomavirus and Epstein-Barr virus in the etiology of testicular germ cell tumours

    DEFF Research Database (Denmark)

    Rajpert-De Meyts, E; Hørding, U; Nielsen, H W

    1994-01-01

    Epidemiological features suggest that the risk of testicular cancer may be related to exposure to unknown infectious agents, including viruses. Therefore a series of twenty specimens of testicular germ cell tumours, including preinvasive carcinoma in-situ, were tested for the presence of DNA...... sequences of two viruses with known transforming abilities, human papillomavirus (HPV) and Epstein-Barr virus (EBV). The polymerase chain reaction (PCR) technique was used. In none of the 19 successfully amplified samples were DNA sequences of HPV type 16 or type 18 detected. In six cases a faint trace...... that a significant direct involvement of HPV and EBV in human testicular germ cell carcinogenesis is unlikely. However, a putative growth-stimulating role of EBV-transformed lymphocytes, which are frequently present in the stromal tissues of testicular tumours, cannot be excluded....

  12. Acute cor pulmonale due to pulmonary tumour thrombotic microangiopathy from renal cell carcinoma.

    Science.gov (United States)

    Story, Maria; Kwon, Sook Kyung; Robinson, Robert; Fortis, Spyridon

    2017-06-28

    We report the case of a previously healthy man who presented with subacute dyspnoea after a long drive. He developed hypoxic respiratory failure, thought secondary to a massive pulmonary embolism and was treated with tissue plasminogen activator but died in the hospital despite aggressive medical measures. Autopsy revealed pulmonary tumour thrombotic microangiopathy (PTTM) from papillary renal cell carcinoma. PTTM is a rare clinicopathological syndrome that clinically results in symptoms of dyspnoea and right heart failure. Pathologically, a localised paraneoplastic process evolves from tumour microemboli in the pulmonary arterioles, resulting in fibrocellular proliferation and narrowing of the vessels, causing subacute right heart failure. To our knowledge, this is the first case of PTTM due to papillary renal cell carcinoma. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  13. Growth inhibition and cell cycle arrest effects of epigallocatechin gallate in the NBT-II bladder tumour cell line.

    Science.gov (United States)

    Chen, J J; Ye, Z-Q; Koo, M W L

    2004-05-01

    To examine the growth inhibition and cell cycle arrest effects of epigallocatechin gallate (EGCG), a major constituent of green tea polyphenols, on the NBT-II bladder tumour cell line. Growth inhibition and cell cycle arrest effects of EGCG were evaluated by the tetrazolium assay, flow cytometry and apoptotic DNA ladder tests. The cell cycle-related oncogene and protein expressions in NBT-II bladder tumour cells, when incubated with EGCG, were detected with reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. EGCG inhibited growth of the NBT-II bladder tumour cells in a dose- and time-dependent manner. Flow cytometry showed a G0/G1 arrest in cells when cultured with EGCG at doses of 10, 20 or 40 micro mol/L for 48 or 72 h. The apoptotic DNA ladder test showed that EGCG at 10 micro mol/L induced early apoptosis after 48 h of incubation. A down-regulation of cyclin D1 was detected by RT-PCR when the cells were incubated with EGCG (20 micro mol/L for 48 h. EGCG also down-regulated protein expression of cyclin D1, cyclin-dependent kinase 4/6 and phosphorylated retinoblastoma protein, in both a time- and dose-dependent manner, when detected by Western blot. EGCG had growth inhibition and cell-cycle arrest effects in NBT-II bladder tumour cells by down-regulating the cyclin D1, cyclin-dependent kinase 4/6 and retinoblastoma protein machinery for regulating cell-cycle progression.

  14. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours

    DEFF Research Database (Denmark)

    Hoei-Hansen, C E; Almstrup, K; Nielsen, J E

    2005-01-01

    AIMS: NANOG is a key regulator of embryonic stem cell (ESC) self-renewal and pluripotency. Our recent genome-wide gene expression profiling study of the precursor of testicular germ cell tumours, carcinoma in situ testis (CIS), showed close similarity between ESC and CIS, including high NANOG...... earlier than for OCT-4. We detected no expression at the protein level in normal testis. CONCLUSIONS: NANOG is a new marker for testicular CIS and germ cell tumours and the high level of NANOG along with OCT-4 are determinants of the stem cell-like pluripotency of the preinvasive CIS cell. Timing of NANOG......; seminoma and embryonal carcinoma were strongly positive, differentiated somatic elements of teratoma were negative. We provide evidence for the fetal origin of testicular cancer as we detected strong expression of NANOG in fetal gonocytes up to gestational week 20, with subsequent down-regulation occurring...

  15. Surface topography during neural stem cell differentiation regulates cell migration and cell morphology.

    Science.gov (United States)

    Czeisler, Catherine; Short, Aaron; Nelson, Tyler; Gygli, Patrick; Ortiz, Cristina; Catacutan, Fay Patsy; Stocker, Ben; Cronin, James; Lannutti, John; Winter, Jessica; Otero, José Javier

    2016-12-01

    We sought to determine the contribution of scaffold topography to the migration and morphology of neural stem cells by mimicking anatomical features of scaffolds found in vivo. We mimicked two types of central nervous system scaffolds encountered by neural stem cells during development in vitro by constructing different diameter electrospun polycaprolactone (PCL) fiber mats, a substrate that we have shown to be topographically similar to brain scaffolds. We compared the effects of large fibers (made to mimic blood vessel topography) with those of small-diameter fibers (made to mimic radial glial process topography) on the migration and differentiation of neural stem cells. Neural stem cells showed differential migratory and morphological reactions with laminin in different topographical contexts. We demonstrate, for the first time, that neural stem cell biological responses to laminin are dependent on topographical context. Large-fiber topography without laminin prevented cell migration, which was partially reversed by treatment with rock inhibitor. Cell morphology complexity assayed by fractal dimension was inhibited in nocodazole- and cytochalasin-D-treated neural precursor cells in large-fiber topography, but was not changed in small-fiber topography with these inhibitors. These data indicate that cell morphology has different requirements on cytoskeletal proteins dependent on the topographical environment encountered by the cell. We propose that the physical structure of distinct scaffolds induces unique signaling cascades that regulate migration and morphology in embryonic neural precursor cells. J. Comp. Neurol. 524:3485-3502, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling.

    Science.gov (United States)

    Kallifatidis, G; Rausch, V; Baumann, B; Apel, A; Beckermann, B M; Groth, A; Mattern, J; Li, Z; Kolb, A; Moldenhauer, G; Altevogt, P; Wirth, T; Werner, J; Schemmer, P; Büchler, M W; Salnikov, A V; Herr, I

    2009-07-01

    Emerging evidence suggests that highly treatment-resistant tumour-initiating cells (TICs) play a central role in the pathogenesis of pancreatic cancer. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to be a novel anticancer agent; however, recent studies have shown that many pancreatic cancer cells are resistant to apoptosis induction by TRAIL due to TRAIL-activated nuclear factor-kappaB (NF-kappaB) signalling. Several chemopreventive agents are able to inhibit NF-kappaB, and favourable results have been obtained--for example, for the broccoli compound sulforaphane-in preventing metastasis in clinical studies. The aim of the study was to identify TICs in pancreatic carcinoma for analysis of resistance mechanisms and for definition of sensitising agents. TICs were defined by expression patterns of a CD44(+)/CD24(-), CD44(+)/CD24(+) or CD44(+)/CD133(+) phenotype and correlation to growth in immunodeficient mice, differentiation grade, clonogenic growth, sphere formation, aldehyde dehydrogenase (ALDH) activity and therapy resistance. Mechanistically, specific binding of transcriptionally active cRel-containing NF-kappaB complexes in TICs was observed. Sulforaphane prevented NF-kappaB binding, downregulated apoptosis inhibitors and induced apoptosis, together with prevention of clonogenicity. Gemcitabine, the chemopreventive agents resveratrol and wogonin, and the death ligand TRAIL were less effective. In a xenograft model, sulforaphane strongly blocked tumour growth and angiogenesis, while combination with TRAIL had an additive effect without obvious cytotoxicity in normal cells. Freshly isolated patient tumour cells expressing markers for TICs could be sensitised by sulforaphane for TRAIL-induced cytotoxicity. The data provide new insights into resistance mechanisms of TICs and suggest the combination of sulforaphane with TRAIL as a promising strategy for targeting of pancreatic TICs.

  17. Depletion of Treg cells inhibits minimal residual disease after surgery of HPV16-associated tumours

    Czech Academy of Sciences Publication Activity Database

    Šímová, Jana; Bubeník, Jan; Bieblová, Jana; Rosalia, Rodney Alexander; Frič, Jan; Reiniš, Milan

    2006-01-01

    Roč. 29, č. 6 (2006), s. 1567-1571 ISSN 1019-6439 R&D Projects: GA ČR(CZ) GA301/04/0492 EU Projects: European Commission(XE) 18933 - CLINIGENE Grant - others:Liga proti rakovině(CZ) XX Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV16 * residual tumour disease * Treg cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.556, year: 2006

  18. On a accumulation of 131-I-RNase by ascites tumour cells of mice

    International Nuclear Information System (INIS)

    Sarrach, D.; Waldner, H.

    1976-01-01

    The accumulation of 131-I-labelled RNase by Ehrlich ascites tumour cells of mice was investigated in dependence on time, concentration, and pH. Kinetically a fast and a slow stage of reaction is distinguished. In both, the dependence on concentration is of the Langmuir type. Only the stage-I binding is reversibly diminished with increasing pH. Absorption due to electrostatic forces is suggested for this stae. (author)

  19. HPV16-associated tumours: Therapy of surgical minimal residual disease with dendritic cell-based vaccines

    Czech Academy of Sciences Publication Activity Database

    Reiniš, Milan; Indrová, Marie; Mendoza, Luis; Mikyšková, Romana; Bieblová, Jana; Bubeník, Jan; Šímová, Jana

    2004-01-01

    Roč. 25, č. 4 (2004), s. 1165-1170 ISSN 1019-6439 R&D Projects: GA MZd NC7148; GA ČR GA301/04/0492; GA ČR GA301/01/0985; GA AV ČR IAA5052203 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV 16 * minimal residual tumour disease * dendritic cells Subject RIV: EC - Immunology Impact factor: 3.056, year: 2004

  20. MANAGEMENT OF A RARE RECURRENCE OF DISTAL TIBIAL GIANT CELL TUMOUR BY SANDWICH TECHNIQUE

    Directory of Open Access Journals (Sweden)

    Rajesh Kishanrao

    2016-02-01

    Full Text Available INTRODUCTION First described by Jaffe et al in 1940, giant cell tumour (GCT constitutes 20% of all the skeletal neoplasms with a higher rate of recurrence after excision. Most common sites for the involvement are distal femur and proximal tibia followed by the distal end of radius. Ankle and foot involvement is rare <4%. Usually benign, they are locally aggressive and may occasionally undergo malignant transformation. The surgeon needs to strike a balance during treatment between being aggressive in order to reduce the incidence of local recurrence and being conservative in removing the normal bone to attain maximal function. Current literature suggests that intralesional curettage strikes the best balance between controlling disease and preserving optimum function in the majority of the cases though there may be occasions where the extent of the disease mandates resection to ensure adequate disease clearance. We report a case of Giant Cell Tumour of distal end of left Tibia in a 32-year-old female patient. Initially the condition was treated by curettage and bone grafting. But, due to recurrence of the condition within 9 months, she was treated with extended curettage using hydrogen peroxide, burr and bone cement as adjuvants and reconstruction using the “SANDWICH” Technique. At One year follow up there is no recurrence and reasonably good function around the ankle joint is maintained. Primary Giant Cell Tumours have been traditionally treated with curettage of the lesion followed by bone grafts/bone cement. Recurrent cases often require aggressive management. The adjuvant treatment used in our case offered good stability and allowed early mobilization of the ankle joint. This case substantiates the use of bone cement in the treatment of recurrent Giant Cell Tumour of distal tibia whenever the articular integrity is intact with reasonably good functional outcomes. However, a periodic follow-up is still recommended to watch-out for late re-recurrences

  1. Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells

    Directory of Open Access Journals (Sweden)

    Takahashi Takashi

    2007-04-01

    Full Text Available Abstract Background TGF-beta is one of the key cytokines implicated in various disease processes including cancer. TGF-beta inhibits growth and promotes apoptosis in normal epithelial cells and in contrast, acts as a pro-tumour cytokine by promoting tumour angiogenesis, immune-escape and metastasis. It is not clear if various actions of TGF-beta on normal and tumour cells are due to differential gene regulations. Hence we studied the regulation of gene expression by TGF-beta in normal and cancer cells. Results Using human 19 K cDNA microarrays, we show that 1757 genes are exclusively regulated by TGF-beta in A549 cells in contrast to 733 genes exclusively regulated in HPL1D cells. In addition, 267 genes are commonly regulated in both the cell-lines. Semi-quantitative and real-time qRT-PCR analysis of some genes agrees with the microarray data. In order to identify the signalling pathways that influence TGF-beta mediated gene regulation, we used specific inhibitors of p38 MAP kinase, ERK kinase, JNK kinase and integrin signalling pathways. The data suggest that regulation of majority of the selected genes is dependent on at least one of these pathways and this dependence is cell-type specific. Interestingly, an integrin pathway inhibitor, RGD peptide, significantly affected TGF-beta regulation of Thrombospondin 1 in A549 cells. Conclusion These data suggest major differences with respect to TGF-beta mediated gene regulation in normal and transformed cells and significant role of non-canonical TGF-beta pathways in the regulation of many genes by TGF-beta.

  2. Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.

    Directory of Open Access Journals (Sweden)

    Jason R Sutherland

    Full Text Available Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2, cytokines interleukin (IL -6, and -11 and vascular endothelial growth factor-A (VEGF-A. To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

  3. Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.

    Science.gov (United States)

    Sutherland, Jason R; Sales, Kurt J; Jabbour, Henry N; Katz, Arieh A

    2012-01-01

    Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A (VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

  4. Cell Migration According to Shape of Graphene Oxide Micropatterns

    Directory of Open Access Journals (Sweden)

    Sung Eun Kim

    2016-10-01

    Full Text Available Photolithography is a unique process that can effectively manufacture micro/nano-sized patterns on various substrates. On the other hand, the meniscus-dragging deposition (MDD process can produce a uniform surface of the substrate. Graphene oxide (GO is the oxidized form of graphene that has high hydrophilicity and protein absorption. It is widely used in biomedical fields such as drug delivery, regenerative medicine, and tissue engineering. Herein, we fabricated uniform GO micropatterns via MDD and photolithography. The physicochemical properties of the GO micropatterns were characterized by atomic force microscopy (AFM, scanning electron microscopy (SEM, and Raman spectroscopy. Furthermore, cell migration on the GO micropatterns was investigated, and the difference in cell migration on triangle and square GO micropatterns was examined for their effects on cell migration. Our results demonstrated that the GO micropatterns with a desired shape can be finely fabricated via MDD and photolithography. Moreover, it was revealed that the shape of GO micropatterns plays a crucial role in cell migration distance, speed, and directionality. Therefore, our findings suggest that the GO micropatterns can serve as a promising biofunctional platform and cell-guiding substrate for applications to bioelectric devices, cell-on-a-chip, and tissue engineering scaffolds.

  5. Squamous Cell Carcinoma Arising in a Giant Condyloma Acuminatum (Buschke-Lowenstein Tumour

    Directory of Open Access Journals (Sweden)

    Michael W.T. Chao

    2005-07-01

    Full Text Available Giant condyloma acuminatum (GCA is a tumour that primarily affects the genital and perianal areas. Despite the histologically benign appearance, it behaves in a malignant fashion, destroying adjacent tissues, and is regarded as an entity intermediate between an ordinary condyloma acuminatum and squamous cell carcinoma. Primary anorectal lesions account for only a small number of GCA cases and, as with squamous cell carcinoma, the human papilloma virus is the causative agent. The hallmark of GCA is the high rate of local recurrence and transformation into squamous cell carcinoma. We describe a case of GCA complicated by malignant transformation, where locoregional control was achieved with combined chemoradiotherapy.

  6. Origin of pluripotent germ cell tumours: the role of microenvironment during embryonic development

    DEFF Research Database (Denmark)

    Kristensen, David Møbjerg; Sonne, Si Brask; Ottesen, Anne Marie

    2008-01-01

    has recently been explained by a close resemblance of their expression profile to that of embryonic inner cell mass cells studied in culture as embryonic stem cells, with high expression of transcription factors associated with pluripotency, such as NANOG and OCT3/4, as well as proteins found...... in several tissue specific stem cells, such as TFAP2C (AP-2gamma) or KIT. CIS and seminomas highly express a number of pre-meiotic germ cell specific genes, which are down-regulated during development to non-seminomas, while the expression of other embryonic markers, such as SOX2, is up......Carcinoma in situ (CIS) testis, known also as intratubular germ cell neoplasia, is the cancer stem cell from which the great majority of testicular germ cell derived tumours (TGCTs) of the testis arise. TGCTs can proliferate into morphologically homogeneous seminomas or can differentiate...

  7. Increase in the fraction of necrotic, not apoptotic, cells in SiHa xenograft tumours shortly after irradiation

    International Nuclear Information System (INIS)

    Olive, P.L.; Vikse, C.M.; Vanderbyl, S.

    1999-01-01

    Background and purpose: Approximately 18% of the cells recovered by rapid mechanical dissociation of SiHa xenograft tumours contain large numbers of DNA strand breaks. The number of damaged cells increases to 30-40% 4-6 h after exposure to 5 or 15 Gy, returning to normal levels by 12 h. This observation is reminiscent of the rate of production of apoptotic cells in other murine and human xenograft tumours. The nature of this damage, rate of development and relation to cell proliferation rate were therefore examined in detail.Materials and methods: SiHa human cervical carcinoma cells were grown as xenograft tumours in SCID mice. Single-cell suspensions were prepared as a function of time after irradiation of the mouse and examined for DNA damage using the alkaline comet assay. Cell cycle progression was measured by flow cytometry evaluation of anti-bromodeoxyuridine-labelled tumour cells.Results: Significant numbers of apoptotic cells could not be detected in irradiated SiHa tumours using an end-labelling assay, electron microscopy, or histological examination of thin sections. Instead, xenograft cells exhibiting extensive DNA damage in the comet assay were predominantly necrotic cells. The increase in the proportion of heavily damaged cells 4-6 h after irradiation could be the result of an interplay between several factors including loss of viable cells and change in production or loss of necrotic cells. Analysis of the progression of BrdUrd-labelled cells confirmed that while 35% of cells from untreated SiHa tumours had divided and entered G 1 phase by 6 h after BrdUrd injection, none of the labelled cells from tumours exposed to 5 or 15 Gy had progressed to G 1 .Conclusions: The increase in the percentage of SiHa tumour cells with extensive DNA damage 4-6 h after irradiation is attributable to necrosis, not apoptosis. Cell cycle progression and cell loss are likely to influence the kinetics of appearance of both apoptotic and necrotic cells in irradiated tumours

  8. In vivo assay of the radiation sensitivity of hypoxic tumour cells. Influence of radiation quality and hypoxic sensitization

    International Nuclear Information System (INIS)

    Porschen, W.; Bosiljanoff, P.; Gewehr, K.; Muehlensiepen, H.; Feinendegen, L.E.

    1977-01-01

    In order to measure quantitatively tumour cell kinetics in living mice, tumour bearing animals (sarcoma-180) received intravenously 5-iodo-2'-deoxyuridine (IUdR), a thymidine analogue, which was labelled with 125 I or with 131 I, both of which can be easily externally counted by their gamma emission. IUdR is stably bound to DNA, reutilization is minimal and the measured activity loss from the tumour later than 50 hours after injection signals cell loss or cell death. The effect of irradiation on euoxic and average tumour cells was studied by sequentially labelling the tumour bearing animals first with 125 IUdR and, 70 hours later, with 131 IUdR. At the time of the second injection the average tumour cell population is labelled by the first injection of 125 IUdR, and the second injection of 131 IUdR nearly exclusively tags the perivascular tumour cells; these are euoxic in contrast to the average tumour cell, a large proportion of which is hypoxic. The radiation-induced activity loss rates from the two labelled tumour cell populations indicate the sensitivities of the two populations. At dose levels that cause identical effects on euoxic cells, the ratio of radiation-induced enhancement of cell loss rates for euoxic cells to average cells was 2.6 for 60 Co gamma radiation, 1.4 for 15MeV neutron irradiation, and 1.0 for alpha irradiation (1.5.MeV). The effect of five hypoxic cell sensitizers was analysed. The sensitization was limited to hypoxic cells, and the most effective drug was Ro-07-0582, showing at the 50% level of maximum effect a dose modifying factor of 1.5. Sensitization was highest when the drug was given 15 min prior to irradiation. Hyperthermia affected nearly exclusively hypoxic cells and showed a dose modifying factor of about 2 when the tumours were heated at 42 0 C for 30 min immediately after irradiation. The resulting enhancement of effect was reduced when hyperthermia was applied prior to irradiation. (author)

  9. Membrane fatty acid composition and radiation response of Bp8 sarcoma ascites tumour cells

    International Nuclear Information System (INIS)

    Harms-Ringdahl, M.

    1987-01-01

    Radiation responses of Bp8 sarcoma ascites tumour cells with differences in membrane fatty acid composition was studied. The cells were grown i.p. in NMRI mice and their membrane composition was changed in response to different dietary regimes provided to the hosts. Cell survival, varied insignificantly between the four dietary groups, while repair capacity differed significantly. Increased repair capacity was observed for ascites cells grown in animals on diets enriched in sunflower seed oil and coconut oil, compared with cells from mice fed the hydrogenated lard diet or from cells from the control animals. The membrane fatty acid composition of the cells from the two dietary groups with increased levels of repair capacity differed extensively, and in general there was no correlation between radiation response and the membrane fatty acid composition of the four groups. For coconut oil and control groups with marked differences in membrane fatty acid composition, the effects of irradiation on ascites tumour growth rate and cell cycle distribution were followed in vivo. For none of the parameters was an effect on membrane fatty acid composition on radiation response observed. (author)

  10. [Application of PLA Method for Detection of p53/p63/p73 Complexes in Situ in Tumour Cells and Tumour Tissue].

    Science.gov (United States)

    Hrabal, V; Nekulová, M; Nenutil, R; Holčaková, J; Coates, P J; Vojtěšek, B

    2017-01-01

    PLA (proximity ligation assay) can be used for detection of protein-protein interactions in situ directly in cells and tissues. Due to its high sensitivity and specificity it is useful for detection, localization and quantification of protein complexes with single molecule resolution. One of the mechanisms of mutated p53 gain of function is formation of proten-protein complexes with other members of p53 family - p63 and p73. These interactions influences chemosensitivity and invasivity of cancer cells and this is why these complexes are potential targets of anti-cancer therapy. The aim of this work is to detect p53/p63/p73 interactions in situ in tumour cells and tumour tissue using PLA method. Unique in-house antibodies for specific detection of p63 and p73 isoforms were developed and characterized. Potein complexes were detected using PLA in established cell lines SVK14, HCC1806 and FaDu and in paraffin sections of colorectal carcinoma tissue. Cell lines were also processed to paraffin blocks. p53/T-antigen and ΔNp63/T-antigen protein complexes were detected in SVK14 cells using PLA. Interactions of ΔNp63 and TAp73 isoforms were found in HCC1806 cell line with endogenous expression of these proteins. In FaDu cell line mut-p53/TAp73 complex was localized but not mut-p53/ΔNp63 complex. p53 tetramer was detected directly in colorectal cancer tissue. During development of PLA method for detection of protein complexes between p53 family members we detected interactions of p53 and p63 with T-antigen and mut-p53 and ΔNp63 with TAp73 tumour suppressor in tumour cell lines and p53 tetramers in paraffin sections of colorectal cancer tissue. PLA will be further used for detection of p53/p63, p53/p73 and p63/p73 interactions in tumour tissues and it could be also used for screening of compounds that can block formation of p53/p63/p73 protein complexes.Key words: p53 protein family - protein interaction mapping - immunofluorescence This work was supported by MEYS - NPS I

  11. Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells

    International Nuclear Information System (INIS)

    Collins, Hilary M; Kundu, Tapas K; Heery, David M; Abdelghany, Magdy K; Messmer, Marie; Yue, Baigong; Deeves, Sian E; Kindle, Karin B; Mantelingu, Kempegowda; Aslam, Akhmed; Winkler, G Sebastiaan

    2013-01-01

    Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2. In

  12. Physical guidance of the actin cytoskeleton and cell migration dynamics in epithelial cells

    Science.gov (United States)

    Lee, Rachel; Schmidt, B. U. Sebastian; Campanello, Leonard; Hourwitz, Matt J.; Fourkas, John T.; Losert, Wolfgang

    Many cell types have been shown to exhibit contact guidance, in which cells sense and follow the texture of their environment. Contact guidance can lead to persistent directional migration that does not require the coordinated spatial and temporal cues required for guidance cues such as chemical concentration (i.e. chemotaxis). Actin polymerization has been shown to be guided by topographical features (esotaxis) in Dictyostelium discoideum cells, leading to guided cell migration. In this work, we show that actin dynamics are also guided by nanotopography in epithelial MCF10A cells despite large differences in the normal migration behavior of these two cell types. The existence of esotaxis and guided migration across phyla suggests that cytoskeletal dynamics play an important role in texture sensing and directional cell migration.

  13. Migration of Cells in a Social Context

    DEFF Research Database (Denmark)

    Vedel, Søren; Tay, Savas; Johnston, Darius M.

    2013-01-01

    and speed, which are all modulated by the local cell density. We developed a mathematical model based on the experimentally identified ‘‘cellular traffic rules’’, previous knowledge from isolated-cell chemotaxis and Newton’s second law, which revealed that these emergent behaviors are caused...

  14. Plectin deficiency in liver cancer cells promotes cell migration and sensitivity to sorafenib treatment.

    Science.gov (United States)

    Cheng, Chiung-Chi; Chao, Wei-Ting; Liao, Chen-Chun; Tseng, Yu-Hui; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Hsu, Yung-Hsiang; Liu, Yi-Hsiang

    2018-01-02

    Plectin involved in activation of kinases in cell signaling pathway and plays important role in cell morphology and migration. Plectin knockdown promotes cell migration by activating focal adhesion kinase and Rac1-GTPase activity in liver cells. Sorafenib is a multi-targeting tyrosine kinase inhibitor that improves patient survival on hepatocellular carcinoma. The aim of this study is to investigate the correlation between the expression of plectin and cell migration as well as the sensitivity of hepatoma cell lines exposing to sorafenib. Hepatoma cell lines PLC/PRF/5 and HepG2 were used to examine the level of plectin expression and cell migration in comparison with Chang liver cell line. In addition, sensitivity of the 3 cell lines to sorafenib treatment was also measured. Expression of plectin was lower in PLC/PRF/5 and HepG2 hepatoma cells than that of Chang liver cells whereas HepG2 and PLC/PRF/5 cells exhibit higher rate of cell migration in trans-well migration assay. Immunohistofluorecent staining on E-cadherin revealed the highest rate of collective cell migration in HepG2 cells and the lowest was found in Chang liver cells. Likewise, HepG2 cell line was most sensitive to sorafenib treatment and Chang liver cells exhibited the least sensitivity. The drug sensitivity to sorafenib treatment showed inverse correlation with the expression of plectin. We suggest that plectin deficiency and increased E-cadherin in hepatoma cells were associated with higher rates of cell motility, collective cell migration as well as higher drug sensitivity to sorafenib treatment.

  15. Effects of radiation on metastasis and tumor cell migration.

    Science.gov (United States)

    Vilalta, Marta; Rafat, Marjan; Graves, Edward E

    2016-08-01

    It is well known that tumor cells migrate from the primary lesion to distant sites to form metastases and that these lesions limit patient outcome in a majority of cases. However, the extent to which radiation influences this process and to which migration in turn alters radiation response remains controversial. There are preclinical and clinical reports showing that focal radiotherapy can both increase the development of distant metastasis, as well as that it can induce the regression of established metastases through the abscopal effect. More recently, preclinical studies have suggested that radiation can attract migrating tumor cells and may, thereby, facilitate tumor recurrence. In this review, we summarize these phenomena and their potential mechanisms of action, and evaluate their significance for modern radiation therapy strategies.

  16. Reciprocal control of cell proliferation and migration

    Directory of Open Access Journals (Sweden)

    De Donatis Alina

    2010-09-01

    Full Text Available Abstract In adult tissue the quiescent state of a single cell is maintained by the steady state conditions of its own microenvironment for what concern both cell-cell as well as cell-ECM interaction and soluble factors concentration. Physiological or pathological conditions can alter this quiescent state through an imbalance of both soluble and insoluble factors that can trigger a cellular phenotypic response. The kind of cellular response depends by many factors but one of the most important is the concentration of soluble cytokines sensed by the target cell. In addition, due to the intrinsic plasticity of many cellular types, every single cell is able, in response to the same stimulus, to rapidly switch phenotype supporting minimal changes of microenviromental cytokines concentration. Wound healing is a typical condition in which epithelial, endothelial as well as mesenchymal cells are firstly subjected to activation of their motility in order to repopulate the damaged region and then they show a strong proliferative response in order to successfully complete the wound repair process. This schema constitute the leitmotif of many other physiological or pathological conditions such as development vasculogenesis/angiogenesis as well as cancer outgrowth and metastasis. Our review focuses on the molecular mechanisms that control the starting and, eventually, the switching of cellular phenotypic outcome in response to changes in the symmetry of the extracellular environment.

  17. EGFR-TK inhibition before radiotherapy reduces tumour volume but does not improve local control: Differential response of cancer stem cells and nontumourigenic cells?

    International Nuclear Information System (INIS)

    Krause, Mechthild; Prager, Jenny; Zhou Xuanjing; Yaromina, Ala; Doerfler, Annegret; Eicheler, Wolfgang; Baumann, Michael

    2007-01-01

    Background and purpose: Waiting times before radiotherapy may reduce tumour control probability due to proliferation of tumour cells. The aim of the experiment was to test whether the growth inhibiting effect of epidermal growth factor receptor (EGFR)-inhibitors after surgery or tumour transplantation results in a lower tumour mass at time of irradiation and can thereby improve local tumour control. Materials and methods: The EGFR-tyrosine kinase inhibitor BIBX1382BS was applied over 14 days starting from microscopically non-in-sano-resection of FaDu tumours or from tumour transplantation, followed by irradiation (5f/5d). Endpoint was local tumour control. In addition, vital tumour areas, pimonidazole hypoxic fraction, BrdU labelling index, and colony forming ability in vitro were tested in control tumours and after BIBX1382BS treatment (starting from transplantation). Results: The tumour volume at start of irradiation was significantly lower in the BIBX1382BS treated tumours as compared to the control groups by factors of 11 (post-surgery setting) and 2.7 (transplantation setting). However, the reduced volume did not translate into improved local control after irradiation. The TCD 50 values after surgery were 25.4 Gy [95% CI 18; 33 Gy] in the control group and 30.5 Gy [24; 37] in the BIBX1382BS group (p = 0.25). Treatment after transplantation resulted in TCD 50 values of 41.1 Gy [35; 47] in the control group and 41.1 Gy [33; 49] in the BIBX1382BS group (p = 1). While the proportion of S-phase cells decreased after BIBX1382BS treatment, no differences were observed between the pimonidazole hypoxic fractions and in vitro colony forming ability. Conclusions: EGFR-TK inhibition with BIBX1382BS over 14 days between macroscopically complete tumour resection or tumour transplantation and start of radiotherapy significantly reduced tumour volume but did not improve local tumour control. One possible explanation is that the EGFR-TK inhibitor has a higher activity in

  18. Comparison of CT scan and colour flow doppler ultrasound in detecting venous tumour thrombous in renal cell carcinoma

    International Nuclear Information System (INIS)

    Khan, A.R.; Anwar, K.

    2008-01-01

    Renal cell carcinoma has marked tendency to spread into renal vein, inferior vena cava and right side of heart. Extension of tumour thrombus into these veins will alter the surgical approach. We have compared the CT scan with Colour flow Doppler ultrasound in detecting venous tumour thrombus in renal vein and inferior vena cava. This cross-sectional study included 30 adult patients presenting with renal tumour. Patients of either gender were included in the study. Non probability convenience sampling was used. All patients underwent colour flow Doppler ultrasound and CT scan with contrast to asses the renal vein and inferior vena cava. The results were confirmed by intra operative findings and histopathology. The data was analyzed using SPSS version 12. Out of 30 patients, 20 (66%) were males and 10 (34%) female. The tumour was predominantly on the right side (60%), as was renal venous tumour thrombus (44%). Inferior vena cava was involved in 4 cases predominantly due to right sided tumours. The sensitivity of Doppler ultrasound in detecting renal venous tumour thrombus (88% on right and 100% on left side) was higher than CT scan (63% on right and 60% on left side). Doppler ultrasound was also superior to CT scan in detecting vena caval thrombus. The overall sensitivity of Doppler sonography was higher than CT scan in detecting tumour extension into renal veins and inferior vena cava. Therefore, it can be used as a complementary tool in equivocal cases. (author)

  19. Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study.

    Science.gov (United States)

    Benusiglio, Patrick R; Giraud, Sophie; Deveaux, Sophie; Méjean, Arnaud; Correas, Jean-Michel; Joly, Dominique; Timsit, Marc-Olivier; Ferlicot, Sophie; Verkarre, Virginie; Abadie, Caroline; Chauveau, Dominique; Leroux, Dominique; Avril, Marie-Françoise; Cordier, Jean-François; Richard, Stéphane

    2014-10-29

    The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome. We studied French Birt-Hogg-Dubé patients with a history of renal tumour. We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it. Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dubé, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt-Hogg-Dubé in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers.

  20. Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone

    Directory of Open Access Journals (Sweden)

    Balke Maurice

    2010-08-01

    Full Text Available Abstract Background Giant cell tumour of bone (GCTB is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts. Method In this study, we have examined clinical and radiological outcomes of treatment with aminobisphosphonates on 25 cases of aggressive primary, recurrent and metastatic GCTB derived from four European centres. We also analysed in vitro the inhibitory effect of zoledronic acid on osteoclasts isolated from GCTBs. Results Treatment protocols differed with several different aminobisphosphonates being employed, but stabilisation of disease was achieved in most of these cases which were refractory to conventional treatment. Most inoperable sacral/pelvic tumours did not increase in size and no further recurrence was seen in GCTBs that had repeatedly recurred in bone and soft tissues. Lung metastases did not increase in size or number following treatment. Zoledronic acid markedly inhibited lacunar resorption by GCTB-derived osteoclasts in vitro. Conclusion Our findings suggest that bisphosphonates may be useful in controlling disease progression in GCTB and that these agents directly inhibit GCTB - derived osteoclast resorption. These studies highlight the need for the establishment of standardised protocols to assess the efficacy of bisphosphonate treatment of GCTB.

  1. Children's brain tumour cells produce RNA particles with incomplete retrovirus characteristics.

    Science.gov (United States)

    Thorne, H J; Jose, D G; Adams, F C; Coelen, R J; Whitehead, R H; Klugg, G

    1982-01-01

    Short-term cultures of cells from human rain tumours have been reported to synthesise RNA particles of density in the range characteristic of C type RNA retroviruses, with associated DNA polymerase activity. Fresh tumour cells obtained from 6 children with astrocytoma and 7 children with medulloblastoma, together with one sample of normal brain tissue and normal leukocytes from brain tumour patients were assayed by several characteristics for the primate retrovirus. 1 or 6 (17%) astrocytomas and 4 of 7 (57%) medulloblastomas released RNA particles which banded in sucrose gradients at a density of 1.16-1.18 g/cm3 together with a short segment of DNA, which was eliminated by prior ribonuclease treatment and two proteins of 28k and 16k daltons. These findings were compatible with the presence of a primate retrovirus. Immune coprecipitation of 125I-labelled proteins from the 1.16-1.18 g/cm3 gradient region failed to show any reactivity with antisera to p28 core antigens or the p70 reverse transcriptase antigens of simian sarcoma virus, baboon endogenous virus or Mason Pfizer virus. Assays for DNA polymerase activity in culture supernatant fluid showed only a low amount of activity with template preferences not characteristic of the retroviral reverse transcriptase enzyme.

  2. HPV 16-associated tumours: IL-12 can repair the absence of cytotoxic and proliferative responses of tumour infiltrating cells after chemotherapy

    Czech Academy of Sciences Publication Activity Database

    Indrová, Marie; Bieblová, Jana; Rossowska, J.; Kuropka, P.; Pajtasz-Piasecka, E.; Bubeník, Jan; Reiniš, Milan

    2009-01-01

    Roč. 34, č. 1 (2009), s. 173-180 ISSN 1019-6439 R&D Projects: GA ČR GA301/06/0774 EU Projects: European Commission(XE) 18933 - CLINIGENE Grant - others:Polish Ministry of Science and Higher Education(PL) N401 235334 Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV 16 * vaccines * tumour-infiltrating cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.447, year: 2009

  3. Metabolism, migration and memory in cytotoxic T cells

    OpenAIRE

    Finlay, David; Cantrell, Doreen

    2011-01-01

    The transcriptional and metabolic programs that control CD8+ T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8+ T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine...

  4. An automated cell-counting algorithm for fluorescently-stained cells in migration assays

    Directory of Open Access Journals (Sweden)

    Novielli Nicole M

    2011-10-01

    Full Text Available Abstract A cell-counting algorithm, developed in Matlab®, was created to efficiently count migrated fluorescently-stained cells on membranes from migration assays. At each concentration of cells used (10,000, and 100,000 cells, images were acquired at 2.5 ×, 5 ×, and 10 × objective magnifications. Automated cell counts strongly correlated to manual counts (r2 = 0.99, P

  5. Emerging role for nuclear rotation and orientation in cell migration

    Czech Academy of Sciences Publication Activity Database

    Maninová, Miloslava; Iwanicki, M. P.; Vomastek, Tomáš

    2014-01-01

    Roč. 8, č. 1 (2014), s. 42-48 ISSN 1933-6918 R&D Projects: GA ČR GA204/09/0614 Grant - others:Marie Cúrie EU FP7(BE) 231086 Institutional support: RVO:61388971 Keywords : cell polarity * actin * migration * microtubules Subject RIV: EE - Microbiology, Virology Impact factor: 4.505, year: 2014

  6. [FRET-based biosensors in cell migration research].

    Science.gov (United States)

    Lasota, Sławomir; Baster, Zbigniew; Witko, Tomasz; Zimoląg, Eliza; Sroka, Jolanta; Rajfur, Zenon; Madeja, Zbigniew

    2017-01-01

    Cell migration is a complicated process, which is crucial for functioning of multicellular organisms. Multiple signalling pathways are deeply involved in the precise control of consecutive cell migration stages based on remodelling of the actin cytoskeleton. Small Rho GTPases (RhoA, Rac1 and Cdc42) as well as multiple protein and lipid kinases, calcium ions and mechanosensors are crucial components in this process. Exploration of those complicated correlations is possible with constant advancement of fluorescence microscopy. A significant progress in this field has been achieved since discovery of fluorescent proteins and subsequently FRET-based biosensors. Such protein constructs react with a change of FRET efficiency in response to the particular protein activity change. Properly designed and regularly improved biosensors offer the possibility of real-time imaging of signalling pathways dynamics in migrating cells. The perception of Rho GTPases involvement and some other signalling pathways connected with cell migration have been clarified with multiple experiments already carried out with such FRET-based biosensors.

  7. Molecular mechanisms governing primordial germ cell migration in zebrafish

    NARCIS (Netherlands)

    Doitsidou, M.

    2005-01-01

    In most sexually reproducing organisms primordial germ cells (pGCs) are specified early in development in places that are distinct from the region where the somatic part of the gonad develops. From their places of specification they have to migrate towards the site where they associate with somatic

  8. Endogenous electric fields as guiding cue for cell migration.

    Science.gov (United States)

    Funk, Richard H W

    2015-01-01

    This review covers two topics: (1) "membrane potential of low magnitude and related electric fields (bioelectricity)" and (2) "cell migration under the guiding cue of electric fields (EF)."Membrane potentials for this "bioelectricity" arise from the segregation of charges by special molecular machines (pumps, transporters, ion channels) situated within the plasma membrane of each cell type (including eukaryotic non-neural animal cells). The arising patterns of ion gradients direct many cell- and molecular biological processes such as embryogenesis, wound healing, regeneration. Furthermore, EF are important as guiding cues for cell migration and are often overriding chemical or topographic cues. In osteoblasts, for instance, the directional information of EF is captured by charged transporters on the cell membrane and transferred into signaling mechanisms that modulate the cytoskeleton and motor proteins. This results in a persistent directional migration along an EF guiding cue. As an outlook, we discuss questions concerning the fluctuation of EF and the frequencies and mapping of the "electric" interior of the cell. Another exciting topic for further research is the modeling of field concepts for such distant, non-chemical cellular interactions.

  9. TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer.

    Science.gov (United States)

    Bruna, Alejandra; Greenwood, Wendy; Le Quesne, John; Teschendorff, Andrew; Miranda-Saavedra, Diego; Rueda, Oscar M; Sandoval, Jose L; Vidakovic, Ana Tufegdzic; Saadi, Amel; Pharoah, Paul; Stingl, John; Caldas, Carlos

    2012-01-01

    The role of transforming growth factor-beta (TGFβ) in the progression of different molecular subtypes of breast cancer has not been clarified. Here we show that TGFβ increases breast tumour-initiating cell (BTIC) numbers but only in claudin(low) breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worse clinical outcome in breast cancer patients. NEDD9, a member of the Cas family of integrin scaffold proteins, is necessary to mediate these TGFβ-specific effects through a positive feedback loop that integrates TGFβ/Smad and Rho-actin-SRF-dependent signals. In normal human mammary epithelium, TGFβ induces progenitor activity only in the basal/stem cell compartment, where claudin(low) cancers are presumed to arise. These data show opposing responses to TGFβ in both breast malignant cell subtypes and normal mammary epithelial cell subpopulations and suggest therapeutic strategies for a subset of human breast cancers.

  10. Reactive Hypertrophy of an Accessory Spleen Mimicking Tumour Recurrence of Metastatic Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Christin Tjaden

    2011-01-01

    Full Text Available De novo occurrence of an accessory spleen after splenectomy is worth noting for two reasons. First, it is known that splenectomy can cause reactive hypertrophy of initially inactive and macroscopically invisible splenic tissue. Second, it can mimic tumour recurrence in situations in which splenectomy has been performed for oncological reasons. This might cause difficulties in differential diagnosis and the clinical decision for reoperation. We report the case of a patient with suspected recurrence of renal cell carcinoma after total pancreatectomy and splenectomy for metastatic renal cell carcinoma, which finally revealed an accessory spleen as the morphological correlate of the newly diagnosed mass in the left retroperitoneum.

  11. Drosophila syndecan regulates tracheal cell migration by stabilizing Robo levels

    Science.gov (United States)

    Schulz, Joachim G; Ceulemans, Helga; Caussinus, Emmanuel; Baietti, Maria F; Affolter, Markus; Hassan, Bassem A; David, Guido

    2011-01-01

    Here we identify a new role for Syndecan (Sdc), the only transmembrane heparan sulphate proteoglycan in Drosophila, in tracheal development. Sdc is required cell autonomously for efficient directed migration and fusion of dorsal branch cells, but not for dorsal branch formation per se. The cytoplasmic domain of Sdc is dispensable, indicating that Sdc does not transduce a signal by itself. Although the branch-specific phenotype of sdc mutants resembles those seen in the absence of Slit/Robo2 signalling, genetic interaction experiments indicate that Sdc also helps to suppress Slit/Robo2 signalling. We conclude that Sdc cell autonomously regulates Slit/Robo2 signalling in tracheal cells to guarantee ordered directional migration and branch fusion. PMID:21836636

  12. Untangling cell tracks: Quantifying cell migration by time lapse image data analysis.

    Science.gov (United States)

    Svensson, Carl-Magnus; Medyukhina, Anna; Belyaev, Ivan; Al-Zaben, Naim; Figge, Marc Thilo

    2018-03-01

    Automated microscopy has given researchers access to great amounts of live cell imaging data from in vitro and in vivo experiments. Much focus has been put on extracting cell tracks from such data using a plethora of segmentation and tracking algorithms, but further analysis is normally required to draw biologically relevant conclusions. Such relevant conclusions may be whether the migration is directed or not, whether the population has homogeneous or heterogeneous migration patterns. This review focuses on the analysis of cell migration data that are extracted from time lapse images. We discuss a range of measures and models used to analyze cell tracks independent of the biological system or the way the tracks were obtained. For single-cell migration, we focus on measures and models giving examples of biological systems where they have been applied, for example, migration of bacteria, fibroblasts, and immune cells. For collective migration, we describe the model systems wound healing, neural crest migration, and Drosophila gastrulation and discuss methods for cell migration within these systems. We also discuss the role of the extracellular matrix and subsequent differences between track analysis in vitro and in vivo. Besides methods and measures, we are putting special focus on the need for openly available data and code, as well as a lack of common vocabulary in cell track analysis. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

  13. Immunotherapy of MHC class I-deficient tumours and epigenetic upregulation of MHC class I molecules on tumour cells

    Czech Academy of Sciences Publication Activity Database

    Reiniš, Milan; Manning, Jasper; Indrová, Marie; Přibylová, Hana; Bieblová, Jana; Šímová, Jana; Bubeník, Jan

    2007-01-01

    Roč. 20, Suppl. 1 (2007), S29-S29 ISSN 1107-3756. [World Congress on Advances in Oncology /12./ and International Symposium on Molecular Medicine /10./. 11.10.2007-12.10.2007, Hernissos] R&D Projects: GA ČR GA301/04/0492; GA ČR GA301/07/1410 Institutional research plan: CEZ:AV0Z50520514 Keywords : Immunotherapy * MHC I-deficient tumours * epigenetics Subject RIV: EB - Genetics ; Molecular Biology

  14. Primary Cilia, Signaling Networks and Cell Migration

    DEFF Research Database (Denmark)

    Veland, Iben Rønn

    Primary cilia are microtubule-based, sensory organelles that emerge from the centrosomal mother centriole to project from the surface of most quiescent cells in the human body. Ciliary entry is a tightly controlled process, involving diffusion barriers and gating complexes that maintain a unique...

  15. Hypoxia stimulates invasion and migration of human cervical cancer ...

    Indian Academy of Sciences (India)

    Here we show that hypoxiaincreases tumour cell invasion and migration by the modulation of Rab11, an important molecule for vesicular trafficking.In our study, we found that Rab11, together with the activation of Rac1, could stimulate invasion and migration of cervicalcancer cell lines HeLa/SiHa in hypoxia. Activation of ...

  16. An Immunofluorescence-Assisted Microfluidic Single Cell Quantitative Reverse Transcription Polymerase Chain Reaction Analysis of Tumour Cells Separated from Blood

    Directory of Open Access Journals (Sweden)

    Kazunori Hoshino

    2015-11-01

    Full Text Available Circulating tumour cells (CTCs are important indicators of metastatic cancer and may provide critical information for individualized treatment. As CTCs are usually very rare, the techniques to obtain information from very small numbers of cells are crucial. Here, we propose a method to perform a single cell quantitative reverse transcription polymerase chain reaction (qPCR analysis of rare tumour cells. We utilized a microfluidic immunomagnetic assay to separate cancer cells from blood. A combination of detailed immunofluorescence and laser microdissection enabled the precise selection of individual cells. Cancer cells that were spiked into blood were successfully separated and picked up for a single cell PCR analysis. The breast cancer cell lines MCF7, SKBR3 and MDAMB231 were tested with 10 different genes. The result of the single cell analysis matched the results from a few thousand cells. Some markers (e.g., ER, HER2 that are commonly used for cancer identification showed relatively large deviations in expression levels. However, others (e.g., GRB7 showed deviations that are small enough to supplement single cell disease profiling.

  17. Modification of nucleotide metabolism in relationship with differentiation and in response to irradiation in human tumour cells

    International Nuclear Information System (INIS)

    Wei, Shuang

    1998-01-01

    This research thesis reports the study of the metabolism of nucleotides in human tumour cells. The first part addresses the modifications of nucleotide (more specifically purine) metabolism in relationship with human melanoma cell proliferation and differentiation. The second part addresses the modifications of this metabolism in response to an irradiation in human colon tumour cells. For each part, the author proposes a bibliographic synthesis, and a presentation of studied cells and of methods used to grow cells, and respectively to proliferate and differentiate them or to irradiate them, and then discusses the obtained results [fr

  18. Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes

    Directory of Open Access Journals (Sweden)

    Chris L. Smith

    2016-06-01

    Full Text Available Glioblastoma multiforme is a heterogeneous and infiltrative cancer with dismal prognosis. Studying the migratory behavior of tumor-derived cell populations can be informative, but it places a high premium on the precision of in vitro methods and the relevance of in vivo conditions. In particular, the analysis of 2D cell migration may not reflect invasion into 3D extracellular matrices in vivo. Here, we describe a method that allows time-resolved studies of primary cell migration with single-cell resolution on a fibrillar surface that closely mimics in vivo 3D migration. We used this platform to screen 14 patient-derived glioblastoma samples. We observed that the migratory phenotype of a subset of cells in response to platelet-derived growth factor was highly predictive of tumor location and recurrence in the clinic. Therefore, migratory phenotypic classifiers analyzed at the single-cell level in a patient-specific way can provide high diagnostic and prognostic value for invasive cancers.

  19. Bleb Expansion in Migrating Cells Depends on Supply of Membrane from Cell Surface Invaginations.

    Science.gov (United States)

    Goudarzi, Mohammad; Tarbashevich, Katsiaryna; Mildner, Karina; Begemann, Isabell; Garcia, Jamie; Paksa, Azadeh; Reichman-Fried, Michal; Mahabaleshwar, Harsha; Blaser, Heiko; Hartwig, Johannes; Zeuschner, Dagmar; Galic, Milos; Bagnat, Michel; Betz, Timo; Raz, Erez

    2017-12-04

    Cell migration is essential for morphogenesis, organ formation, and homeostasis, with relevance for clinical conditions. The migration of primordial germ cells (PGCs) is a useful model for studying this process in the context of the developing embryo. Zebrafish PGC migration depends on the formation of cellular protrusions in form of blebs, a type of protrusion found in various cell types. Here we report on the mechanisms allowing the inflation of the membrane during bleb formation. We show that the rapid expansion of the protrusion depends on membrane invaginations that are localized preferentially at the cell front. The formation of these invaginations requires the function of Cdc42, and their unfolding allows bleb inflation and dynamic cell-shape changes performed by migrating cells. Inhibiting the formation and release of the invaginations strongly interfered with bleb formation, cell motility, and the ability of the cells to reach their target. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting

    DEFF Research Database (Denmark)

    Munthe, Sune; Sørensen, Mia D; Thomassen, Mads

    2016-01-01

    Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem...... cells (CSCs), has been identified in gliomas and many other cancers. These tumor cells have a stem cell-like phenotype and are suggested to be responsible for tumor growth, chemo- and radio-resistance as well as recurrence. However, functional evidence for migrating glioma cells having a stem cell......-like phenotype is currently lacking. In the present study, the aim was to characterize the phenotype of migrating tumor cells using a novel migration assay based on serum-free stem cell medium and patient-derived spheroid cultures. The results showed pronounced migration of five different GBM spheroid cultures...

  1. The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac.

    Directory of Open Access Journals (Sweden)

    Juan Cabello

    2010-02-01

    Full Text Available Wnt signalling pathways have extremely diverse functions in animals, including induction of cell fates or tumours, guidance of cell movements during gastrulation, and the induction of cell polarity. Wnt can induce polar changes in cellular morphology by a remodelling of the cytoskeleton. However, how activation of the Frizzled receptor induces cytoskeleton rearrangement is not well understood. We show, by an in depth 4-D microscopy analysis, that the Caenorhabditis elegans Wnt pathway signals to CED-10/Rac via two separate branches to regulate modulation of the cytoskeleton in different cellular situations. Apoptotic cell clearance and migration of the distal tip cell require the MOM-5/Fz receptor, GSK-3 kinase, and APC/APR-1, which activate the CED-2/5/12 branch of the engulfment machinery. MOM-5 (Frizzled thus can function as an engulfment receptor in C. elegans. Our epistatic analyses also suggest that the two partially redundant signalling pathways defined earlier for engulfment may act in a single pathway in early embryos. By contrast, rearrangement of mitotic spindles requires the MOM-5/Fz receptor, GSK-3 kinase, and beta-catenins, but not the downstream factors LIT-1/NLK or POP-1/Tcf. Taken together, our results indicate that in multiple developmental processes, CED-10/Rac can link polar signals mediated by the Wnt pathway to rearrangements of the cytoskeleton.

  2. Tumour macrophages as potential targets of bisphosphonates

    Science.gov (United States)

    2011-01-01

    Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use. Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to

  3. Metabolism, migration and memory in cytotoxic T cells.

    Science.gov (United States)

    Finlay, David; Cantrell, Doreen A

    2011-02-01

    The transcriptional and metabolic programmes that control CD8(+) T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8(+) T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine the effector versus memory fate of CD8(+) T cells. We speculate that one link between metabolism and immunological memory is provided by kinases that originally evolved to control T cell metabolism and have subsequently acquired the ability to control the expression of key transcription factors that regulate CD8(+) T cell effector function and migratory capacity.

  4. Gliadin fragments promote migration of dendritic cells

    Czech Academy of Sciences Publication Activity Database

    Chládková, Barbara; Kamanová, Jana; Palová-Jelínková, Lenka; Cinová, Jana; Šebo, Peter; Tučková, Ludmila

    2011-01-01

    Roč. 15, č. 4 (2011), 938-948 ISSN 1582-1838 R&D Projects: GA ČR GA310/07/0414; GA ČR GD310/08/H077; GA ČR GA310/08/0447; GA AV ČR IAA500200801; GA AV ČR IAA500200914 Institutional research plan: CEZ:AV0Z50200510 Keywords : celiac disease * gliadin * dendritic cell Subject RIV: EC - Immunology Impact factor: 4.125, year: 2011

  5. Anandamide inhibits adhesion and migration of breast cancer cells

    International Nuclear Information System (INIS)

    Grimaldi, Claudia; Pisanti, Simona; Laezza, Chiara; Malfitano, Anna Maria; Santoro, Antonietta; Vitale, Mario; Caruso, Maria Gabriella; Notarnicola, Maria; Iacuzzo, Irma; Portella, Giuseppe; Di Marzo, Vincenzo; Bifulco, Maurizio

    2006-01-01

    The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB 1 receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB 1 antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB 1 receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB 1 receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo

  6. A model for cell type localization in the migrating slug of ...

    Indian Academy of Sciences (India)

    PRAKASH

    . Localization of the three major cell types within the migrating slug stage is a dynamic process (Sternfeld 1992;. A model for cell type localization in the migrating slug of Dictyostelium discoideum based on differential chemotactic sensitivity to ...

  7. Nucleotropic doxorubicin nanoparticles decrease cancer cell viability, destroy mitochondria, induce autophagy and enhance tumour necrosis.

    Science.gov (United States)

    Friedhuber, Anna M; Chandolu, Vijay; Manchun, Somkamon; Donkor, Osaana; Sriamornsak, Pornsak; Dass, Crispin R

    2015-01-01

    Doxorubicin (Dox) is used clinically against various neoplasias, but suffers from serious side effects, and for the past three decades, this shortcoming has spurred research towards finding better drug delivery systems (DDSs) for this frontline drug. A non-targeted nucleotropic Dox-loaded nanoparticle (DNP) DDS is described, which has a simple chemical design, is easy to formulate and administer, is inexpensive, non-biohazardous and may prove to be useful clinically. The DNP formulated via vortex-assisted complex coarcevation enhanced (300-fold) cell-inhibitory activity of the drug in a panel of human cancer cells (osteosarcoma, breast, prostate and colorectal cancer) and enhanced (10-fold) efficacy against osteosarcoma (OS) in vivo. The slow-release DNPs localised to the endoplasmic reticulum disrupted the mitochondria and entered the nucleus. Prominent cytosolic vacuolisation, budding off of portions of the cytoplasm, both suggestive of autophagy, were observed. Mice that were administered with DNPs intratumorally had the smallest tumours at the end of the study, with more necrotic hotspots. This promising nucleotropic DDS enhances the cell delivery and activity of Dox against a variety of human cancer cell lines and in OS tumours in mice. © 2014 Royal Pharmaceutical Society.

  8. Collision Tumour of Squamous Cell Carcinoma and Malignant Melanoma in the Oral Cavity of a Dog.

    Science.gov (United States)

    Rodríguez, F; Castro, P; Ramírez, G A

    2016-05-01

    A 7-year-old, male cocker spaniel was presented with a gingival proliferative lesion in the rostral maxilla and enlargement of the regional lymph node. Morphological and immunohistochemical analysis revealed a collision tumour composed of two malignant populations, epithelial and melanocytic, with metastasis of the neoplastic melanocytes to the regional lymph node. The epithelial component consisted of trabeculae and islands of well-differentiated squamous epithelium immunoreactive to cytokeratins. The melanocytic component had a varying degree of pigmentation of polygonal and spindle-shaped cells, growing in nests or densely packed aggregates and immunolabelled with S100, melanoma-associated antigen (melan A), neuron-specific enolase and vimentin antibodies. Protein markers involved in tumorigenesis or cell proliferation (i.e. COX-2, p53, c-kit and Ki67), were overexpressed by the neoplastic cells. To the authors' knowledge, this is the first description of an oral collision tumour involving malignant melanoma and squamous cell carcinoma in the dog. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Characterisation of multidrug-resistant Ehrlich ascites tumour cells selected in vivo for resistance to etoposide

    DEFF Research Database (Denmark)

    Nielsen, D; Maare, C; Eriksen, J

    2000-01-01

    An Ehrlich ascites tumour cell line (EHR2) was selected for resistance to etoposide (VP16) by in vivo exposure to this agent. The resulting cell line (EHR2/VP16) was 114.3-, 5.7-, and 4.0-fold resistant to VP16, daunorubicin, and vincristine, respectively. The amount of salt-extractable immunorea......An Ehrlich ascites tumour cell line (EHR2) was selected for resistance to etoposide (VP16) by in vivo exposure to this agent. The resulting cell line (EHR2/VP16) was 114.3-, 5.7-, and 4.0-fold resistant to VP16, daunorubicin, and vincristine, respectively. The amount of salt......-extractable immunoreactive topoisomerase IIalpha and beta in EHR2/VP16 was reduced by 30-40% relative to that in EHR2. The multidrug resistance-associated protein (MRP) mRNA was increased 20-fold in EHR2/VP16 as compared with EHR2, whereas the expression of P-glycoprotein was unchanged. In EHR2/VP16, the steady...

  10. Variation in sensitizing effect of caffeine in human tumour cell lines after γ-irradiation

    International Nuclear Information System (INIS)

    Valenzuela, M.T.; Almodovar, M.R. de; Mateos, S.; McMillan, T.J.

    2000-01-01

    We have investigated whether the protective role of the G2 checkpoint has increasing importance when the p53-dependent G1 checkpoint is inactivated. We have studied the differential effect of caffeine by clonogenic assays and flow cytometry in three human tumour cell lines with different functionality of p53 protein. The radiosensitizing effect of caffeine (2 mM) expressed itself as a significant decrease in surviving fraction at 2 Gy and a significant increase in α-values in RT112 and TE671, both with non-functional p53. However, no radiosensitizing effect was seen in cells with a normal p53 function (MCF-7 BUS). Two millimoles of caffeine also caused important changes in the cell cycle progression after irradiation. MCF-7 BUS showed a G1 arrest after irradiation and an early G2 arrest but those cells that reached the second G2 did not arrest significantly. In contrast, TE671 exhibited radiosensitization by caffeine, no G1 arrest, a G2 arrest in those cells irradiated in G2, no significant accumulation in the second G2 but an overall delay in release from the first cell cycle, which could be abrogated by caffeine. RT112 was similar to TE671 except that the emphasis in a G2 arrest was shifted from the block in cells irradiated in G2 to those irradiated at other cell cycle phases. The data presented confirm that p53 status can be a significant determinant of the efficacy of caffeine as radiosensitizer in these tumour cell lines, and document the importance of the G2 checkpoint in this effect. (author)

  11. Does tumour location influence postoperative long-term survival in patients with oesophageal squamous cell carcinoma?

    Science.gov (United States)

    Shi, Hui; Zhang, Kun; Niu, Zhong-Xi; Wang, Wen-Ping; Gao, Qiang; Chen, Long-Qi

    2015-08-01

    The seventh edition of the American Joint Committee on Cancer (AJCC) staging system introduced tumour location for the first time as an determinant of stage grouping in pathological T2N0M0 and T3N0M0 (pT2-3N0M0) oesophageal squamous cell carcinoma (OSCC). However, the new modification remains controversial. The objective of this study was to investigate the correlation between tumour location and postoperative long-term survival in patients with OSCC in China. The clinicopathological data and over 10 years of follow-up results from a large cohort of 988 patients with OSCC undergoing radical-intent oesophagectomy from 1984 to 1995 without preoperative and postoperative chemoradiotherapy were reviewed, in which 632 patients were staged as pT2-3N0M0. Tumour location was redefined according to the seventh edition of the AJCC staging system. Survival was calculated by the Kaplan-Meier method; univariate log-rank and multivariate Cox proportional hazard models were used to further determine the impact of tumour location on long-term survival. Univariate analysis showed that OSCC tumour location was closely associated with long-term survival for the entire cohort of 988 patients (odds ratio [OR]: 0.82; 95% confidence interval [95% CI]: 0.67-0.99; P = 0.049), and for pT2-3N0M0 patients (OR: 0.63; 95% CI: 0.48-0.84; P = 0.001). The median survival times for patients with pT2-3N0M0 OSCC in the upper, middle and lower third of the oesophagus were 38.1, 46.6 and 66.0 months, respectively, with corresponding 5-year survival rates of 40.0, 51.8 and 66.2%, respectively. Overall survival rates among three categories of patients according to tumour location in the pT2-3N0M0 patients were statistically different (P = 0.004). Multivariate analysis demonstrated that tumour location was a significant independent predictor of long-term survival for pT2-3N0M0 patients (OR: 0.53; 95% CI: 0.42-0.67; P = 0.0001), but not for the entire cohort of 988 patients (OR: 0.99; 95% CI: 0.79-1.23; P

  12. Inhibition of Rho-associated kinases disturbs the collective cell migration of stratified TE-10 cells

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    Taro Mikami

    2015-01-01

    Full Text Available BACKGROUND: The collective cell migration of stratified epithelial cells is considered to be an important phenomenon in wound healing, development, and cancer invasion; however, little is known about the mechanisms involved. Furthermore, whereas Rho family proteins, including RhoA, play important roles in cell migration, the exact role of Rho-associated coiled coil-containing protein kinases (ROCKs in cell migration is controversial and might be cell-type dependent. Here, we report the development of a novel modified scratch assay that was used to observe the collective cell migration of stratified TE-10 cells derived from a human esophageal cancer specimen. RESULTS: Desmosomes were found between the TE-10 cells and microvilli of the surface of the cell sheet. The leading edge of cells in the cell sheet formed a simple layer and moved forward regularly; these rows were followed by the stratified epithelium. ROCK inhibitors and ROCK small interfering RNAs (siRNAs disturbed not only the collective migration of the leading edge of this cell sheet, but also the stratified layer in the rear. In contrast, RhoA siRNA treatment resulted in more rapid migration of the leading rows and disturbed movement of the stratified portion. CONCLUSIONS: The data presented in this study suggest that ROCKs play an important role in mediating the collective migration of TE-10 cell sheets. In addition, differences between the effects of siRNAs targeting either RhoA or ROCKs suggested that distinct mechanisms regulate the collective cell migration in the simple epithelium of the wound edge versus the stratified layer of the epithelium.

  13. Multiple modes of proepicardial cell migration require heartbeat.

    Science.gov (United States)

    Plavicki, Jessica S; Hofsteen, Peter; Yue, Monica S; Lanham, Kevin A; Peterson, Richard E; Heideman, Warren

    2014-05-15

    The outermost layer of the vertebrate heart, the epicardium, forms from a cluster of progenitor cells termed the proepicardium (PE). PE cells migrate onto the myocardium to give rise to the epicardium. Impaired epicardial development has been associated with defects in valve development, cardiomyocyte proliferation and alignment, cardiac conduction system maturation and adult heart regeneration. Zebrafish are an excellent model for studying cardiac development and regeneration; however, little is known about how the zebrafish epicardium forms. We report that PE migration occurs through multiple mechanisms and that the zebrafish epicardium is composed of a heterogeneous population of cells. Heterogeneity is first observed within the PE and persists through epicardium formation. Using in vivo imaging, histology and confocal microscopy, we show that PE cells migrate through a cellular bridge that forms between the pericardial mesothelium and the heart. We also observed the formation of PE aggregates on the pericardial surface, which were released into the pericardial cavity. It was previously reported that heartbeat-induced pericardiac fluid advections are necessary for PE cluster formation and subsequent epicardium development. We manipulated heartbeat genetically and pharmacologically and found that PE clusters clearly form in the absence of heartbeat. However, when heartbeat was inhibited the PE failed to migrate to the myocardium and the epicardium did not form. We isolated and cultured hearts with only a few epicardial progenitor cells and found a complete epicardial layer formed. However, pharmacologically inhibiting contraction in culture prevented epicardium formation. Furthermore, we isolated control and silent heart (sih) morpholino (MO) injected hearts prior to epicardium formation (60 hpf) and co-cultured these hearts with "donor" hearts that had an epicardium forming (108 hpf). Epicardial cells from donor hearts migrated on to control but not sih MO

  14. The origin and migration of primordial germ cells in sturgeons.

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    Taiju Saito

    Full Text Available Primordial germ cells (PGCs arise elsewhere in the embryo and migrate into developing gonadal ridges during embryonic development. In several model animals, formation and migration patterns of PGCs have been studied, and it is known that these patterns vary. Sturgeons (genus Acipenser have great potential for comparative and evolutionary studies of development. Sturgeons belong to the super class Actinoptergii, and their developmental pattern is similar to that of amphibians, although their phylogenetic position is an out-group to teleost fishes. Here, we reveal an injection technique for sturgeon eggs allowing visualization of germplasm and PGCs. Using this technique, we demonstrate that the PGCs are generated at the vegetal pole of the egg and they migrate on the yolky cell mass toward the gonadal ridge. We also provide evidence showing that PGCs are specified by inheritance of maternally supplied germplasm. Furthermore, we demonstrate that the migratory mechanism is well-conserved between sturgeon and other remotely related teleosts, such as goldfish, by a single PGCs transplantation (SPT assay. The mode of PGCs specification in sturgeon is similar to that of anurans, but the migration pattern resembles that of teleosts.

  15. The Origin And Migration Of Primordial Germ Cells In Sturgeons

    Science.gov (United States)

    Saito, Taiju; Pšenička, Martin; Goto, Rie; Adachi, Shinji; Inoue, Kunio; Arai, Katsutoshi; Yamaha, Etsuro

    2014-01-01

    Primordial germ cells (PGCs) arise elsewhere in the embryo and migrate into developing gonadal ridges during embryonic development. In several model animals, formation and migration patterns of PGCs have been studied, and it is known that these patterns vary. Sturgeons (genus Acipenser) have great potential for comparative and evolutionary studies of development. Sturgeons belong to the super class Actinoptergii, and their developmental pattern is similar to that of amphibians, although their phylogenetic position is an out-group to teleost fishes. Here, we reveal an injection technique for sturgeon eggs allowing visualization of germplasm and PGCs. Using this technique, we demonstrate that the PGCs are generated at the vegetal pole of the egg and they migrate on the yolky cell mass toward the gonadal ridge. We also provide evidence showing that PGCs are specified by inheritance of maternally supplied germplasm. Furthermore, we demonstrate that the migratory mechanism is well-conserved between sturgeon and other remotely related teleosts, such as goldfish, by a single PGCs transplantation (SPT) assay. The mode of PGCs specification in sturgeon is similar to that of anurans, but the migration pattern resembles that of teleosts. PMID:24505272

  16. Analysis of individual cell trajectories in lattice-gas cellular automaton models for migrating cell populations.

    Science.gov (United States)

    Mente, Carsten; Voss-Böhme, Anja; Deutsch, Andreas

    2015-04-01

    Collective dynamics of migrating cell populations drive key processes in tissue formation and maintenance under normal and diseased conditions. Collective cell behavior at the tissue level is typically characterized by considering cell density patterns such as clusters and moving cell fronts. However, there are also important observables of collective dynamics related to individual cell behavior. In particular, individual cell trajectories are footprints of emergent behavior in populations of migrating cells. Lattice-gas cellular automata (LGCA) have proven successful to model and analyze collective behavior arising from interactions of migrating cells. There are well-established methods to analyze cell density patterns in LGCA models. Although LGCA dynamics are defined by cell-based rules, individual cells are not distinguished. Therefore, individual cell trajectories cannot be analyzed in LGCA so far. Here, we extend the classical LGCA framework to allow labeling and tracking of individual cells. We consider cell number conserving LGCA models of migrating cell populations where cell interactions are regulated by local cell density and derive stochastic differential equations approximating individual cell trajectories in LGCA. This result allows the prediction of complex individual cell trajectories emerging in LGCA models and is a basis for model-experiment comparisons at the individual cell level.

  17. Low-level shear stress promotes migration of liver cancer stem cells via the FAK-ERK1/2 signalling pathway.

    Science.gov (United States)

    Sun, Jinghui; Luo, Qing; Liu, Lingling; Song, Guanbin

    2018-04-18

    Cancer stem cells (CSCs) are a small subpopulation of tumour cells that have been proposed to be responsible for cancer initiation, chemotherapy resistance and cancer recurrence. Shear stress activated cellular signalling is involved in cellular migration, proliferation and differentiation. However, little is known about the effects of shear stress on the migration of liver cancer stem cells (LCSCs). Here, we studied the effects of shear stress that are generated from a parallel plated flow chamber system, on LCSC migration and the activation of focal adhesion kinase (FAK) and extracellular signal regulated kinase1/2 (ERK1/2), using transwell assay and western blot, respectively. We found that 2 dyne/cm 2 shear stress loading for 6 h promotes LCSC migration and activation of the FAK and ERK1/2 signalling pathways, whereas treatment with the FAK phosphorylation inhibitor PF573228 or the ERK1/2 phosphorylation inhibitor PD98059 suppressed the shear stress-promoted migration, indicating the involvement of FAK and ERK1/2 activation in shear stress-induced LCSC migration. Additionally, atomic force microscopy (AFM) analysis showed that shear stress lowers LCSC stiffness via the FAK and ERK1/2 pathways, suggesting that the mechanism by which shear stress promotes LCSC migration might partially be responsible for the decrease in cell stiffness. Further experiments focused on the role of the actin cytoskeleton, demonstrating that the F-actin filaments in LCSCs are less well-defined after shear stress treatment, providing an explanation for the reduction in cell stiffness and the promotion of cell migration. Overall, our study demonstrates that shear stress promotes LCSC migration through the activation of the FAK-ERK1/2 signalling pathways, which further results in a reduction of organized actin and softer cell bodies. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Mib1 contributes to persistent directional cell migration by regulating the Ctnnd1-Rac1 pathway.

    Science.gov (United States)

    Mizoguchi, Takamasa; Ikeda, Shoko; Watanabe, Saori; Sugawara, Michiko; Itoh, Motoyuki

    2017-10-31

    Persistent directional cell migration is involved in animal development and diseases. The small GTPase Rac1 is involved in F-actin and focal adhesion dynamics. Local Rac1 activity is required for persistent directional migration, whereas global, hyperactivated Rac1 enhances random cell migration. Therefore, precise control of Rac1 activity is important for proper directional cell migration. However, the molecular mechanism underlying the regulation of Rac1 activity in persistent directional cell migration is not fully understood. Here, we show that the ubiquitin ligase mind bomb 1 (Mib1) is involved in persistent directional cell migration. We found that knockdown of MIB1 led to an increase in random cell migration in HeLa cells in a wound-closure assay. Furthermore, we explored novel Mib1 substrates for cell migration and found that Mib1 ubiquitinates Ctnnd1. Mib1-mediated ubiquitination of Ctnnd1 K547 attenuated Rac1 activation in cultured cells. In addition, we found that posterior lateral line primordium cells in the zebrafish mib1 ta52b mutant showed increased random migration and loss of directional F-actin-based protrusion formation. Knockdown of Ctnnd1 partially rescued posterior lateral line primordium cell migration defects in the mib1 ta52b mutant. Taken together, our data suggest that Mib1 plays an important role in cell migration and that persistent directional cell migration is regulated, at least in part, by the Mib1-Ctnnd1-Rac1 pathway. Published under the PNAS license.

  19. Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro.

    Science.gov (United States)

    Dorward, Hilary S; Du, Alice; Bruhn, Maressa A; Wrin, Joseph; Pei, Jinxin V; Evdokiou, Andreas; Price, Timothy J; Yool, Andrea J; Hardingham, Jennifer E

    2016-02-24

    Aquaporins (AQP) are water channel proteins that enable fluid fluxes across cell membranes, important for homeostasis of the tissue environment and for cell migration. AQP1 knockout mouse models of human cancers showed marked inhibition of tumor-induced angiogenesis, and in pre-clinical studies of colon adenocarcinomas, forced over-expression of AQP1 was shown to increase angiogenesis, invasion and metastasis. We have synthesized small molecule antagonists of AQP1. Our hypothesis is that inhibition of AQP1 will reduce migration and invasiveness of colon cancer cells, and the migration and tube-forming capacity of endothelial cells in vitro. Expression of AQP1 in cell lines was assessed by quantitative (q) PCR, western blot and immunofluorescence, while expression of AQP1 in human colon tumour tissue was assessed by immunohistochemistry. The effect of varying concentrations of the AQP1 inhibitor AqB013 was tested on human colon cancer cell lines expressing high versus low levels of AQP1, using wound closure (migration) assays, matrigel invasion assays, and proliferation assays. The effect of AqB013 on angiogenesis was tested using an endothelial cell tube-formation assay. HT29 colon cancer cells with high AQP1 levels showed significant inhibition of migration compared to vehicle control of 27.9% ± 2.6% (p colon cancer.

  20. Tumour Cell Labelling by Magnetic Nanoparticles with Determination of Intracellular Iron Content and Spatial Distribution of the Intracellular Iron

    Directory of Open Access Journals (Sweden)

    Alfred Cuschieri

    2013-04-01

    Full Text Available Magnetically labelled cells are used for in vivo cell tracking by MRI, used for the clinical translation of cell-base therapies. Studies involving magnetic labelled cells may include separation of labelled cells, targeted delivery and controlled release of drugs, contrast enhanced MRI and magnetic hyperthermia for the in situ ablation of tumours. Dextran-coated super-paramagnetic iron oxide (SPIO ferumoxides are used clinically as an MR contrast agents primarily for hepatic imaging. The material is also widely used for in vitro cell labelling, as are other SPIO-based particles. Our results on the uptake by human cancer cell lines of ferumoxides indicate that electroporation in the presence of protamine sulphate (PS results in rapid high uptake of SPIO nanoparticles (SPIONs by parenchymal tumour cells without significant impairment of cell viability. Quantitative determination of cellular iron uptake performed by colorimetric assay is in agreement with data from the literature. These results on intracellular iron content together with the intracellular distribution of SPIONs by magnetic force microscopy (MFM following in vitro uptake by parenchymal tumour cells confirm the potential of this technique for clinical tumour cell detection and destruction.

  1. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

    International Nuclear Information System (INIS)

    Yan, Bing; Stantic, Marina; Zobalova, Renata; Bezawork-Geleta, Ayenachew; Stapelberg, Michael; Stursa, Jan; Prokopova, Katerina; Dong, Lanfeng; Neuzil, Jiri

    2015-01-01

    Accumulating evidence suggests that breast cancer involves tumour-initiating cells (TICs), which play a role in initiation, metastasis, therapeutic resistance and relapse of the disease. Emerging drugs that target TICs are becoming a focus of contemporary research. Mitocans, a group of compounds that induce apoptosis of cancer cells by destabilising their mitochondria, are showing their potential in killing TICs. In this project, we investigated mitochondrially targeted vitamin E succinate (MitoVES), a recently developed mitocan, for its in vitro and in vivo efficacy against TICs. The mammosphere model of breast TICs was established by culturing murine NeuTL and human MCF7 cells as spheres. This model was verified by stem cell marker expression, tumour initiation capacity and chemotherapeutic resistance. Cell susceptibility to MitoVES was assessed and the cell death pathway investigated. In vivo efficacy was studied by grafting NeuTL TICs to form syngeneic tumours. Mammospheres derived from NeuTL and MCF7 breast cancer cells were enriched in the level of stemness, and the sphere cells featured altered mitochondrial function. Sphere cultures were resistant to several established anti-cancer agents while they were susceptible to MitoVES. Killing of mammospheres was suppressed when the mitochondrial complex II, the molecular target of MitoVES, was knocked down. Importantly, MitoVES inhibited progression of syngeneic HER2 high tumours derived from breast TICs by inducing apoptosis in tumour cells. These results demonstrate that using mammospheres, a plausible model for studying TICs, drugs that target mitochondria efficiently kill breast tumour-initiating cells. The online version of this article (doi:10.1186/s12885-015-1394-7) contains supplementary material, which is available to authorized users

  2. Important surgical considerations in the management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus.

    Science.gov (United States)

    Lawindy, Samuel M; Kurian, Tony; Kim, Timothy; Mangar, Devanand; Armstrong, Paul A; Alsina, Angel E; Sheffield, Cedric; Sexton, Wade J; Spiess, Philippe E

    2012-10-01

    What's known on the subject? and What does the study add? Historically, the surgical management of renal tumours with intravascular tumour thrombus has been associated with high morbidity and mortality. In addition, few cases are treated, and typically at tertiary care referral centres, hence little is known and published about the ideal surgical management of such complex cases. The present comprehensive review details how a multidisciplinary surgical approach to renal tumours with intravascular tumour thrombus can optimise patient outcomes. Similarly, we have developed a treatment algorithm in this review that can be used in the surgical planning of such cases. To detail the perioperative and technical considerations essential to the surgical management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus, as historically patients with RCC and IVC tumour thrombus have had an adverse clinical outcome. • Recent surgical and perioperative advances have for the most part optimized the clinical outcome of such patients. A comprehensive review of the scientific literature was conducted using MEDLINE from 1990 to present using as the keywords 'renal cell carcinoma' and 'IVC tumor thrombus'. • In all, 62 manuscripts were reviewed, 58 of which were in English. Of these, 25 peer-reviewed articles were deemed of scientific merit and were assessed in detail as part of this comprehensive review. • These articles consist of medium to large (≥25 patients) peer-reviewed studies containing contemporary data pertaining to the surgical management of RCC and IVC tumour thrombus. • Many of these studies highlight important surgical techniques and considerations in the management of such patients and report on their respective clinical outcomes. Careful preoperative planning is essential to optimising the outcomes within this patient cohort. High quality and detailed preoperative imaging studies help delineate the proximal extension of the IVC tumour

  3. Molecular aspects of tumor cell migration and invasion

    Directory of Open Access Journals (Sweden)

    Giuseppina Bozzuto

    2010-03-01

    Full Text Available Cell migration and invasion are crucial steps in many physiological events. However, they are also implicated in the physiopathology of many diseases, such as cancer. To spread through the tissues, tumor cells use mechanisms that involve several molecular actors: adhesion receptor families, receptor tyrosine kinases, cytoskeleton proteins, adapter and signalling proteins interplay in a complex scenario. The balance of cellular signals for proliferation and survival responses also regulates migratory behaviours of tumor cells. To complicate the scene of crime drug resistance players can interfere thus worsening this delicate situation. The complete understanding of this molecular jungle is an impossible mission: some molecular aspects are reviewed in this paper.

  4. Nifedipine promotes the proliferation and migration of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Dong-Qing Guo

    Full Text Available Nifedipine is widely used as a calcium channel blocker (CCB to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn't exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3. Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3-Erk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers.

  5. Aquaporin 2 promotes cell migration and epithelial morphogenesis.

    Science.gov (United States)

    Chen, Ying; Rice, William; Gu, Zhizhan; Li, Jian; Huang, Jianmin; Brenner, Michael B; Van Hoek, Alfred; Xiong, Jianping; Gundersen, Gregg G; Norman, Jim C; Hsu, Victor W; Fenton, Robert A; Brown, Dennis; Lu, Hua A Jenny

    2012-09-01

    The aquaporin 2 (AQP2) water channel, expressed in kidney collecting ducts, contributes critically to water homeostasis in mammals. Animals lacking or having significantly reduced levels of AQP2, however, have not only urinary concentrating abnormalities but also renal tubular defects that lead to neonatal mortality from renal failure. Here, we show that AQP2 is not only a water channel but also an integrin-binding membrane protein that promotes cell migration and epithelial morphogenesis. AQP2 expression modulates the trafficking and internalization of integrin β1, facilitating its turnover at focal adhesions. In vitro, disturbing the interaction between AQP2 and integrin β1 by mutating the RGD motif led to reduced endocytosis, retention of integrin β1 at the cell surface, and defective cell migration and tubulogenesis. Similarly, in vivo, AQP2-null mice exhibited significant retention of integrin β1 at the basolateral membrane and had tubular abnormalities. In summary, these data suggest that the water channel AQP2 interacts with integrins to promote renal epithelial cell migration, contributing to the structural and functional integrity of the mammalian kidney.

  6. Anesthetic pentobarbital inhibits proliferation and migration of malignant glioma cells.

    Science.gov (United States)

    Xie, Jun; Li, Yan; Huang, Yijun; Qiu, Pengxin; Shu, Minfeng; Zhu, Wenbo; Ou, Yanqiu; Yan, Guangmei

    2009-09-08

    Malignant gliomas are common and aggressive brain tumors in adults. The rapid proliferation and diffuse brain migration are main obstacles to successful treatment. Here we show that pentobarbital, a central depressant introduced clinically a century ago, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner. Pentobarbital also leads to a G1 phase cell cycle arrest accompanied by suppressed G1 cell cycle regulatory proteins Cyclin D1, Cyclin D3, CDK2 and phosphorylated Rb. In addition, noticeable morphological changes and interrupted alpha-tubulin microtubule assembly are induced by pentobarbital exposure. Intracellular signal pathways involved in the effect of pentobarbital is concerned with inactivation of ERK, c-Jun and Akt. Together, these findings suggest anti-proliferation and anti-migration effects of pentobarbital on malignant gliomas, most likely by arresting cell cycle and interfering microtubule. ERK, c-Jun MAPK and PI3K/Akt are possible signaling pathways involved.

  7. Dendritic cell-based vaccines for therapy of HPV16-induced tumours

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan; Šímová, Jana; Vonka, V.; Šmahel, M.; Mikyšková, Romana; Mendoza, Luis

    2001-01-01

    Roč. 495, - (2001), s. 359-363 ISSN 0065-2598 R&D Projects: GA MZd NC5526; GA ČR GA312/98/0826; GA ČR GA312/99/0542; GA ČR GA301/00/0114; GA ČR GA301/01/0985; GA AV ČR IAA7052002 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * dendritic cells * tumour vaccines Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.513, year: 2000

  8. Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration.

    Directory of Open Access Journals (Sweden)

    Erika Costa de Alvarenga

    Full Text Available The angiotensin-I converting enzyme (ACE plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II. More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet.Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration.We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC, and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5 showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein.ACE activation regulates melanoma cell proliferation and migration.

  9. Angiotensin II facilitates breast cancer cell migration and metastasis.

    Directory of Open Access Journals (Sweden)

    Sylvie Rodrigues-Ferreira

    Full Text Available Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.

  10. Dose-dependent biological damage of tumour cells by laser-accelerated proton beams

    International Nuclear Information System (INIS)

    Kraft, S.D.; Zeil, K.; Beyreuther, E.; Cowan, T.E.; Lessmann, E.; Richter, C.; Baumann, M.

    2010-01-01

    Complete text of publication follows. Cancer therapy using protons or heavier ions such as carbon plays a more and more important role in oncology. In contrast to the widely used X-rays, the ions deposit their energy mainly in a small spatial region before they come so a stop (Bragg peak) and thus it is possible to deposit energy within the tumour in a more controlled way sparring the surrounding tissue. So far, the required accelerators are quit complex and costly, since laser accelerated ion technology has made large progress over the last years, it has been proposed to use lasers in order to replace conventional accelerators. To reach this goal, among obvious tasks as an increase in ion energy, precise dosimetry measurements for ultrashort ion bunches have to be established and the biological effectiveness of laser accelerated protons has to be determined. We report on the first experiments, showing dose dependent biological damage of tumour cells by laser-accelerated protons. In order to apply the dose in a controlled way an energy filter system as well as a dedicated dosimetry system and an in-air cell irradiation site has been set up. The cells could be irradiated with protons of an energy range between 5 and 15 MeV applying doses of a few Gray within a few minutes.

  11. Integrin-mediated cell surface recruitment of autotaxin promotes persistent directional cell migration

    Science.gov (United States)

    Wu, Tao; Kooi, Craig Vander; Shah, Pritom; Charnigo, Richard; Huang, Cai; Smyth, Susan S.; Morris, Andrew J.

    2014-01-01

    Autotaxin (ATX) is a secreted lysophospholipase D (lysoPLD) that binds to integrin adhesion receptors. We dissected the roles of integrin binding and lysoPLD activity in stimulation of human breast cancer and mouse aortic vascular smooth muscle cell migration by ATX. We compared effects of wild-type human ATX, catalytically inactive ATX, an integrin binding-defective ATX variant with wild-type lysoPLD activity, the isolated ATX integrin binding N-terminal domain, and a potent ATX selective lysoPLD inhibitor on cell migration using transwell and single-cell tracking assays. Stimulation of transwell migration was reduced (18 or 27% of control, respectively) but not ablated by inactivation of integrin binding or inhibition of lysoPLD activity. The N-terminal domain increased transwell migration (30% of control). ATX lysoPLD activity and integrin binding were necessary for a 3.8-fold increase in the fraction of migrating breast cancer cell step velocities >0.7 μm/min. ATX increased the persistent directionality of single-cell migration 2-fold. This effect was lysoPLD activity independent and recapitulated by the integrin binding N-terminal domain. Integrin binding enables uptake and intracellular sequestration of ATX, which redistributes to the front of migrating cells. ATX binding to integrins and lysoPLD activity therefore cooperate to promote rapid persistent directional cell migration.—Wu, T., Kooi, C. V., Shah, P., Charnigo, R., Huang, C., Smyth, S. S., Morris, A. J. Integrin-mediated cell surface recruitment of autotaxin promotes persistent directional cell migration. PMID:24277575

  12. MEIS1 inhibits clear cell renal cell carcinoma cells proliferation and in vitro invasion or migration.

    Science.gov (United States)

    Zhu, Jie; Cui, Liang; Xu, Axiang; Yin, Xiaotao; Li, Fanglong; Gao, Jiangping

    2017-03-07

    Myeloid ecotropic viral integration site 1 (MEIS1) protein plays a synergistic causative role in acute myeloid leukemia (AML). However, MEIS1 has also shown to be a potential tumor suppressor in some other cancers, such as non-small-cell lung cancer (NSCLC) and prostate cancer. Although multiple roles of MEIS1 in cancer development and progression have been identified, there is an urgent demand to discover more functions of this molecule for further therapeutic design. MEIS1 was overexpressed via adenovirus vector in clear cell renal cell carcinoma (ccRCC) cells. Western blot and real-time qPCR (quantitative Polymerase Chain Reaction) was performed to examine the protein and mRNA levels of MEIS1. Cell proliferation, survival, in vitro migration and invasion were tested by MTT, colony formation, soft-agar, transwell (in vitro invasion/migration) assays, and tumor in vivo growthwas measured on nude mice model. In addition, flow-cytometry analysis was used to detect cell cycle arrest or non-apoptotic cell death of ccRCC cells induced by MEIS1. MEIS1 exhibits a decreased expression in ccRCC cell lines than that in non-tumor cell lines. MEIS1 overexpression inhibits ccRCC cells proliferation and induces G1/S arrest concomitant with marked reduction of G1/S transition regulators, Cyclin D1 and Cyclin A. Moreover, MEIS1-1 overexpression also induces non-apoptotic cell death of ccRCC cells via decreasing the levels of pro-survival regulators Survivin and BCL-2. Transwell migration assay (TMA) shows that MEIS1 attenuates in vitro invasion and migration of ccRCC cells with down-regulated epithelial-mesenchymal transition (EMT) process. Further, in nude mice model, MEIS1 inhibits the in vivo growth of Caki-1 cells. By investigating the role of MEIS1 in ccRCC cells' survival, proliferation, anchorage-independent growth, cell cycle progress, apoptosis and metastasis, in the present work, we propose that MEIS1 may play an important role in clear cell renal cell carcinoma (cc

  13. Urothelial atypia and survival rate of 500 unselected patients with primary transitional-cell tumour of the urinary bladder

    DEFF Research Database (Denmark)

    Rosenkilde Olsen, P; Wolf, H; Schroeder, T

    1988-01-01

    In a consecutive series of 500 unselected patients with primary urinary bladder tumours the influence of urothelial atypia on the 5 years survival-rate was examined. All tumours were transitional-cell tumours categorized according to the T-classification. Mucosal biopsies from 7 pre-selected sites...... were taken at the initial cystoscopy in 391 patients (78%) to identify urothelial atypia. The over-all cumulative 5 years survival-rate was 48%. Submucosal and muscle invasion had major influence on survival, whereas tumour grade was less important. Patients with urothelial atypia fared significantly...... worse than those with normal bladder mucosa (5 years survival 42% versus 62%). This difference in survival-rate became apparent first after two years of observation. Grade II atypia in the bladder mucosa and grade III (carcinoma in situ) had equal significance assessed by the survival-rates....

  14. CD155/PVR plays a key role in cell motility during tumor cell invasion and migration

    International Nuclear Information System (INIS)

    Sloan, Kevin E; Ilag, Leodevico L; Jay, Daniel G; Eustace, Brenda K; Stewart, Jean K; Zehetmeier, Carol; Torella, Claudia; Simeone, Marina; Roy, Jennifer E; Unger, Christine; Louis, David N

    2004-01-01

    Invasion is an important early step of cancer metastasis that is not well understood. Developing therapeutics to limit metastasis requires the identification and validation of candidate proteins necessary for invasion and migration. We developed a functional proteomic screen to identify mediators of tumor cell invasion. This screen couples Fluorophore Assisted Light Inactivation (FALI) to a scFv antibody library to systematically inactivate surface proteins expressed by human fibrosarcoma cells followed by a high-throughput assessment of transwell invasion. Using this screen, we have identified CD155 (the poliovirus receptor) as a mediator of tumor cell invasion through its role in migration. Knockdown of CD155 by FALI or by RNAi resulted in a significant decrease in transwell migration of HT1080 fibrosarcoma cells towards a serum chemoattractant. CD155 was found to be highly expressed in multiple cancer cell lines and primary tumors including glioblastoma (GBM). Knockdown of CD155 also decreased migration of U87MG GBM cells. CD155 is recruited to the leading edge of migrating cells where it colocalizes with actin and αv-integrin, known mediators of motility and adhesion. Knockdown of CD155 also altered cellular morphology, resulting in cells that were larger and more elongated than controls when plated on a Matrigel substrate. These results implicate a role for CD155 in mediating tumor cell invasion and migration and suggest that CD155 may contribute to tumorigenesis

  15. Methylene blue modulates transendothelial migration of peripheral blood cells.

    Directory of Open Access Journals (Sweden)

    Isabella Werner

    Full Text Available Vasoplegia is a severe complication after cardiac surgery. Within the last years the administration of nitric oxide synthase inhibitor methylene blue (MB became a new therapeutic strategy. Our aim was to investigate the role of MB on transendothelial migration of circulating blood cells, the potential role of cyclic cGMP, eNOS and iNOS in this process, and the influence of MB on endothelial cell apoptosis. Human vascular endothelial cells (HuMEC-1 were treated for 30 minutes or 2 hours with different concentrations of MB. Inflammation was mimicked by LPS stimulation prior and after MB. Transmigration of PBMCs and T-Lymphocytes through the treated endothelial cells was investigated. The influence of MB upon the different subsets of PBMCs (Granulocytes, T- and B-Lymphocytes, and Monocytes was assessed after transmigration by means of flow-cytometry. The effect of MB on cell apoptosis was evaluated using Annexin-V and Propidium Iodide stainings. Analyses of the expression of cyclic cGMP, eNOS and iNOS were performed by means of RT-PCR and Western Blot. Results were analyzed using unpaired Students T-test. Analysis of endothelial cell apoptosis by MB indicated a dose-dependent increase of apoptotic cells. We observed time- and dose-dependent effects of MB on transendothelial migration of PBMCs. The prophylactic administration of MB led to an increase of transendothelial migration of PBMCs but not Jurkat cells. Furthermore, HuMEC-1 secretion of cGMP correlated with iNOS expression after MB administration but not with eNOS expression. Expression of these molecules was reduced after MB administration at protein level. This study clearly reveals that endothelial response to MB is dose- and especially time-dependent. MB shows different effects on circulating blood cell-subtypes, and modifies the release patterns of eNOS, iNOS, and cGMP. The transendothelial migration is modulated after treatment with MB. Furthermore, MB provokes apoptosis of endothelial

  16. Adhesion and migration of cells responding to microtopography.

    Science.gov (United States)

    Estévez, Maruxa; Martínez, Elena; Yarwood, Stephen J; Dalby, Matthew J; Samitier, Josep

    2015-05-01

    It is known that cells respond strongly to microtopography. However, cellular mechanisms of response are unclear. Here, we study wild-type fibroblasts responding to 25 µm(2) posts and compare their response to that of FAK(-/-) fibroblasts and fibroblasts with PMA treatment to stimulate protein kinase C (PKC) and the small g-protein Rac. FAK knockout cells modulated adhesion number and size in a similar way to cells on topography; that is, they used more, smaller adhesions, but migration was almost completely stalled demonstrating the importance of FAK signaling in contact guidance and adhesion turnover. Little similarity, however, was observed to PKC stimulated cells and cells on the topography. Interestingly, with PKC stimulation the cell nuclei became highly deformable bringing focus on these surfaces to the study of metastasis. Surfaces that aid the study of cellular migration are important in developing understanding of mechanisms of wound healing and repair in aligned tissues such as ligament and tendon. © 2014 Wiley Periodicals, Inc.

  17. Small cell neuroendocrine tumour of the endometrium and the importance of pathologic diagnosis.

    Science.gov (United States)

    Estruch, Adriana; Minig, Lucas; Illueca, Carmen; Romero, Ignacio; Guinot, Jose Luis; Poveda, Andrés

    2016-01-01

    Small cell carcinoma of the endometrium is a very rare entity. They are very aggressive tumours, with a poor prognosis. They represent a clinical challenge because of a lack of a standardised treatment. We see here a case of a 67-year-old woman with a history of a lobular breast carcinoma, diagnosed in 2002. After presenting with postmenopausal vaginal bleeding in October 2014, she underwent a hysteroscopy-guided biopsy which revealed a metastasis of breast carcinoma. A hysterectomy and bilateral oophorectomy was performed because of uncontrolled uterine bleeding. The pathologic diagnosis was small cell carcinoma (SCC) of the endometrium. A surgical complete cytoreduction was achieved after the case being presented in a multidisciplinary tumour board. Pathologic results revealed metastasis from peritoneal implants of SCC on the endometrium, and metastasis in pelvic and para-aortic lymph nodes from serous carcinoma of the endometrium. A total of four cycles of adjuvant chemotherapy based on cisplatin (80mg/m² day one) and etoposide (100mg/m² day one, two, three) every 21 days was given. The patient experienced persistent disease and died 17 months after the diagnosis. SCC of the endometrium is a very rare and aggressive disease that requires an individualised multidisciplinary management.

  18. Novel population of small tumour-initiating stem cells in the ovaries of women with borderline ovarian cancer

    Science.gov (United States)

    Virant-Klun, Irma; Stimpfel, Martin

    2016-01-01

    Small stem cells with diameters of up to 5 μm previously isolated from adult human ovaries indicated pluripotency and germinal lineage, especially primordial germ cells, and developed into primitive oocyte-like cells in vitro. Here, we show that a comparable population of small stem cells can be found in the ovarian tissue of women with borderline ovarian cancer, which, in contrast to small stem cells in “healthy” ovaries, formed spontaneous tumour-like structures and expressed some markers related to pluripotency and germinal lineage. The gene expression profile of these small putative cancer stem cells differed from similar cells sorted from “healthy” ovaries by 132 upregulated and 97 downregulated genes, including some important forkhead box and homeobox genes related to transcription regulation, developmental processes, embryogenesis, and ovarian cancer. These putative cancer stem cells are suggested to be a novel population of ovarian tumour-initiating cells in humans. PMID:27703207

  19. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Garrido Federico

    2008-03-01

    Full Text Available Abstract Background Protein-bound polysaccharide (PSK is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated. Methods The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells. Results PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation. Conclusion These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells.

  20. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

    International Nuclear Information System (INIS)

    Jiménez-Medina, Eva; Berruguilla, Enrique; Romero, Irene; Algarra, Ignacio; Collado, Antonia; Garrido, Federico; Garcia-Lora, Angel

    2008-01-01

    Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated. The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells. PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G 0 /G 1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation. These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells

  1. The role of meiotic cohesin REC8 in chromosome segregation in {gamma} irradiation-induced endopolyploid tumour cells

    Energy Technology Data Exchange (ETDEWEB)

    Erenpreisa, Jekaterina [Latvian Biomedicine Research and Study Centre, Riga, LV-1067 (Latvia); Cragg, Mark S. [Tenovus Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton SO16 6YD (United Kingdom); Salmina, Kristine [Latvian Biomedicine Research and Study Centre, Riga, LV-1067 (Latvia); Hausmann, Michael [Kirchhoff Inst. fuer Physik, Univ. of Heidelberg, D-69120 Heidelberg (Germany); Scherthan, Harry, E-mail: scherth@web.de [Inst. fuer Radiobiologie der Bundeswehr in Verbindung mit der Univ. Ulm, D-80937 Munich (Germany); MPI for Molec. Genetics, 14195 Berlin (Germany)

    2009-09-10

    Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a potential survival strategy of tumour cells in response to genotoxic treatments. ETCs that resume the mitotic cell cycle have reduced ploidy and are often resistant to these treatments. In search for a mechanism for genome reduction, we previously observed that ETCs express meiotic proteins among which REC8 (a meiotic cohesin component) is of particular interest, since it favours reductional cell division in meiosis. In the present investigation, we induced endopolyploidy in p53-dysfunctional human tumour cell lines (Namalwa, WI-L2-NS, HeLa) by gamma irradiation, and analysed the sub-cellular localisation of REC8 in the resulting ETCs. We observed by RT-PCR and Western blot that REC8 is constitutively expressed in these tumour cells, along with SGOL1 and SGOL2, and that REC8 becomes modified after irradiation. REC8 localised to paired sister centromeres in ETCs, the former co-segregating to opposite poles. Furthermore, REC8 localised to the centrosome of interphase ETCs and to the astral poles in anaphase cells where it colocalised with the microtubule-associated protein NuMA. Altogether, our observations indicate that radiation-induced ETCs express features of meiotic cell divisions and that these may facilitate chromosome segregation and genome reduction.

  2. Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation.

    Directory of Open Access Journals (Sweden)

    Lisa Y Pang

    Full Text Available Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs, which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05, and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation.

  3. Artemisinin-derived sesquiterpene lactones as potential antitumour compounds : Cytotoxic action against bone marrow and tumour cells

    NARCIS (Netherlands)

    Beekman, AC; Wierenga, PK; Woerdenbag, HJ; Van Uden, W; Pras, N; Konings, AWT; El-Feraly, FS; Galal, AM; Wikstrom, HV

    1998-01-01

    We determined the in vitro cytotoxic activity of the sesquiterpene lactone endoperoxide artemisinin (1) and some chemically prepared derivatives, which have been found to display cytotoxicity to cloned murine Ehrlich ascites tumour (EAT) cells and human HeLa cells and against murine bone marrow

  4. Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks.

    Science.gov (United States)

    Carey, Shawn P; Rahman, Aniqua; Kraning-Rush, Casey M; Romero, Bethsabe; Somasegar, Sahana; Torre, Olivia M; Williams, Rebecca M; Reinhart-King, Cynthia A

    2015-03-15

    Tumor cell invasion through the stromal extracellular matrix (ECM) is a key feature of cancer metastasis, and understanding the cellular mechanisms of invasive migration is critical to the development of effective diagnostic and therapeutic strategies. Since cancer cell migration is highly adaptable to physiochemical properties of the ECM, it is critical to define these migration mechanisms in a context-specific manner. Although extensive work has characterized cancer cell migration in two- and three-dimensional (3D) matrix environments, the migration program employed by cells to move through native and cell-derived microtracks within the stromal ECM remains unclear. We previously reported the development of an in vitro model of patterned type I collagen microtracks that enable matrix metalloproteinase-independent microtrack migration. Here we show that collagen microtracks closely resemble channel-like gaps in native mammary stroma ECM and examine the extracellular and intracellular mechanisms underlying microtrack migration. Cell-matrix mechanocoupling, while critical for migration through 3D matrix, is not necessary for microtrack migration. Instead, cytoskeletal dynamics, including actin polymerization, cortical tension, and microtubule turnover, enable persistent, polarized migration through physiological microtracks. These results indicate that tumor cells employ context-specific mechanisms to migrate and suggest that selective targeting of cytoskeletal dynamics, but not adhesion, proteolysis, or cell traction forces, may effectively inhibit cancer cell migration through preformed matrix microtracks within the tumor stroma. Copyright © 2015 the American Physiological Society.

  5. Tumour Cell Membrane Poration and Ablation by Pulsed Low-Intensity Electric Field with Carbon Nanotubes

    Directory of Open Access Journals (Sweden)

    Lijun Wang

    2015-03-01

    Full Text Available Electroporation is a physical method to increase permeabilization of cell membrane by electrical pulses. Carbon nanotubes (CNTs can potentially act like “lighting rods” or exhibit direct physical force on cell membrane under alternating electromagnetic fields thus reducing the required field strength. A cell poration/ablation system was built for exploring these effects of CNTs in which two-electrode sets were constructed and two perpendicular electric fields could be generated sequentially. By applying this system to breast cancer cells in the presence of multi-walled CNTs (MWCNTs, the effective pulse amplitude was reduced to 50 V/cm (main field/15 V/cm (alignment field at the optimized pulse frequency (5 Hz of 500 pulses. Under these conditions instant cell membrane permeabilization was increased to 38.62%, 2.77-fold higher than that without CNTs. Moreover, we also observed irreversible electroporation occurred under these conditions, such that only 39.23% of the cells were viable 24 h post treatment, in contrast to 87.01% cell viability without presence of CNTs. These results indicate that CNT-enhanced electroporation has the potential for tumour cell ablation by significantly lower electric fields than that in conventional electroporation therapy thus avoiding potential risks associated with the use of high intensity electric pulses.

  6. Hyper-IL-15 suppresses metastatic and autochthonous liver cancer by promoting tumour-specific CD8+ T cell responses.

    Science.gov (United States)

    Cheng, Liang; Du, Xuexiang; Wang, Zheng; Ju, Jianqi; Jia, Mingming; Huang, Qibin; Xing, Qiao; Xu, Meng; Tan, Yi; Liu, Mingyue; Du, Peishuang; Su, Lishan; Wang, Shengdian

    2014-12-01

    Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor α chain, on metastatic and autochthonous liver cancers. Liver metastatic tumour models were established by intraportally injecting syngeneic mice with murine CT26 colon carcinoma cells or B16-OVA melanoma cells. Primary hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DEN). A hydrodynamics-based gene delivery method was used to achieve sustained hyper-IL-15 expression in the liver. Liver gene delivery of hyper-IL-15 robustly expanded CD8(+) T and NK cells, leading to a long-term (more than 40 days) accumulation of CD8(+) T cells in vivo, especially in the liver. Hyper-IL-15 treatment exerted remarkable therapeutic effects on well-established liver metastatic tumours and even on DEN-induced autochthonous HCC, and these effects were abolished by depletion of CD8(+) T cells but not NK cells. Hyper-IL-15 triggered IL-12 and interferon-γ production and reduced the expression of co-inhibitory molecules on dendritic cells in the liver. Adoptive transfer of T cell receptor (TCR) transgenic OT-1 cells showed that hyper-IL-15 preferentially expanded tumour-specific CD8(+) T cells and promoted their interferon-γ synthesis and cytotoxicity. Liver delivery of hyper-IL-15 provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by preferentially expanding tumour-specific CD8(+) T cells and promoting their anti-tumour effects. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  7. Frequent loss of Fas expression and function in human lung tumours with overexpression of FasL in small cell lung carcinoma.

    Science.gov (United States)

    Viard-Leveugle, Isabelle; Veyrenc, Sylvie; French, Lars E; Brambilla, Christian; Brambilla, Elisabeth

    2003-10-01

    Fas (CD95) and its ligand FasL signal apoptosis and are involved in tissue homeostasis and the elimination of target cells by cytotoxic T cells. Corruption of this signalling pathway in tumour cells, for example by reduced Fas expression or increased FasL expression, can participate in tumour development and immune escape. The present study has analysed Fas/FasL expression and Fas death signalling function in vivo in lung tumour tissues [57 non-small cell lung carcinomas and 64 neuroendocrine lung tumours including small cell lung carcinoma (SCLC)] in comparison with normal lung tissue, and in vitro in neuroendocrine tumour cell lines in comparison with normal human bronchial epithelial cells. The Fas expression score was markedly decreased compared with normal lung tissue in 90% of the 121 lung tumours and was completely lost in 24%. The Fas staining pattern suggested cytoplasmic Fas expression in tumours, whereas membrane expression was observed in normal lung tissue. Loss of Fas at the cell surface was also shown in vitro by FACS analysis of neuroendocrine tumour cell lines and was concomitant with the resistance of tumour cells to FasL-mediated apoptosis according to in vitro cell viability. The lack of cell surface Fas expression in tumour cell lines resulted from the lack of intracellular Fas protein due to impaired Fas gene transcription. The FasL expression score was also decreased in most non-small cell lung carcinomas compared with normal bronchial cells, whereas 91% of SCLCs had higher expression than normal cells. FasL overexpression was related to advanced tumour stage as well as to a Fas/FasL ratio less than 1. It is concluded that a marked decrease in Fas expression may be part of lung tumourigenesis allowing tumour cells to escape from apoptosis. FasL overexpression in the context of Fas down-regulation in SCLC predicts the ability of SCLC cells to induce paracrine killing of Fas-expressing cytotoxic T cells. In lung tumours, Fas restoration may

  8. Co-culture with Sertoli cells promotes proliferation and migration of umbilical cord mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Fenxi, E-mail: fxzhang0824@gmail.com [Department of Anatomy, Sanquan College, Xinxiang Medical University, Henan 453003, People' s Republic of China (China); Hong, Yan; Liang, Wenmei [Department of Histology and Embryology, Guiyang Medical University, Guizhou 550004, People' s Republic of China (China); Ren, Tongming [Department of Anatomy, Sanquan College, Xinxiang Medical University, Henan 453003, People' s Republic of China (China); Jing, Suhua [ICU Center, The Third Hospital of Xinxiang Medical University, Henan 453003, People' s Republic of China (China); Lin, Juntang [Stem Cell Center, Xinxiang Medical University, Henan 453003, People' s Republic of China (China)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer Co-culture of Sertoli cells (SCs) with human umbilical cord mesenchymal stem cells (UCMSCs). Black-Right-Pointing-Pointer Presence of SCs dramatically increased proliferation and migration of UCMSCs. Black-Right-Pointing-Pointer Presence of SCs stimulated expression of Mdm2, Akt, CDC2, Cyclin D, CXCR4, MAPKs. -- Abstract: Human umbilical cord mesenchymal stem cells (hUCMSCs) have been recently used in transplant therapy. The proliferation and migration of MSCs are the determinants of the efficiency of MSC transplant therapy. Sertoli cells are a kind of 'nurse' cells that support the development of sperm cells. Recent studies show that Sertoli cells promote proliferation of endothelial cells and neural stem cells in co-culture. We hypothesized that co-culture of UCMSCs with Sertoli cells may also promote proliferation and migration of UCMSCs. To examine this hypothesis, we isolated UCMSCs from human cords and Sertoli cells from mouse testes, and co-cultured them using a Transwell system. We found that UCMSCs exhibited strong proliferation ability and potential to differentiate to other cell lineages such as osteocytes and adipocytes. The presence of Sertoli cells in co-culture significantly enhanced the proliferation and migration potential of UCMSCs (P < 0.01). Moreover, these phenotypic changes were accompanied with upregulation of multiple genes involved in cell proliferation and migration including phospho-Akt, Mdm2, phospho-CDC2, Cyclin D1, Cyclin D3 as well as CXCR4, phospho-p44 MAPK and phospho-p38 MAPK. These findings indicate that Sertoli cells boost UCMSC proliferation and migration potential.

  9. Co-culture with Sertoli cells promotes proliferation and migration of umbilical cord mesenchymal stem cells

    International Nuclear Information System (INIS)

    Zhang, Fenxi; Hong, Yan; Liang, Wenmei; Ren, Tongming; Jing, Suhua; Lin, Juntang

    2012-01-01

    Highlights: ► Co-culture of Sertoli cells (SCs) with human umbilical cord mesenchymal stem cells (UCMSCs). ► Presence of SCs dramatically increased proliferation and migration of UCMSCs. ► Presence of SCs stimulated expression of Mdm2, Akt, CDC2, Cyclin D, CXCR4, MAPKs. -- Abstract: Human umbilical cord mesenchymal stem cells (hUCMSCs) have been recently used in transplant therapy. The proliferation and migration of MSCs are the determinants of the efficiency of MSC transplant therapy. Sertoli cells are a kind of “nurse” cells that support the development of sperm cells. Recent studies show that Sertoli cells promote proliferation of endothelial cells and neural stem cells in co-culture. We hypothesized that co-culture of UCMSCs with Sertoli cells may also promote proliferation and migration of UCMSCs. To examine this hypothesis, we isolated UCMSCs from human cords and Sertoli cells from mouse testes, and co-cultured them using a Transwell system. We found that UCMSCs exhibited strong proliferation ability and potential to differentiate to other cell lineages such as osteocytes and adipocytes. The presence of Sertoli cells in co-culture significantly enhanced the proliferation and migration potential of UCMSCs (P < 0.01). Moreover, these phenotypic changes were accompanied with upregulation of multiple genes involved in cell proliferation and migration including phospho-Akt, Mdm2, phospho-CDC2, Cyclin D1, Cyclin D3 as well as CXCR4, phospho-p44 MAPK and phospho-p38 MAPK. These findings indicate that Sertoli cells boost UCMSC proliferation and migration potential.

  10. Giant-cell tumour of proximal radius in a 50-year-old female with wrist drop: a rare case report

    OpenAIRE

    Anshul Dahuja; Rashmeet Kaur; Shiraz Bhatty; Simmi Garg; Kapil Bansal; Mandeep Singh

    2017-01-01

    Abstract Giant-cell tumour is a locally aggressive tumour of long bones of epiphyseal region commonly occurring in adults aged 20–40 years. Most common location is distal femur, proximal tibia, and distal radius. Different treatment options being used are curettage with bone graft or bone cement, resection with arthrodesis, reconstruction, radiation, and chemotherapy. We are reporting a case of giant-cell tumour of right proximal radius in a 50-year-old female with posterior interosseous nerv...

  11. Laryngeal giant cell tumour presenting as a tongue base lesion causing severe dysphagia

    Directory of Open Access Journals (Sweden)

    Mohd Razi M. Saud, MBBS

    2018-04-01

    Full Text Available الملخص: أورام الخلايا العملاقة هي آفات حميدة وغير مألوفة تظهر في الحنجرة. قد يصاب المريض بصعوبة في البلع، وبحة في الصوت وتورم في الجهة الأمامية من الرقبة. أورام الخلايا العملاقة هي نادرة للغاية، وهناك حالات قليلة في الأدبيات المنشورة. نعرض لحالة إمرأة مسنة قدمت بصعوبة شديدة في البلع، وورم في قاعدة اللسان. أظهرت نتيجة الورم بأنه ورم الخلايا العملاقة في الحنجرة وتم علاجه بنجاح باستخدام المعالجة الكيميائية. Abstract: Giant cell tumours are benign lesions that are uncommonly found in the larynx. Patients with these tumours may present with dysphagia, hoarseness and anterior neck swelling. Giant cell tumours are extremely rare and only a few cases have been reported. We present a case of an elderly woman who presented with severe dysphagia and a mass at the base of her tongue. The mass was found to be a laryngeal giant cell tumour and was successfully treated with chemotherapy. الكلمات المفتاحية: أورام الخلايا العملاقة, الحنجرة, صعوبة البلع, دينوسوماب, المعالجة الكيميائية, Keywords: Chemotherapy, Denosumab, Dysphagia, Giant cell tumour, Larynx

  12. Cytomorphological Diagnosis of Giant Cell Tumour of Distal End Radius in Elderly Patient

    Directory of Open Access Journals (Sweden)

    Priya Bagale

    2013-11-01

    Full Text Available Giant cell tumours (GCTs of bone have been described as the most challenging benign bone tumors. It is very unusual for GCT to occur in patients younger than 20 yrs or older than 55 years. GCT is seen with a slightly increased frequency in females. The typical giant cell tumor (GCT is a solitary neoplasm that occurs in the epiphysis or metaphysis of long bones. The most common sites include the distal femur, proximal tibia and distal radius. The sacrum, distal tibia, proximal humerus, proximal femur, pelvis and proximal fibula are not infrequent sites. Here we report cytologically diagnosed case of GCT distal end radius in 75 yrs male patient. We discuss its clinicopathologic features, differential diagnosis and its optimal treatment.

  13. Endoprosthetic Reconstruction of distal Humerus following Resection of distal Humeral Giant Cell Tumours in Six Patients in Rural India

    Directory of Open Access Journals (Sweden)

    Balasubramanian N

    2017-07-01

    Full Text Available Giant cell tumour is a commonly occurring benign bone tumour in the Indian population. The common sites of involvement in descending order of frequency are distal femur, proximal tibia, distal radius and proximal humerus. The less commonly occurring sites are distal humerus, pelvis and proximal femur. We present six cases of giant cell tumour involving the distal humerus in rural India. After obtaining a tissue diagnosis by Trucut biopsy and classifying using Enneking's classification, we proceeded to perform wide resection followed by endoprosthetic reconstruction using custom mega prosthesis. We present here six patients (M: F: 2: 4 who were managed by us between 2008-2014. They presented to us with pain around the elbow and restriction in range of movements. They were each noted radiographically to have a lytic lesion involving the distal humerus with the likely diagnosis of giant cell tumour. Closed biopsy was done in all of them to obtain a definitive diagnosis. All patients underwent wide resection and reconstruction using distal humerus custom prosthesis. All patients were followed up at 6, 12, 18 and 24 weeks and thereafter six monthly until the last review. They were assessed using the DASH scoring system. All patients were well with no evidence of recurrence with good to fair functional outcome. We conclude that careful pre-operative planning with meticulous soft tissue dissection and good implant metallurgy and design, these tumours can be treated with good long term functional results.

  14. Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment.

    Science.gov (United States)

    Wu, Amy; Liao, David; Tlsty, Thea D; Sturm, James C; Austin, Robert H

    2014-08-06

    Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apoptosis of cancer cells. On the other hand, competition among cancer and ST cells for space or resources should not be ignored. We explore the population dynamics of multiple myeloma (MM) versus bone marrow ST cells by using an experimental microecology that we call the death galaxy, with a stable drug gradient and connected microhabitats. Evolutionary game theory is a quantitative way to capture the frequency-dependent nature of interactive populations. Therefore, we use evolutionary game theory to model the populations in the death galaxy with the gradients of pay-offs and successfully predict the future densities of MM and ST cells. We discuss the possible clinical use of such analysis for predicting cancer progression.

  15. Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.

    LENUS (Irish Health Repository)

    Anoopkumar-Dukie, S

    2009-10-01

    Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax\\/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.

  16. TCDD induces cell migration via NFATc1/ATX-signaling in MCF-7 cells.

    Science.gov (United States)

    Seifert, Anja; Rau, Steffi; Küllertz, Gerhard; Fischer, Bernd; Santos, Anne Navarrete

    2009-01-10

    Breast cancer is characterized, among others, by the concurrence of lipophilic xenobiotica such as 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) with hypoxic tissue conditions. This condition activates the transcription factors hypoxia inducible factor-1alpha (HIF-1alpha) and aryl hydrocarbon receptor (AhR) that are known to promote tumor progression. An interrelation between these transcription factors and nuclear factor of activated T-cells (NFAT) was implied by gene array analysis. In the present study, the interplay of the three transcription factors was studied and correlated with the migration of MCF-7 cells in response to TCDD and/or hypoxia. An AhR-activation by 10nM TCDD and HIF-1alpha activation by 5% oxygen induced activation of NFATc1. The effects were inhibited by cyclosporine A (CsA), suggesting that the activation of NFAT by AhR or HIF-1alpha signaling is calcineurin-dependent. The expression/activity of the NFAT target gene autotaxin (ATX) was increased. ATX is known to stimulate migration of tumor cells. The hydrolysis product of ATX, lysophosphatidic acid (LPA), increased the migration of MCF-7 cells under normoxia but not under hypoxia. This effect correlated with increased migration observed after TCDD treatment. Hypoxia did not promote migration of MCF-7 cells, suggesting that ATX down-stream signaling was inhibited by hypoxia. In conclusion, the TCDD-mediated activation of NFATc1 is suggested to promote cell migration via ATX/LPA-signaling.

  17. Mismatch in mechanical and adhesive properties induces pulsating cancer cell migration in epithelial monolayer.

    Science.gov (United States)

    Lee, Meng-Horng; Wu, Pei-Hsun; Staunton, Jack Rory; Ros, Robert; Longmore, Gregory D; Wirtz, Denis

    2012-06-20

    The mechanical and adhesive properties of cancer cells significantly change during tumor progression. Here we assess the functional consequences of mismatched stiffness and adhesive properties between neighboring normal cells on cancer cell migration in an epithelial-like cell monolayer. Using an in vitro coculture system and live-cell imaging, we find that the speed of single, mechanically soft breast carcinoma cells is dramatically enhanced by surrounding stiff nontransformed cells compared with single cells or a monolayer of carcinoma cells. Soft tumor cells undergo a mode of pulsating migration that is distinct from conventional mesenchymal and amoeboid migration, whereby long-lived episodes of slow, random migration are interlaced with short-lived episodes of extremely fast, directed migration, whereas the surrounding stiff cells show little net migration. This bursty migration is induced by the intermittent, myosin II-mediated deformation of the soft nucleus of the cancer cell, which is induced by the transient crowding of the stiff nuclei of the surrounding nontransformed cells, whose movements depend directly on the cadherin-mediated mismatched adhesion between normal and cancer cells as well as α-catenin-based intercellular adhesion of the normal cells. These results suggest that a mechanical and adhesive mismatch between transformed and nontransformed cells in a cell monolayer can trigger enhanced pulsating migration. These results shed light on the role of stiff epithelial cells that neighbor individual cancer cells in early steps of cancer dissemination. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  18. Basal Cell Carcinoma Surgery: Simple Undermining Approach in Two Patients with Different Tumour Locations

    Directory of Open Access Journals (Sweden)

    Georgi Tchernev

    2017-07-01

    Full Text Available Basal cell carcinoma (BCC is the most common human malignancy, accounting for the majority of all non-melanoma skin cancers (NMSC. In the past several decades the worldwide incidence of BCC has constantly been increasing. Even though it is a slow growing tumour that, left untreated, rarely metastasizes, it has a distinctive invasive growth pattern, posing a considerable risk for local invasion and destruction of underlying tissues, such as muscle, cartilage, bone or vital structures. Advanced BCCs include such locally invasive or metastatic tumours. Complete surgical excision is the standard therapy for most uncomplicated BCC cases with good prognosis and cure rates. Treatment of advanced forms of BCCs poses significant therapeutic challenges, most often requiring complicated surgery, radiotherapy, and/or targeted therapies directed towards the sonic hedgehog signalling pathway (SHH. We present two cases of large BCCs located on the scalp and posterior thorax, which underwent surgical excision with clear margins, followed by reconstruction of the defect after extensive undermining of the skin.

  19. Prevalence and risk factors for mast cell tumours in dogs in England.

    Science.gov (United States)

    Shoop, Stephanie Jw; Marlow, Stephanie; Church, David B; English, Kate; McGreevy, Paul D; Stell, Anneliese J; Thomson, Peter C; O'Neill, Dan G; Brodbelt, David C

    2015-01-01

    Mast cell tumour (MCT) appears to be a frequent tumour type in dogs, though there is little published in relation to its frequency in dogs in the UK. The current study aimed to investigate prevalence and risk factors for MCTs in dogs attending English primary-care veterinary practices. Electronic patient records from practices participating in the VetCompass animal surveillance project between July 2007 and June 2013 were searched for MCT diagnosis. Various search terms and standard diagnostic terms (VeNom codes) identified records containing MCT diagnoses, which were evaluated against clinical criteria for inclusion to the study. MCT prevalence for the entire dataset and specific breed types were calculated. Descriptive statistics characterised MCT cases and multivariable logistic regression methods evaluated risk factors for association with MCT (P Border Collie, West Highland White Terrier, Springer Spaniel and Cocker Spaniel had reduced odds of MCT diagnosis compared with crossbred dogs. No association was found between MCT diagnosis and sex. This study highlights a clinically significant prevalence of MCT and identifies specific breed types with predisposition to MCT, potentially aiding veterinarian awareness and facilitating diagnosis.

  20. The migrations of Drosophila muscle founders and primordial germ cells are interdependent.

    Science.gov (United States)

    Stepanik, Vincent; Dunipace, Leslie; Bae, Young-Kyung; Macabenta, Frank; Sun, Jingjing; Trisnadi, Nathanie; Stathopoulos, Angelike

    2016-09-01

    Caudal visceral mesoderm (CVM) cells migrate from posterior to anterior of the Drosophila embryo as two bilateral streams of cells to support the specification of longitudinal muscles along the midgut. To accomplish this long-distance migration, CVM cells receive input from their environment, but little is known about how this collective cell migration is regulated. In a screen we found that wunen mutants exhibit CVM cell migration defects. Wunens are lipid phosphate phosphatases known to regulate the directional migration of primordial germ cells (PGCs). PGC and CVM cell types interact while PGCs are en route to the somatic gonadal mesoderm, and previous studies have shown that CVM impacts PGC migration. In turn, we found here that CVM cells exhibit an affinity for PGCs, localizing to the position of PGCs whether mislocalized or trapped in the endoderm. In the absence of PGCs, CVM cells exhibit subtle changes, including more cohesive movement of the migrating collective, and an increased number of longitudinal muscles is found at anterior sections of the larval midgut. These data demonstrate that PGC and CVM cell migrations are interdependent and suggest that distinct migrating cell types can coordinately influence each other to promote effective cell migration during development. © 2016. Published by The Company of Biologists Ltd.

  1. Immunotherapeutic efficacy of vaccines generated by fusion of dendritic cells and HPV16-associated tumour cells

    Czech Academy of Sciences Publication Activity Database

    Šímová, Jana; Bubeník, Jan; Bieblová, Jana; Indrová, Marie; Jandlová, Táňa

    2005-01-01

    Roč. 51, č. 1 (2005), s. 19-24 ISSN 0015-5500 R&D Projects: GA AV ČR(CZ) IAA5052203; GA ČR(CZ) GA301/04/0492 Grant - others:Liga proti rakovině, Praha(CZ) - Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV16 * DC-tumour hybrids * immunotherapy Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.719, year: 2005

  2. Selective toxicity of a quinoxaline 1,4-di-N-oxide derivative in human tumour cell lines.

    Science.gov (United States)

    Amaia, Azquetaa; Pachón, Gisela; Cascante, Marta; Creppy, Edmond E; Monge, Antonio; López de Cerain, Adela

    2005-01-01

    The presence of hypoxic cells in human solid tumours is one of the causes of tumour resistance to conventional therapy, and is also associated with processes that promote the tumour progression. Different chemical agents have been designed in order to take advantage of the particular metabolic characteristics of hypoxic regions. These drugs, called bioreductive agents, are activated inside the hypoxic cells to give active species that, in the presence of oxygen, are oxidised back to the non-toxic parent compound. Several quinoxaline 1,4-di-N-oxides have been described as potential bioreductive agents, and among them, 7-cloro-3-[[(N,N-dimethylamino)propy]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxide hydrocloride (Q-85 HCl) appeared to be the most promising one. In the present work, the selective cytotoxicity of Q-85 HCl was studied in several human tumour cell lines of different origin (Caco2, MCF-7, HT-29 and Tk-10). Cell viability was calculated after 2 h treatment under hypoxic and well-oxygenated conditions. The potency (the concentration that gives 1% of cell survival) in hypoxia and hypoxia cytotoxicity ratio (HCR = potency in oxygenated conditions/potency in hypoxia) were calculated after a 14-day clonogenic assay. Q-85 HCl was more toxic in hypoxia than in well-oxygenated cells in all the tumour cell lines. The best profile of potency in hypoxia (0.4 micromol/L) and selectivity (HCR=155) was found in CaCo-2 cells. Altogether, these results suggest an in vitro biological profile for Q-85 HCl that makes it an interesting candidate for the development as a bioreductive agent.

  3. Simultaneous immunisation with a Wilms' tumour 1 epitope and its ubiquitin fusions results in enhanced cell mediated immunity and tumour rejection in C57BL/6 mice.

    Science.gov (United States)

    Eslami, Nasir Saeedi; Shokrgozar, Mohammad Ali; Mousavi, Asadollah; Azadmanesh, Kayhan; Nomani, Alireza; Apostolopoulos, Vasso; Day, Stephanie; Amanzadeh, Amir; Alimohammadian, Mohammad Hossein

    2012-07-01

    Protein fusion to ubiquitin results in its targeting to proteasome and processing through MHC class I pathway. We used this approach to induce cytotoxic T lymphocyte (CTL) response against a MHC class I epitope. Therefore, two known proteasome targeting systems, "ubiquitin fusion degradation" (UFD) and "N-end rule", were used to immunise C57BL/6 mice. Two plasmids encoding an epitope from Wilms' Tumour 1 (WT1-126), fused N-terminally to ubiquitin, were constructed. They were designated as "pUbVVPT" and "pUbGRPT", targeting the fused epitope to UFD and N-end pathways, respectively. A plasmid encoding WT1-126 without ubiquitin fusion (pPT) was also constructed as control. Three mice groups were immunised using these constructs (UGR, UVV and PT groups). Two other groups received mixed immunisations of pUbVVPT or pUbGRPT plus pPT plasmids (UVV+PT and UGR+PT). All mice received a WT1-126 peptide booster. Lymphoproliferative responses following stimulation with WT1-126 were observed in all immunisation groups, with mice receiving the mixture of plasmids eliciting the highest proliferation (UVV+PT>UGR+PT>PT). Moreover, In vivo cytotoxicity assay results revealed highest specific lysis of target cells in UVV+PT group. Tumour growth was decreased in all immunised groups, and was completely abrogated in UGR+PT group. In addition, T(H)1 type cytokines patterns were detected from all immunised groups and WT1-126-specific IFNγ producing lymphocytes were developed in them. These results suggest that the delivery of ubiquitin-fused epitopes along with epitopes alone can be used to optimise the effect of DNA vaccines on the induction of anti-tumour immunity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Tre1, a G protein-coupled receptor, directs transepithelial migration of Drosophila germ cells.

    Directory of Open Access Journals (Sweden)

    Prabhat S Kunwar

    2003-12-01

    Full Text Available In most organisms, germ cells are formed distant from the somatic part of the gonad and thus have to migrate along and through a variety of tissues to reach the gonad. Transepithelial migration through the posterior midgut (PMG is the first active step during Drosophila germ cell migration. Here we report the identification of a novel G protein-coupled receptor (GPCR, Tre1, that is essential for this migration step. Maternal tre1 RNA is localized to germ cells, and tre1 is required cell autonomously in germ cells. In tre1 mutant embryos, most germ cells do not exit the PMG. The few germ cells that do leave the midgut early migrate normally to the gonad, suggesting that this gene is specifically required for transepithelial migration and that mutant germ cells are still able to recognize other guidance cues. Additionally, inhibiting small Rho GTPases in germ cells affects transepithelial migration, suggesting that Tre1 signals through Rho1. We propose that Tre1 acts in a manner similar to chemokine receptors required during transepithelial migration of leukocytes, implying an evolutionarily conserved mechanism of transepithelial migration. Recently, the chemokine receptor CXCR4 was shown to direct migration in vertebrate germ cells. Thus, germ cells may more generally use GPCR signaling to navigate the embryo toward their target.

  5. Prognostic implications of occult nodal tumour cells in stage I and II colon cancer: The correlation between micrometastasis and disease recurrence

    NARCIS (Netherlands)

    Sloothaak, D. A. M.; van der Linden, R. L. A.; van de Velde, C. J. H.; Bemelman, W. A.; Lips, D. J.; van der Linden, J. C.; Doornewaard, H.; Tanis, P. J.; Bosscha, K.; van der Zaag, E. S.; Buskens, C. J.

    2017-01-01

    Occult nodal tumour cells should be categorised as micrometastasis (MMs) and isolated tumour cells (ITCs). A recent meta-analysis demonstrated that MMs, but not ITCs, are prognostic for disease recurrence in patients with stage I/II colon cancer. The objective of this retrospective multicenter study

  6. Prevalence of human papillomavirus (HPV in oesophageal squamous cell carcinoma in relation to anatomical site of the tumour.

    Directory of Open Access Journals (Sweden)

    Hedvig E Löfdahl

    Full Text Available BACKGROUND: The prevalence and role of human papillomavirus (HPV in the aetiology of oesophageal squamous cell carcinoma is uncertain. Based on the presence of HPV in the oral cavity and its causal association with squamous cell carcinoma of the oropharynx, we hypothesised that HPV is more strongly associated with proximal than distal oesophageal squamous cell carcinoma. METHODS: A population-based study comparing HPV infection in relation to tumour site in patients diagnosed with oesophageal squamous cell carcinomas in the Stockholm County in 1999-2006. Multiplex polymerase chain reaction genotyping (PCR with Luminex was conducted on pre-treatment endoscopic biopsies to identify type specify HPV. Carcinogenic activity of HPV was assessed by p16(INK4a expression. Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Among 204 patients, 20 (10% had tumours harbouring HPV DNA, almost all (90% of HPV high-risk type, mainly HPV16. Tumours containing HPV were not overrepresented in the upper compared to the middle or lower third of the oesophagus (odds ratio 0.6, 95% confidence interval 0.2-1.9. P16(INK4a expression was similarly common (24% and 16% in the HPV-positive and HPV-negative groups. CONCLUSION: This study found a limited presence of HPV in oesophageal squamous cell carcinoma of uncertain oncogenic relevance and did not demonstrate that HPV was more strongly associated with proximal than distal tumours.

  7. Silencing of semaphorin 3C suppresses cell proliferation and migration in MCF-7 breast cancer cells.

    Science.gov (United States)

    Zhu, Xiaofang; Zhang, Xiangjian; Ye, Zhiqiang; Chen, Yizuo; Lv, Lin; Zhang, Xiaohua; Hu, Hongye

    2017-11-01

    Previous studies have suggested that semaphorin 3C (SEMA3C) is involved in the tumorigenesis and metastasis of a number of types of cancer. The aim of the present study was to investigate the role of SEMA3C in the proliferation and migration of MCF-7 breast cancer cells. Small interfering (si)RNA sequences targeting SEMA3C were constructed and transfected into MCF-7 cells in order to silence the expression of SEMA3C. Cell proliferation and migration were measured using CCK-8 and Transwell assays, respectively. Transfection with SEMA3C siRNA significantly downregulated the expression of SEMA3C in MCF-7 cells, and significantly suppressed cell proliferation and migration. Therefore, SEMA3C-targeted siRNA may be of potential use for the early diagnosis and treatment of breast cancer.

  8. Granular cell tumour of the neurohypophysis: an unusual cause of hypopituitarism

    Directory of Open Access Journals (Sweden)

    Carlos Tavares Bello

    2018-04-01

    Full Text Available Granular cell tumours (GCT are rare, slow-growing, benign neoplasms that are usually located in the head and neck. They are more frequent in the female gender and typically have an asymptomatic clinical course, being diagnosed only at autopsy. Symptomatic GCT of the neurohypophysis are exceedingly rare, being less than 70 cases described so far. The authors report on a case of a 28-year-old male that presented to the Endocrinology clinic with clinical and biochemical evidence of hypogonadism. He also reported minor headaches without any major visual symptoms. Further laboratory tests confirmed hypopituitarism (hypogonadotrophic hypogonadism, central hypothyroidism and hypocortisolism and central nervous system imaging revealed a pituitary macroadenoma. The patient underwent transcranial pituitary adenoma resection and the pathology report described a GCT of the neurohypophysis with low mitotic index. The reported case is noteworthy for the rarity of the clinicopathological entity.

  9. A Rare Case of Metastatic Desmoplastic Small Round Cell Tumour: Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Shahzaib Nabi

    2015-01-01

    Full Text Available A 26-year-old male without any significant past medical history presented to the hospital with shortness of breath, cough, pleuritic chest pain, and weight loss for the past 3 months. On chest CT, he was found to have extensive mediastinal and hilar lymphadenopathy and multiple pulmonary nodules. On physical examination, a right groin mass was noted which had been slowly growing for the past 2 years. Ultrasound of the groin showed complex solid mass with internal vascular channels. CT guided biopsy of the mass showed desmoplastic small round cell tumour. His hospital course was complicated by hypoxic respiratory failure requiring emergent intubation and ICU admission where he completed one cycle of vincristine, cyclophosphamide, and doxorubicin with subsequent improvement, followed by extubation. His condition continued to improve after second cycle of chemotherapy and he was ultimately discharged in a stable condition to continue outpatient chemotherapy after a 2-month inpatient stay.

  10. Walker 256 tumour cells increase substance P immunoreactivity locally and modify the properties of the blood-brain barrier during extravasation and brain invasion.

    Science.gov (United States)

    Lewis, Kate M; Harford-Wright, Elizabeth; Vink, Robert; Nimmo, Alan J; Ghabriel, Mounir N

    2013-01-01

    It is not yet known how tumour cells traverse the blood-brain barrier (BBB) to form brain metastases. Substance P (SP) release is a key component of neurogenic inflammation which has been recently shown to increase the permeability of the BBB following CNS insults, making it a possible candidate as a mediator of tumour cell extravasation into the brain. This study investigated the properties of the BBB in the early stages of tumour cell invasion into the brain, and the possible involvement of SP. Male Wistar rats were injected with Walker 256 breast carcinoma cells via the internal carotid artery and euthanised at 1, 3, 6 and 9 days post tumour inoculation. Culture medium-injected animals served as controls at 1 and 9 days. Evidence of tumour cell extravasation across the BBB was first observed at 3 days post-inoculation, which corresponded with significantly increased albumin (p p p p < 0.001). The increased SP immunoreactivity and altered BBB properties at 3 days post-inoculation that coincided with early tumour invasion may be indicative of a mechanism for tumour cell extravasation into the brain. Thus, extravasation of tumour cells into the brain to form cerebral metastases may be a SP-mediated process.

  11. Basics elements for modelling the dynamics of cell migration in cell culture

    International Nuclear Information System (INIS)

    FarIas, Ro; Vidal, Cs; Rapacioli, M; Flores, V

    2007-01-01

    This paper introduces some basic elements for modelling the dynamics of cell migration activity over a bi-dimensional substratum. A square matrix, representing the substratum, is implemented in order to generate virtual cells with an initial random uniform distribution, with the ability to freely move within the matrix and to interact with each others by mean of adhesive forces. Two different conditions were examined: A) cells can freely move and after contacting with another cell they both completely inhibit their migration; B) cells that come into contact have the ability to rotate respect to each other without losing their contacts and retaining the ability to move together but at a slower rate, being the decrease in the rate of movement proportional to the number of contacting cells. The dynamics of the migration process in these two conditions was evaluated by recording the evolution of several parameters as a function of time. Minor modifications in some parameters (mobility, intensity of cell-cell and cell-substratum adhesiveness) significantly change the dynamics and the final result of the virtual migrating cells

  12. Stromal Cell-Derived Factor-1 Promotes Cell Migration, Tumor Growth of Colorectal Metastasis

    Directory of Open Access Journals (Sweden)

    Otto Kollmar

    2007-10-01

    Full Text Available In a mouse model of established extrahepatic colorectal metastasis, we analyzed whether stromal cellderived factor (SDF 1 stimulates tumor cell migration in vitro, angiogenesis, tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis, tumor growth in vivo, green fluorescent protein-transfected CT26.WT cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, tumors were locally exposed to SDF-1. Cell proliferation, tumor microvascularization, growth were studied during a further 9-day period using intravital fluorescence microscopy, histology, immunohistochemistry. Tumors exposed to PBS only served as controls. RESULTS:In vitro, > 30% of unstimulated CT26.WT cells showed expression of the SDF-1 receptor CXCR4. On chemotaxis assay, SDF-1 provoked a dose-dependent increase in cell migration. In vivo, SDF-1 accelerated neovascularization, induced a significant increase in tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation. Of interest, SDF-1 treatment was associated with a significantly increased expression of proliferating cell nuclear antigen, a downregulation of cleaved caspase-3. CONCLUSION: Our study indicates that the CXC chemokine SDF-1 promotes tumor cell migration in vitro, tumor growth of established extrahepatic metastasis in vivo due to angiogenesis-dependent induction of tumor cell proliferation, inhibition of apoptotic cell death.

  13. Actin-Based Feedback Circuits in Cell Migration and Endocytosis

    Science.gov (United States)

    Wang, Xinxin

    In this thesis, we study the switch and pulse functions of actin during two important cellular processes, cell migration and endocytosis. Actin is an abundant protein that can polymerize to form a dendritic network. The actin network can exert force to push or bend the cell membrane. During cell migration, the actin network behaves like a switch, assembling mostly at one end or at the other end. The end with the majority of the actin network is the leading edge, following which the cell can persistently move in the same direction. The other end, with the minority of the actin network, is the trailing edge, which is dragged by the cell as it moves forward. When subjected to large fluctuations or external stimuli, the leading edge and the trailing edge can interchange and change the direction of motion, like a motion switch. Our model of the actin network in a cell reveals that mechanical force is crucial for forming the motion switch. We find a transition from single state symmetric behavior to switch behavior, when tuning parameters such as the force. The model is studied by both stochastic simulations, and a set of rate equations that are consistent with the simulations. Endocytosis is a process by which cells engulf extracellular substances and recycle the cell membrane. In yeast cells, the actin network is transiently needed to overcome the pressure difference across the cell membrane caused by turgor pressure. The actin network behaves like a pulse, which assembles and then disassembles within about 30 seconds. Using a stochastic model, we reproduce the pulse behaviors of the actin network and one of its regulatory proteins, Las17. The model matches green fluorescence protein (GFP) experiments for wild-type cells. The model also predicts some phenotypes that modify or diminish the pulse behavior. The phenotypes are verified with both experiments performed at Washington University and with other groups' experiments. We find that several feedback mechanisms are

  14. Histone H1x is highly expressed in human neuroendocrine cells and tumours

    International Nuclear Information System (INIS)

    Warneboldt, Julia; Haller, Florian; Horstmann, Olaf; Danner, Bernhard C; Füzesi, László; Doenecke, Detlef; Happel, Nicole

    2008-01-01

    Histone H1x is a ubiquitously expressed member of the H1 histone family. H1 histones, also called linker histones, stabilize compact, higher order structures of chromatin. In addition to their role as structural proteins, they actively regulate gene expression and participate in chromatin-based processes like DNA replication and repair. The epigenetic contribution of H1 histones to these mechanisms makes it conceivable that they also take part in malignant transformation. Based on results of a Blast data base search which revealed an accumulation of expressed sequence tags (ESTs) of H1x in libraries from neuroendocrine tumours (NETs), we evaluated the expression of H1x in NETs from lung and the gastrointestinal tract using immunohistochemisty. Relative protein and mRNA levels of H1x were analysed by Western blot analysis and quantitative real-time RT-PCR, respectively. Since several reports describe a change of the expression level of the replacement subtype H1.0 during tumourigenesis, the analysis of this subtype was included in this study. We found an increased expression of H1x but not of H1.0 in NET tissues in comparison to corresponding normal tissues. Even though the analysed NETs were heterogenous regarding their grade of malignancy, all except one showed a considerably higher protein amount of H1x compared with corresponding non-neoplastic tissue. Furthermore, double-labelling of H1x and chromogranin A in sections of pancreas and small intestine revealed that H1x is highly expressed in neuroendocrine cells of these tissues. We conclude that the high expression of histone H1x in NETs is probably due to the abundance of this protein in the cells from which these tumours originate

  15. Histological characteristics of human papilloma-virus-positive and -negative invasive and in situ squamous cell tumours of the penis

    DEFF Research Database (Denmark)

    Krustrup, Dorrit; Jensen, Helle Lone; van den Brule, Adriaan J C

    2009-01-01

    A high prevalence of cervical cancer associated high-risk types of human papillomavirus (hrHPV) has been demonstrated in premalignant and invasive squamous cell lesions of the penis, but large studies correlating histological characteristics with HPV status are few in number. Tumour tissues from...

  16. Diagnosing occult tumour cells and their predictive value in sentinel nodes of histologically negative patients with colorectal cancer

    NARCIS (Netherlands)

    van der Zaag, E. S.; Kooij, N.; van de Vijver, M. J.; Bemelman, W. A.; Peters, H. M.; Buskens, C. J.

    2010-01-01

    Purpose: Most studies on the sentinel node (SN) procedure in patients with colorectal cancer include immunohistochemical analysis of the SN only. To evaluate the real diagnostic accuracy of the SN procedure with immunohistochemical analysis, the presence of occult tumour cells in all histologically

  17. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

    Czech Academy of Sciences Publication Activity Database

    Yan, B.; Stantic, M.; Zobalová, Renata; Bezawork-Geleta, A.; Stapelberg, M.; Stursa, J.; Prokopová, Kateřina; Dong, L.; Neužil, Jiří

    2015-01-01

    Roč. 15, č. 401 (2015) ISSN 1471-2407 R&D Projects: GA MZd NT14078; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Tumour-initiating cells * Mitochondrially targeted vitamin E succinate * Complex II Subject RIV: FD - Oncology ; Hematology Impact factor: 3.265, year: 2015

  18. Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours

    NARCIS (Netherlands)

    von Bueren, A. O.; Bacolod, M. D.; Hagel, C.; Heinimann, K.; Fedier, A.; Kordes, U.; Pietsch, T.; Koster, J.; Grotzer, M. A.; Friedman, H. S.; Marra, G.; Kool, M.; Rutkowski, S.

    2012-01-01

    BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O-6-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA

  19. Hypoxia and prostaglandin E receptor 4 signalling pathways synergise to promote endometrial adenocarcinoma cell proliferation and tumour growth.

    Science.gov (United States)

    Catalano, Rob D; Wilson, Martin R; Boddy, Sheila C; McKinlay, Andrew T M; Sales, Kurt J; Jabbour, Henry N

    2011-05-12

    The prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG) E(2). PTGS2 expression and PGE(2) biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE(2) regulate endometrial tumour growth is unknown. Here we investigated (a) the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3) and PGE receptors (PTGER1-4) in endometrial adenocarcinomas compared with normal endometrium and (b) the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells) xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE(2) and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE(2) and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells.

  20. The effect of translationally controlled tumour protein (TCTP) on programmed cell death in plants.

    Science.gov (United States)

    Hoepflinger, Marion Christine; Reitsamer, Johannes; Geretschlaeger, Anja Maria; Mehlmer, Norbert; Tenhaken, Raimund

    2013-09-16

    Translationally controlled tumour protein (TCTP), a well known protein of the animal kingdom, was shown to be a Ca(2+)-binding protein with important functions in many different cellular processes (e.g. protection against stress and apoptosis, cell growth, cell cycle progression, and microtubule organization). However, only little is known about TCTP in plants. Transcript and protein levels of plant TCTPs were shown to be altered by various stress conditions (e.g. cold, salt, draught, aluminium, and pathogen infection), and Arabidopsis thaliana TCTP (AtTCTP) was described as an important regulator of growth. The aim of this study was to further characterize plant TCTP relating to one of its major functions in animals: the protection against cell death. We used two different activators of programmed cell death (PCD) in plants: the mammalian pro-apoptotic protein BAX and tunicamycin, an inhibitor of glycosylation and trigger of unfolded protein response (UPR). Over-expression of AtTCTP significantly decreased cell death in tobacco leaf discs in both studies. A (45)Ca overlay assay showed AtTCTP to be a Ca(2+)-binding protein and localization experiments revealed cytosolic distribution of AtTCTP-GFP in Arabidopsis seedlings. Our study showed cytoprotective effects of plant TCTP for the first time. Furthermore, we showed the ability of AtTCTP to bind to Ca(2+) and its cytosolic distribution within the cell. If these results are combined, two putative modes of action can be assumed: 1) AtTCTP acts as Ca(2+) sequester, preventing PCD by reducing cytosolic Ca(2+) levels as described for animals. 2) AtTCTP could directly or indirectly interact with other cytosolic or membrane-bound proteins of the cell death machinery, thereby inhibiting cell death progression. As no homologous proteins of the anti-apoptotic machinery of animals were found in plants, and functional homologues still remain to be elucidated, future work will provide more insight.

  1. In vitro study on the effects of irradiation on synchronized tumour cells

    International Nuclear Information System (INIS)

    Reckewell, O.

    1987-01-01

    It was the aim of the study described here to ascertain and compare the individual effects of irradiation on synchronized cells originating from Yoshida's ascites sarcoma or Ehrlich's ascites carcinoma. The methods used for this purpose included growth tests just as well as impulse-cytophotometric and microscopic analyses. In Ehrlich's ascites carcinoma, cell division delays were seen to be slightly more pronounced for the G 2 phase, which was the one subjected to irradiation. The reaction pattern of Yoshida's sarcoma was characterised not only by markedly increased radiosensitivity of the G 1 phase but also by 'G 1 arrest' or suspended G 1 proliferation as a result of irradiation during any other phase of the cell cycle. The available evidence strongly suggests that the G 2 phase can certainly not be regarded as one generally showing increased sensitivity to rays. In view of the considerable variations between individual tumour strains it is also quite obvious that there can be no phase-dependent increases in radiosensitivity, which all cells have in common. (orig./MG) [de

  2. Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells.

    Science.gov (United States)

    Demirci, Selami; Doğan, Ayşegül; Apdik, Hüseyin; Tuysuz, Emre Can; Gulluoglu, Sukru; Bayrak, Omer Faruk; Şahin, Fikrettin

    2018-01-01

    Cell proliferation and migration are crucial in many physiological processes including development, cancer, tissue repair, and wound healing. Cell migration is regulated by several signaling molecules. Identification of genes related to cell migration is required to understand molecular mechanism of non-healing chronic wounds which is a major concern in clinics. In the current study, the role of cytoglobin (CYGB) gene in fıbroblast cell migration and proliferation was described. L929 mouse fibroblast cells were transduced with lentiviral particles for CYGB and GFP, and analyzed for cell proliferation and migration ability. Fibroblast cells overexpressing CYGB displayed decreased cell proliferation, colony formation capacity, and cell migration. Phosphorylation levels of mTOR and two downstream effectors S6 and 4E-BP1 which take part in PI3K/AKT/mTOR signaling declined in CYGB-overexpressing cells. Microarray analysis indicated that CYGB overexpression leads to downregulation of cell proliferation, migration, and tumor growth associated genes in L929 cell line. This study demonstrated the role of CYGB in fibroblast cell motility and proliferation. CYGB could be a promising candidate for further studies as a potential target for diseases related to cell migration such as cancer and chronic wound treatment.

  3. Corticomedullary mixed tumour resembling a small adrenal gland-involvement of cancer stem cells: case report

    OpenAIRE

    Duan, Lian; Fang, Fang; Fu, Wanlei; Fang, Zhenqiang; Wang, Hui; Yu, Shicang; Tang, Zili; Liu, Zhenqi; Zheng, Hongting

    2017-01-01

    Background Adrenal corticomedullary mixed tumours are very rare. Its mechanism is rarely reported. Here we report the first case of a corticomedullary mixed tumour resembling a ?small adrenal gland? with distinct arrangement of the cortical and medullary layers. We further hypothesize regarding the tumorigenic mechanism of this tumour. Case presentation A 58-year man had been diagnosed with diabetes and hypertension for 3?years. His 24-h urine vanillylmandelic acid (VMA) levels were slightly ...

  4. Towards an integrated systems-based modelling framework for drug transport and its effect on tumour cells

    Science.gov (United States)

    2014-01-01

    Background A systematic understanding of chemotherapeutic influence on solid tumours is highly challenging and complex as it encompasses the interplay of phenomena occurring at multiple scales. It is desirable to have a multiscale systems framework capable of disentangling the individual roles of multiple contributing factors, such as transport and extracellular factors, and purely intracellular factors, as well as the interactions among these factors. Based on a recently developed systems-based modelling framework, we have developed a coupled system in order to further elucidate the role of drug transport, and its interplay with cellular signalling by incorporating intra- and extra-vascular drug transport in tumour, dynamic descriptions of intracellular signalling and tumour cell density dynamics. Results Different aspects of the interaction between transport and cell signalling and the effects of transport parameters have been investigated in silico. Limited drug penetration is found to be a major constraint in inducing drug effect; many aspects of the interaction of transport with cell signalling are independent of the details of cell signalling. A sensitivity analysis indicates that the effect of drug diffusivity depends on the balance between interstitial drug transport and the specific requirement for triggering apoptosis (governed by highly nonlinear signalling networks), suggesting that the effect of drug diffusivity in such cases must be considered in conjunction with descriptions of cellular dynamics. Conclusions The modelling framework developed in this study provides qualitative and mechanistic insights into the effect of drug on tumour cells. It provides an in silico experimental platform to investigate the interplay between extracellular factors (e.g. transport) and intracellular factors. Such a platform is essential to understanding the individual and combined effects of transport and cellular factors in solid tumour. PMID:24764492

  5. Integrating chemotaxis and contact-inhibition during collective cell migration: Small GTPases at work.

    Science.gov (United States)

    Theveneau, Eric; Mayor, Roberto

    2010-09-01

    For directional cell migration to occur cells must interpret guiding cues present in their environment. Chemotaxis based on negative or positive signals has been long thought as the main driving force of guided cell migration. However during collective cell migration cells do receive information from external signals but also upon interactions with their direct neighbours. These multiple inputs must be translated into intracellular reorganisation in order to promote efficient directional migration. Small GTPases, being involved in establishing cell polarity and regulating protrusive activity, are likely to play a central role in signal integration. Indeed, recent findings from our laboratory indicate that Contact-Inhibition of Locomotion controlled by N-Cadherin and chemotaxis dependent on Sdf1/Cxcr4 signaling converge towards regulation of the localized activity of RhoA and Rac1. All together they establish cell polarity and select well-oriented cell protrusions to ensure directional cell migration.

  6. Melatonin modulates microfilament phenotypes in epithelial cells, implications for adhesion and inhibition of cancer cell migration

    OpenAIRE

    Benítez-King, Gloria; Soto-Vega, Elena; Ramírez-Rodriguez, Gerardo

    2009-01-01

    Cell migration and adhesion are cytoskeleton- dependent functions that play a key role in epithelial physiology. Specialized epithelial cells in water transport have specific microfilament rearrangements that make these cells adopt a polyhedral shape, forming a sealed monolayer which functions as permeability barrier. Also, specific polarized microfilament phenotypes are formed at the front and the rear of migratory epithelial cells. In pathological processes such a...

  7. Cell intrinsic modulation of Wnt signaling controls neuroblast migration in C. elegans

    NARCIS (Netherlands)

    Mentink, Remco A; Middelkoop, Teije C; Rella, Lorenzo; Ji, Ni; Tang, Chung Yin; Betist, Marco C; van Oudenaarden, Alexander; Korswagen, Hendrik C

    2014-01-01

    Members of the Wnt family of secreted signaling proteins are key regulators of cell migration and axon guidance. In the nematode C. elegans, the migration of the QR neuroblast descendants requires multiple Wnt ligands and receptors. We found that the migration of the QR descendants is divided into

  8. Effects of irradiation and cisplatin on human glioma spheroids: inhibition of cell proliferation and cell migration

    NARCIS (Netherlands)

    Fehlauer, Fabian; Muench, Martina; Rades, Dirk; Stalpers, Lukas J. A.; Leenstra, Sieger; van der Valk, Paul; Slotman, Ben; Smid, Ernst J.; Sminia, Peter

    2005-01-01

    Investigation of cell migration and proliferation of human glioma cell line spheroids (CLS) and evaluation of morphology, apoptosis, and immunohistochemical expression of MIB-1, p53, and p21 of organotypic muticellular spheroids (OMS) following cisplatin (CDDP) and irradiation (RT). Spheroids of the

  9. Epithelial-mesenchymal transition transcription factors control pluripotent adult stem cell migration in vivo in planarians.

    Science.gov (United States)

    Abnave, Prasad; Aboukhatwa, Ellen; Kosaka, Nobuyoshi; Thompson, James; Hill, Mark A; Aboobaker, A Aziz

    2017-10-01

    Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infection. Inappropriate migration also underpins metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in planarians. We demonstrate the use of this system to study the molecular control of stem cell migration and show that snail-1 , snail-2 and zeb-1 EMT transcription factor homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. We also observed that stem cells undergo homeostatic migration to anterior regions that lack local stem cells, in the absence of injury, maintaining tissue homeostasis. This requires the polarity determinant notum Our work establishes planarians as a suitable model for further in-depth study of the processes controlling stem cell migration in vivo . © 2017. Published by The Company of Biologists Ltd.

  10. Collective cell migration of smooth muscle and endothelial cells: impact of injury versus non-injury stimuli.

    Science.gov (United States)

    Ammann, Kaitlyn R; DeCook, Katrina J; Tran, Phat L; Merkle, Valerie M; Wong, Pak K; Slepian, Marvin J

    2015-01-01

    Cell migration is a vital process for growth and repair. In vitro migration assays, utilized to study cell migration, often rely on physical scraping of a cell monolayer to induce cell migration. The physical act of scrape injury results in numerous factors stimulating cell migration - some injury-related, some solely due to gap creation and loss of contact inhibition. Eliminating the effects of cell injury would be useful to examine the relative contribution of injury versus other mechanisms to cell migration. Cell exclusion assays can tease out the effects of injury and have become a new avenue for migration studies. Here, we developed two simple non-injury techniques for cell exclusion: 1) a Pyrex® cylinder - for outward migration of cells and 2) a polydimethylsiloxane (PDMS) insert - for inward migration of cells. Utilizing these assays smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) migratory behavior was studied on both polystyrene and gelatin-coated surfaces. Differences in migratory behavior could be detected for both smooth muscle cells (SMCs) and endothelial cells (ECs) when utilizing injury versus non-injury assays. SMCs migrated faster than HUVECs when stimulated by injury in the scrape wound assay, with rates of 1.26 % per hour and 1.59 % per hour on polystyrene and gelatin surfaces, respectively. The fastest overall migration took place with HUVECs on a gelatin-coated surface, with the in-growth assay, at a rate of 2.05 % per hour. The slowest migration occurred with the same conditions but on a polystyrene surface at a rate of 0.33 % per hour. For SMCs, injury is a dominating factor in migration when compared to the two cell exclusion assays, regardless of the surface tested: polystyrene or gelatin. In contrast, the migrating surface, namely gelatin, was a dominating factor for HUVEC migration, providing an increase in cell migration over the polystyrene surface. Overall, the cell exclusion assays - the in

  11. From cell differentiation to cell collectives: Bacillus subtilis uses division of labor to migrate.

    Directory of Open Access Journals (Sweden)

    Jordi van Gestel

    2015-04-01

    Full Text Available The organization of cells, emerging from cell-cell interactions, can give rise to collective properties. These properties are adaptive when together cells can face environmental challenges that they separately cannot. One particular challenge that is important for microorganisms is migration. In this study, we show how flagellum-independent migration is driven by the division of labor of two cell types that appear during Bacillus subtilis sliding motility. Cell collectives organize themselves into bundles (called "van Gogh bundles" of tightly aligned cell chains that form filamentous loops at the colony edge. We show, by time-course microscopy, that these loops migrate by pushing themselves away from the colony. The formation of van Gogh bundles depends critically on the synergistic interaction of surfactin-producing and matrix-producing cells. We propose that surfactin-producing cells reduce the friction between cells and their substrate, thereby facilitating matrix-producing cells to form bundles. The folding properties of these bundles determine the rate of colony expansion. Our study illustrates how the simple organization of cells within a community can yield a strong ecological advantage. This is a key factor underlying the diverse origins of multicellularity.

  12. Cell Surface Heparan Sulfate Released by Heparanase Promotes Melanoma Cell Migration and Angiogenesis

    Science.gov (United States)

    Roy, Madhuchhanda; Marchetti, Dario

    2009-01-01

    Heparan sulfate proteoglycans are essential components of the cell-surface and extracellular matrix which provide structural integrity and act as storage depots for growth factors and chemokines, through their heparan sulfate (HS) side chains. Heparanase is the only mammalian endoglycosidase known that cleaves HS, thus contributing to matrix degradation and cell invasion. The enzyme acts as an endo-β-D-glucuronidase resulting in HS fragments of discrete molecular weight size. Cell-surface HS is known to inhibit or stimulate tumorigenesis depending upon size and composition. We hypothesized that heparanase contributes to melanoma metastasis by generating bioactive HS from the cell-surface to facilitate biological activities of tumor cells as well as tumor microenvironment. We removed cell-surface HS from melanoma (B16B15b) by HPSE treatment and resulting fragments were isolated. Purified cell-surface HS stimulated in vitro B16B15b cell migration but not proliferation, and importantly, enhanced in vivo angiogenesis. Furthermore, melanoma cell-surface HS did not affect in vitro endothelioma cell (b.End3) migration. Our results provide direct evidence that, in addition to remodeling extracellular matrix and releasing growth factors and chemokines, HPSE contributes to aggressive phenotype of melanoma by releasing bioactive cell-surface HS fragments which can stimulate melanoma cell migration in vitro and angiogenesis in vivo. PMID:19115257

  13. [{sup 177}Lu]pertuzumab: experimental studies on targeting of HER-2 positive tumour cells

    Energy Technology Data Exchange (ETDEWEB)

    Persson, Mikael; Gedda, Lars [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Experimental Urology, Rudbeck Laboratory, Uppsala (Sweden); Tolmachev, Vladimir; Andersson, Karl; Carlsson, Joergen [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Sandstroem, Mattias [Uppsala University, Medical Radiation Physics, Uppsala University Hospital, Uppsala (Sweden)

    2005-12-01

    The new antibody pertuzumab (Omnitarg) targets the dimerisation subdomain of HER-2. The purpose of this study was to analyse whether pertuzumab retains HER-2 targeting capacity after labelling with the therapeutically interesting beta emitter {sup 177}Lu and to make initial characterisations in vitro and in vivo. Pertuzumab was conjugated with isothiocyanate-benzyl-CHX-A{sup ''}-DTPA and chelated to {sup 177}Lu. Immunoreactivity, affinity, cellular retention and internalisation were analysed using SKOV-3 cells. The affinity of non-radioactive pertuzumab was measured using a surface plasmon resonance biosensor. In vivo targeting and specific binding were assessed in Balb/c (nu/nu) mice carrying SKOV-3 xenografts. The biodistribution of {sup 177}Lu was determined 1, 3 and 7 days after [{sup 177}Lu]pertuzumab administration. Gamma camera images were taken after 3 days. The immunoreactivity of [{sup 177}Lu]pertuzumab was 85.8{+-}1.3%. The affinity of non-radioactive pertuzumab was 1.8{+-}1.1 nM, and that of [{sup 177}Lu]pertuzumab, 4.1{+-}0.7 nM. The cellular retention after 5 h pre-incubation was 90{+-}2% at 20 h. The targeting was HER-2 specific both in vitro and in vivo, since excess amounts of non-labelled antibody inhibited the uptake of labelled antibody (p<0.0001 and p<0.01, respectively). The biodistribution and gamma camera images of {sup 177}Lu showed extensive tumour uptake. Normal tissues had a surprisingly low uptake. Pertuzumab was efficiently labelled with {sup 177}Lu and showed good intracellular retention and HER-2 specific binding both in vitro and in vivo. The gamma camera images and the biodistribution study gave excellent tumour targeting results. Thus, [{sup 177}Lu]pertuzumab is of interest for further studies aimed at radionuclide therapy. (orig.)

  14. Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

    Directory of Open Access Journals (Sweden)

    David G. Menter

    2012-01-01

    Full Text Available Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1 are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2, which binds to and activates G-protein-coupled prostaglandin E1-4 receptors (EP1-4. Selectively targeting the COX-2/mPGES-1/PGE2/EP1-4 axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM. Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/EP1-4 axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.

  15. Bayesian parameter estimation for stochastic models of biological cell migration

    Science.gov (United States)

    Dieterich, Peter; Preuss, Roland

    2013-08-01

    Cell migration plays an essential role under many physiological and patho-physiological conditions. It is of major importance during embryonic development and wound healing. In contrast, it also generates negative effects during inflammation processes, the transmigration of tumors or the formation of metastases. Thus, a reliable quantification and characterization of cell paths could give insight into the dynamics of these processes. Typically stochastic models are applied where parameters are extracted by fitting models to the so-called mean square displacement of the observed cell group. We show that this approach has several disadvantages and problems. Therefore, we propose a simple procedure directly relying on the positions of the cell's trajectory and the covariance matrix of the positions. It is shown that the covariance is identical with the spatial aging correlation function for the supposed linear Gaussian models of Brownian motion with drift and fractional Brownian motion. The technique is applied and illustrated with simulated data showing a reliable parameter estimation from single cell paths.

  16. Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells.

    Science.gov (United States)

    Jeet, Varinder; Tevz, Gregor; Lehman, Melanie; Hollier, Brett; Nelson, Colleen

    2014-10-01

    Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa. © 2014 The authors.

  17. Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?

    Science.gov (United States)

    Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Álvarez-Méndez, Ana; Alvarez-Vallina, Luis

    2016-04-15

    Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery. © 2016 Authors; published by Portland Press Limited.

  18. The Mechanosensitive Ca2+ Channel as a Central Regulator of Prostate Tumor Cell Migration and Invasiveness

    Science.gov (United States)

    2010-01-01

    the same concentrations that block PC-3 cell migration, also prevented the development of [Ca2+]i gradients and transients (Fig. 3d and supplementary...L., Heisenberg , C.P., Raz, E. (2006). Migration of zebrafish primordial germ cells: a role for myosin contraction and cytoplasmic flow. Devel. Cell

  19. Giant cell tumour of the distal radius: wide resection and reconstruction by non-vascularised proximal fibular autograft.

    Science.gov (United States)

    Bassiony, Ayman Abdelaziz

    2009-10-01

    Giant cell tumours of the bone are aggressive and potentially malignant lesions. Juxtaarticular giant cell tumours of the lower end radius are common and present a special problem of reconstruction after tumour excision. Out of the various reconstructive procedures described, non-vascularised fibular autograft has been widely used with satisfactory functional results. Ten patients with a mean age of 33.4 years, with either Campanacci grade II or III histologically proven giant cell tumours of lower end radius were treated with wide excision and reconstruction with ipsilateral non-vascularised proximal fibular autograft. Host graft junction was fixed with dynamic compression plate (DCP) in all cases. Wrist ligament reconstruction and fixation of the head of the fibula with carpal bones and distal end of the ulna using K-wires and primary cancellous iliac crest grafting at graft host junction was done in all cases. The follow-up ranged from 30 to 60 months (mean, 46.8). At last follow-up, the average combined range of motion was 100.5 degrees with range varying from 60 degrees to 125 degrees. The average union time was 7 months (range, 4 to 12). Non-union occurred in 1 case. Graft resorption occurred in another case. Localised soft tissue recurrence occurred in another case after 3 years and was treated by excision. There was no case of graft fracture, metastasis, death, local recurrence or significant donor site morbidity. A total of 3 secondary procedures were required. Enbloc resection of giant cell tumours of the lower end radius is a widely accepted method. Reconstruction with non-vascularised fibular graft, internal fixation with DCP with primary corticocancellous bone grafting with transfixation of the fibular head and wrist ligament reconstruction minimises the problem and gives satisfactory functional results.

  20. Treatment of transplanted CT26 tumour with dendritic cell vaccine in combination with blockade of vascular endothelial growth factor receptor 2 and CTLA-4

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Buus, S; Claesson, M H

    2005-01-01

    We investigated the anti CT26 tumour effect of dendritic cell based vaccination with the MuLV gp70 envelope protein-derived peptides AH1 and p320-333. Vaccination lead to generation of AH1 specific cytotoxic lymphocytes (CTL) and some decrease in tumour growth of simultaneously inoculated CT26...... of mice with already established tumours was only obtained after combination of vaccination, DC101 and 9H10 treatment in which setting 80% of the mice rejected their tumours....

  1. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages

    DEFF Research Database (Denmark)

    Yang, Yunlong; Andersson, Patrik; Hosaka, Kayoko

    2016-01-01

    Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33...

  2. Fast-crawling cell types migrate to avoid the direction of periodic substratum stretching.

    Science.gov (United States)

    Okimura, Chika; Ueda, Kazuki; Sakumura, Yuichi; Iwadate, Yoshiaki

    2016-07-03

    To investigate the relationship between mechanical stimuli from substrata and related cell functions, one of the most useful techniques is the application of mechanical stimuli via periodic stretching of elastic substrata. In response to this stimulus, Dictyostelium discoideum cells migrate in a direction perpendicular to the stretching direction. The origins of directional migration, higher migration velocity in the direction perpendicular to the stretching direction or the higher probability of a switch of migration direction to perpendicular to the stretching direction, however, remain unknown. In this study, we applied periodic stretching stimuli to neutrophil-like differentiated HL-60 cells, which migrate perpendicular to the direction of stretch. Detailed analysis of the trajectories of HL-60 cells and Dictyostelium cells obtained in a previous study revealed that the higher probability of a switch of migration direction to that perpendicular to the direction of stretching was the main cause of such directional migration. This directional migration appears to be a strategy adopted by fast-crawling cells in which they do not migrate faster in the direction they want to go, but migrate to avoid a direction they do not want to go.

  3. Soft Micro-Channels for Cell Culturing and Migration Studies

    Science.gov (United States)

    Abbasirazgaleh, Sara

    Various techniques and methods have been studied and developed to aid nerve regeneration and repairing nerve injuries. Among all, nerve grafting is the gold standard for bridging the gap between the injured nerve stumps. Despite the advantages of this technique, there are also various drawbacks that have encouraged the exploration of alternative, less invasive methods for promoting nerve regeneration. In this thesis, we have fabricated soft micro-channels for cell culturing and migration studies which could act as an interface capable of long-term, reliable, and high-resolution stimulation device for nerve regeneration. Micro-channels fabrication is performed using a combination of photolithography technique and physical vapor deposition (PVD) methods. Initially, the surfaces of the micro-channels are treated with oxygen plasma to convert the surface of PDMS from hydrophobic to hydrophilic and to further provide an optimal environment for cells to adhere and grow. Next, in vitro studies were performed on the fabricated micro-channels to demonstrate feasibility of the platform to promote adherence and growth of PC12 cells (cell line derived from a pheochromocytomas of the rat adrenal medulla).

  4. Analysis of T cell receptor alpha beta variability in lymphocytes infiltrating melanoma primary tumours and metastatic lesions

    DEFF Research Database (Denmark)

    Schøller, J; thor Straten, P; Jakobsen, Annette Birck

    1994-01-01

    The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse-transcription-couple......The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse...... usage of the TCR V gene families V alpha 4, V alpha 5, V alpha 22 and V beta 8, whereas the V beta 3 gene family appeared to be expressed together with HLA-A1. Other highly expressed V gene families, apparently not restricted to either HLA-A1 or -A2, were V alpha 1 (expressed in three of four primary...... tumours) and V alpha 21 (expressed in two of four tumours). We found no evidence suggesting any correlations between the haplotypes HLA-A1 and -A2 and preferential V gene family expression in the metastatic lesions, and the only common feature was V alpha 8, which was found to be highly expressed in two...

  5. Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model

    International Nuclear Information System (INIS)

    Dubois, Ludwig; Lieuwes, Natasja G.; Maresca, Alfonso; Thiry, Anne; Supuran, Claudiu T.; Scozzafava, Andrea; Wouters, Bradly G.; Lambin, Philippe

    2009-01-01

    Background and purpose: Carbonic anhydrase (CA) IX is suggested to be an endogenous marker of hypoxia. Fluorescent sulfonamides with a high affinity for CA IX (CAI) have been developed and shown to bind to cells only when CA IX protein was expressed and while cells were hypoxic. The aim of this study was to investigate the in vivo CAI binding properties in a xenograft tumour model using fluorescent imaging. Materials and methods: NMRI-nu mice subcutaneously transplanted with HT-29 colorectal tumours were treated with 7% oxygen or with nicotinamide and carbogen and were compared with control animals. CAI accumulation was monitored by non-invasive fluorescent imaging. Results: Specific CAI accumulation could be observed in delineated tumour areas as compared with a non-sulfonamide analogue (P < 0.01). Administration of nicotinamide and carbogen, decreasing acute and chronic hypoxia, respectively, prevented CAI accumulation (P < 0.05). When treated with 7% oxygen breathing, a 3-fold higher CAI accumulation (P < 0.01) was observed. Furthermore, the bound CAI fraction was rapidly reduced upon tumour reoxygenation (P < 0.01). Conclusions: Our in vivo imaging results confirm previous in vitro data demonstrating that CAI binding and retention require exposure to hypoxia. Fluorescent labelled sulfonamides provide a powerful tool to visualize hypoxia response. An important step is made towards clinical applicability, indicating the potential of patient selection for CA IX-directed therapies.

  6. Diagnostic Efficacy of Radiology in the Diagnosis of Giant Cell Tumour of Bone

    Directory of Open Access Journals (Sweden)

    Afia Akhter

    2014-01-01

    Full Text Available Background: Giant cell tumour (GCT is an aggressive and potentially malignant lesion. Microscopic feature reveals osteoclast like giant cells in a mononuclear stromal cells background. The mononuclear stromal cell is interpreted as neoplastic. Objective: As radiological diagnosis is non invasive and cost effective in comparison to histopathological diagnosis, considering the patients’ compliance, the aim of the study was to observe the diagnostic efficacy of radiology in diagnosis of GCT. Materials and method: This cross sectional study was carried out in the department of Pathology, Delta Hopital Ltd., Dhaka, Bangladesh from July 2011 to December 2012. A total of 30 study subjects were enrolled in the study irrespective of age and sex. Biopsy material and relevant data of clinically suspected cases of GCT along with radiology report were sent from National Institute of Traumatology and Orthopaedic Rehabilitation (NITOR, Dhaka, Bangladesh. Histopathological diagnosis was made by expert pathologists. Results: Mean (±SD age of the study subjects was 29.20 (±7.34 years with highest number of patients were observed in 3rd decade and female was predominant (60% with a male female ratio of 1:1.5. Common site of GCT was around knee (50%. Among 30 clinically diagnosed GCT, 25 (83.3% cases were radiologically diagnosed as GCT, 2 (6.7% diagnosed as fibrous dysplasia, 1 (3.3% as chondroblastoma, 1 (3.3% as simple bone cyst and 1 (3.3% as aneurysmal bone cyst. However among 30 clinically diagnosed GCT, 28 (93.3% patients were histopathologically diagnosed as Giant cell lesion and rest 2 (6.7% patients diagnosed as fibrous dysplasia. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of radiological diagnosis of GCT were found to be 92.6%, 100.0%, 100.0%, 40.0% and 90.0%, respectively. Conclusion: Radiology can be effectively used as a screening tool in diagnosing GCT.

  7. The neural crest cell cycle is related to phases of migration in the head

    Science.gov (United States)

    Ridenour, Dennis A.; McLennan, Rebecca; Teddy, Jessica M.; Semerad, Craig L.; Haug, Jeffrey S.; Kulesa, Paul M.

    2014-01-01

    Embryonic cells that migrate long distances must critically balance cell division in order to maintain stream dynamics and population of peripheral targets. Yet details of individual cell division events and how cell cycle is related to phases of migration remain unclear. Here, we examined these questions using the chick cranial neural crest (NC). In vivo time-lapse imaging revealed that a typical migrating NC cell division event lasted ∼1 hour and included four stereotypical steps. Cell tracking showed that dividing NC cells maintained position relative to non-dividing neighbors. NC cell division orientation and the time and distance to first division after neural tube exit were stochastic. To address how cell cycle is related to phases of migration, we used FACs analysis to identify significant spatiotemporal differences in NC cell cycle profiles. Two-photon photoconversion of single and small numbers of mKikGR-labeled NC cells confirmed that lead NC cells exhibited a nearly fourfold faster doubling time after populating the branchial arches. By contrast, Ki-67 staining showed that one out of every five later emerging NC cells exited the cell cycle after reaching proximal head targets. The relatively quiescent mitotic activity during NC cell migration to the branchial arches was altered when premigratory cells were reduced in number by tissue ablation. Together, our results provide the first comprehensive details of the pattern and dynamics of cell division events during cranial NC cell migration. PMID:24550117

  8. Tumour necrosis factor-alpha-induced protein 8 (TNFAIP8) expression associated with cell survival and death in cancer cell lines infected with canine distemper virus.

    Science.gov (United States)

    Garcia, J A; Ferreira, H L; Vieira, F V; Gameiro, R; Andrade, A L; Eugênio, F R; Flores, E F; Cardoso, T C

    2017-06-01

    Oncolytic virotherapy is a novel strategy for treatment of cancer in humans and companion animals as well. Canine distemper virus (CDV), a paramyxovirus, has proven to be oncolytic through induction of apoptosis in canine-derived tumour cells, yet the mechanism behind this inhibitory action is poorly understood. In this study, three human mammary tumour cell lines and one canine-derived adenofibrosarcoma cell line were tested regarding to their susceptibility to CDV infection, cell proliferation, apoptosis, mitochondrial membrane potential and expression of tumour necrosis factor-alpha-induced protein 8 (TNFAIP8). CDV replication-induced cytopathic effect, decrease of cell proliferation rates, and >45% of infected cells were considered death and/or under late apoptosis/necrosis. TNFAIP8 and CDVM gene expression were positively correlated in all cell lines. In addition, mitochondrial membrane depolarization was associated with increase in virus titres (p < 0.005). Thus, these results strongly suggest that both human and canine mammary tumour cells are potential candidates for studies concerning CDV-induced cancer therapy. © 2015 John Wiley & Sons Ltd.

  9. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    Directory of Open Access Journals (Sweden)

    Kosuke Fujita

    Full Text Available Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be

  10. Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus

    International Nuclear Information System (INIS)

    Stakaitytė, Gabrielė; Wood, Jennifer J.; Knight, Laura M.; Abdul-Sada, Hussein; Adzahar, Noor Suhana; Nwogu, Nnenna; Macdonald, Andrew; Whitehouse, Adrian

    2014-01-01

    A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC

  11. Characterisation of multidrug-resistant Ehrlich ascites tumour cells selected in vivo for resistance to etoposide

    DEFF Research Database (Denmark)

    Nielsen, D; Maare, C; Eriksen, J

    2000-01-01

    -extractable immunoreactive topoisomerase IIalpha and beta in EHR2/VP16 was reduced by 30-40% relative to that in EHR2. The multidrug resistance-associated protein (MRP) mRNA was increased 20-fold in EHR2/VP16 as compared with EHR2, whereas the expression of P-glycoprotein was unchanged. In EHR2/VP16, the steady......M. ATPase activity was slightly stimulated by daunorubicin, whereas vinblastine, verapamil, and cyclosporin A had no effect. In conclusion, development of resistance to VP16 in EHR2 is accompanied by a significant reduction in topoisomerase II (alpha and beta) and by increased expression of MRP mRNA (20......An Ehrlich ascites tumour cell line (EHR2) was selected for resistance to etoposide (VP16) by in vivo exposure to this agent. The resulting cell line (EHR2/VP16) was 114.3-, 5.7-, and 4.0-fold resistant to VP16, daunorubicin, and vincristine, respectively. The amount of salt...

  12. Modulation of epithelial tissue and cell migration by microgrooves.

    NARCIS (Netherlands)

    Dalton, B.A.; Walboomers, X.F.; Dziegielewski, M.; Evans, M.D.; Taylor, S.; Jansen, J.A.; Steele, J.G.

    2001-01-01

    We used a polystyrene substratum to study the response of migrating epithelium to 1- or 5-microm depth microgrooves with groove/ridge widths of 1, 2, 5, or 10 microm. The migration of a tissue sheet was enhanced along the microgrooves, while migration across the microgrooves was inhibited. Changing

  13. Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults

    DEFF Research Database (Denmark)

    Ewen, Katherine A; Olesen, Inge A; Winge, Sofia B

    2013-01-01

    development and to ascertain whether FGFR3 signalling is linked to germ cell proliferation and the pathogenesis of testicular germ cell tumours (TGCTs) of young adult men. Using RT-PCR, immunohistochemistry and Western blotting, we examined 58 specimens of human testes throughout development for FGFR3...... expression, and then compared expression of FGFR3 with proliferation markers (PCNA or Ki67). We also analysed for FGFR3 expression 30 TGCTs and 28 testes containing the tumour precursor cell, carcinoma in situ (CIS). Fetal and adult testes expressed exclusively the FGFR3IIIc isoform. FGFR3 protein expression...... was restricted to the cytoplasm/plasma membrane of spermatogonia and was most prevalent at mid-gestation, infancy and from puberty onwards. Phosphorylated (p)FGFR was detected in pre-spermatogonia at mid-gestation and in spermatogonia during puberty and in the adult testis. Throughout normal human testis...

  14. Mathematical modelling of the spatio-temporal response of cytotoxic T-lymphocytes to a solid tumour.

    Science.gov (United States)

    Matzavinos, Anastasios; Chaplain, Mark A J; Kuznetsov, Vladimir A

    2004-03-01

    In this paper a mathematical model describing the growth of a solid tumour in the presence of an immune system response is presented. In particular, attention is focused upon the attack of tumour cells by so-called tumour-infiltrating cytotoxic lymphocytes (TICLs), in a small, multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. At this stage the immune cells and the tumour cells are considered to be in a state of dynamic equilibrium--cancer dormancy--a phenomenon which has been observed in primary tumours, micrometastases and residual disease after ablation of the primary tumour. Nonetheless, the precise biochemical and cellular mechanisms by which TICLs control cancer dormancy are still poorly understood from a biological and immunological point of view. Therefore we focus on the analysis of the spatio-temporal dynamics of tumour cells, immune cells and chemokines in an immunogenic tumour. The lymphocytes are assumed to migrate into the growing solid tumour and interact with the tumour cells in such a way that lymphocyte-tumour cell complexes are formed. These complexes result in either the death of the tumour cells (the normal situation) or the inactivation (sometimes even the death) of the lymphocytes. The migration of the TICLs is determined by a combination of random motility and chemotaxis in response to the presence of chemokines. The resulting system of four nonlinear partial differential equations (TICLs, tumour cells, complexes and chemokines) is analysed and numerical simulations are presented. We consider two different tumour geometries--multi-layered cell growth and multi-cellular spheroid growth. The numerical simulations demonstrate the existence of cell distributions that are quasi-stationary in time and heterogeneous in space. A linear stability analysis of the underlying (spatially homogeneous) ordinary differential equation (ODE) kinetics coupled with a numerical investigation of the ODE system reveals

  15. Inactivation of a Gα(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis.

    Science.gov (United States)

    Iglesias-Bartolome, Ramiro; Torres, Daniela; Marone, Romina; Feng, Xiaodong; Martin, Daniel; Simaan, May; Chen, Min; Weinstein, Lee S; Taylor, Susan S; Molinolo, Alfredo A; Gutkind, J Silvio

    2015-06-01

    Genomic alterations in GNAS, the gene coding for the Gαs heterotrimeric G protein, are associated with a large number of human diseases. Here, we explored the role of Gαs on stem cell fate decisions by using the mouse epidermis as a model system. Conditional epidermal deletion of Gnas or repression of PKA signalling caused a remarkable expansion of the stem cell compartment, resulting in rapid basal-cell carcinoma formation. In contrast, inducible expression of active Gαs in the epidermis caused hair follicle stem cell exhaustion and hair loss. Mechanistically, we found that Gαs-PKA disruption promotes the cell autonomous Sonic Hedgehog pathway stimulation and Hippo signalling inhibition, resulting in the non-canonical activation of GLI and YAP1. Our study highlights an important tumour suppressive function of Gαs-PKA, limiting the proliferation of epithelial stem cells and maintaining proper hair follicle homeostasis. These findings could have broad implications in multiple pathophysiological conditions, including cancer.

  16. Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

    International Nuclear Information System (INIS)

    Dai, Jin; Van Wie, Peter G.; Fai, Leonard Yenwong; Kim, Donghern; Wang, Lei; Poyil, Pratheeshkumar; Luo, Jia; Zhang, Zhuo

    2016-01-01

    Apigenin is a natural flavonoid which possesses multiple anti-cancer properties such as anti-proliferation, anti-inflammation, and anti-metastasis in many types of cancers including colorectal cancer. Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a multi-domain scaffolding protein of the Cas family which has been shown to correlate with cancer metastasis and progression. The present study investigates the role of NEDD9 in apigenin-inhibited cell migration, invasion, and metastasis of colorectal adenocarcinoma DLD1 and SW480 cells. The results show that knockdown of NEDD9 inhibited cell migration, invasion, and metastasis and that overexpression of NEDD9 promoted cell migration and invasion of DLD1 cells and SW4890 cells. Apigenin treatment attenuated NEDD9 expression at protein level, resulting in reduced phosphorylations of FAK, Src, and Akt, leading to inhibition on cell migration, invasion, and metastasis of both DLD1 and SW480 cells. The present study has demonstrated that apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt cascade in colorectal cancer cells. NEDD9 may function as a biomarker for evaluation of cancer aggressiveness and for selection of therapeutic drugs against cancer progression. - Highlights: • Apigenin inhibits migration, invasion, and metastasis of colorectal cancer cells. • Apigenin downregulates NEDD9. • Apigenin decreases phosphorylations of FAK, Src, and Akt. • Apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt.

  17. Latent cytomegalovirus infection enhances anti‐tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans

    Science.gov (United States)

    Bigley, A. B.; Rezvani, K.; Shah, N.; Sekine, T.; Balneger, N.; Pistillo, M.; Agha, N.; Kunz, H.; O'Connor, D. P.; Bollard, C. M.

    2016-01-01

    Summary Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A− NK cells, which are potent killers of infected cells expressing human leucocyte antigen (HLA)‐E. As HLA‐E is also over‐expressed in several haematological malignancies and CMV has been linked to a reduced risk of leukaemic relapse, we determined the impact of latent CMV infection on NK cell cytotoxicity against four tumour target cell lines with varying levels of HLA‐E expression. NK cell cytotoxicity against K562 (leukaemia origin) and U266 (multiple myeloma origin) target cells was strikingly greater in healthy CMV‐seropositive donors than seronegative donors and was associated strongly with target cell HLA‐E and NK cell NKG2C expression. NK cell cytotoxicity against HLA‐E transfected lymphoma target cells (221.AEH) was ∼threefold higher with CMV, while NK cell cytotoxicity against non‐transfected 721.221 cells was identical between the CMV groups. NK cell degranulation (CD107a+) and interferon (IFN)‐γ production to 221.AEH cells was localized almost exclusively to the NKG2C subset, and antibody blocking of NKG2C completely eliminated the effect of CMV on NK cell cytotoxicity against 221.AEH cells. Moreover, 221.AEH feeder cells and interleukin (IL)−15 were found to expand NKG2C+/NKG2A– NK cells preferentially from CMV‐seronegative donors and increase NK cell cytotoxicity against HLA‐E+ tumour cell lines. We conclude that latent CMV infection enhances NK cell cytotoxicity through accumulation of NKG2C+ NK cells, which may be beneficial in preventing the initiation and progression of haematological malignancies characterized by high HLA‐E expression. PMID:26940026

  18. An ex vivo model to quantitatively analyze cell migration in tissue.

    Science.gov (United States)

    O'Leary, Conor J; Weston, Mikail; McDermott, Kieran W

    2018-01-01

    Within the developing central nervous system, the ability of cells to migrate throughout the tissue parenchyma to reach their target destination and undergo terminal differentiation is vital to normal central nervous system (CNS) development. To develop novel therapies to treat the injured CNS, it is essential that the migratory behavior of cell populations is understood. Many studies have examined the ability of individual neurons to migrate through the developing CNS, describing specific modes of migration including locomotion and somal translocation. Few studies have investigated the mass migration of large populations of neural progenitors, particularly in the developing the spinal cord. Here, we describe a method to robustly analyze large numbers of migrating cells using a co-culture assay. The ex vivo tissue model promotes the survival and differentiation of co-cultured progenitor cells. Using this assay, we demonstrate that migrating neuroepithelial progenitor cells display region specific migration patterns within the dorsal and ventral spinal cord at defined developmental time points. The technique described here is a viable ex vivo model to quantitatively analyze cell migration and differentiation. We demonstrate the ability to detect changes in cell migration within distinct tissue region across tissue samples using the technique described here. Developmental Dynamics 247:201-211, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Recurrence of squamous cell carcinoma of the oesophagus after curative surgery: rates and patterns on imaging studies correlated with tumour location and pathological stage

    International Nuclear Information System (INIS)

    Lee, S.J.; Lee, K.S.; Yim, Y.J.; Kim, T.S.; Shim, Y.M.; Kim, K.

    2005-01-01

    Many factors have been related to recurrence after resection of squamous cell carcinoma of the oesophagus. These include age, gender, location and local stage of tumours, cell differentiation, lymph node metastasis and vascular involvement. The recurrence rates of squamous cell carcinoma after curative surgery are high (34-79%). Tumour recurrence is categorized as locoregional or distant. Lymph node recurrence and haematogenous metastasis to solid organs (commonly to the lung) are the usual patterns of recurrence. Awareness of recurrence patterns, particularly on imaging studies, is essential for the diagnosis of recurrent tumours on follow-up examinations

  20. Ordered patterns of cell shape and orientational correlation during spontaneous cell migration.

    Directory of Open Access Journals (Sweden)

    Yusuke T Maeda

    Full Text Available BACKGROUND: In the absence of stimuli, most motile eukaryotic cells move by spontaneously coordinating cell deformation with cell movement in the absence of stimuli. Yet little is known about how cells change their own shape and how cells coordinate the deformation and movement. Here, we investigated the mechanism of spontaneous cell migration by using computational analyses. METHODOLOGY: We observed spontaneously migrating Dictyostelium cells in both a vegetative state (round cell shape and slow motion and starved one (elongated cell shape and fast motion. We then extracted regular patterns of morphological dynamics and the pattern-dependent systematic coordination with filamentous actin (F-actin and cell movement by statistical dynamic analyses. CONCLUSIONS/SIGNIFICANCE: We found that Dictyostelium cells in both vegetative and starved states commonly organize their own shape into three ordered patterns, elongation, rotation, and oscillation, in the absence of external stimuli. Further, cells inactivated for PI3-kinase (PI3K and/or PTEN did not show ordered patterns due to the lack of spatial control in pseudopodial formation in both the vegetative and starved states. We also found that spontaneous polarization was achieved in starved cells by asymmetric localization of PTEN and F-actin. This breaking of the symmetry of protein localization maintained the leading edge and considerably enhanced the persistence of directed migration, and overall random exploration was ensured by switching among the different ordered patterns. Our findings suggest that Dictyostelium cells spontaneously create the ordered patterns of cell shape mediated by PI3K/PTEN/F-actin and control the direction of cell movement by coordination with these patterns even in the absence of external stimuli.

  1. Progress of research on cytoskeleton and neural cell migration obstacle induced by ionizing radiation

    International Nuclear Information System (INIS)

    Qiu Jun; Wu Cuiping; Wang Mingming

    2012-01-01

    The dynamic changes of the microtubules and microfilaments provide the main force that drives the normal migration. Biological effects in tissues and cells induced by ionizing radiation are closely correlated with the changes happening to the cytoskeleton. It is that the ionizing radiation can induce the depolymeration of microfilaments and the assembly obstacles of microtubules, and make neural cell incapable of entering the model of migration or abnormally migrate. The effects of relevant changes of the cytoskeleton induced by irradiation on neural cell migration were discussed in this paper. (authors)

  2. Galectin-3 induced by hypoxia promotes cell migration in thyroid cancer cells.

    Science.gov (United States)

    Zheng, Jiaojiao; Lu, Weihui; Wang, Cong; Xing, Yang; Chen, Xiaoning; Ai, Zhilong

    2017-11-24

    The aim of this study is to investigate the role of Galectin-3 in human thyroid cancer migration. The expression of Galectin-3 in surgical specimens was investigated using immunohistochemistry and western blot. A papillary thyroid cancer cell line (B-cpap) and an anaplastic thyroid cancer cell line (8305c) were transfected with short-hairpin RNA against Galectin-3 (Gal-3-shRNA). Low-molecular citrus pectin (LCP) was also used to antagonize Galectin-3. The migration and invasion of the cell lines were examined. The related signaling pathways were investigated to explore the Galectin-3 mechanism of action. Galectin-3 was highly expressed in metastasized thyroid cancers. Knocking down and antagonizing Galectin-3 significantly suppressed the migration of thyroid cancer cells. Knocking down Galectin-3 inhibited the activity of Wnt, MAPK, Src and Rho signaling pathways. Galectin-3 was up-regulated via HIF-1α in a hypoxic environment. Galectin-3 knockdown could reduce cell motility in hypoxic environments. This study suggests that Galectin-3 could act as a modulator of thyroid cancer migration, especially in hypoxic microenvironments. This regulation function of Galectin-3 may work through multiple signaling pathways.

  3. TUMOUR VACCINE

    NARCIS (Netherlands)

    Wagner, Ernst; Kircheis, Ralf; Crommelin, D.; Van Slooten, Maaike; Storm, Gert

    1999-01-01

    The invention relates to a tumour vaccine with a tumour antigen base. In addition to a source of tumour antigens, the vaccine contains a release system for the delayed release of the active agent IFN- gamma , the active dose of IFN- gamma being 50 ng to 5 mu g. The IFN- gamma is released over a

  4. Cell-surfa