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Sample records for chemokine promotes tumor

  1. Role of Tumor-Derived Chemokines in Osteolytic Bone Metastasis

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    Salvatore J. Coniglio

    2018-06-01

    Full Text Available Metastasis is the primary cause of mortality and morbidity in cancer patients. The bone marrow is a common destination for many malignant cancers, including breast carcinoma (BC, prostate carcinoma, multiple myeloma, lung carcinoma, uterine cancer, thyroid cancer, bladder cancer, and neuroblastoma. The molecular mechanism by which metastatic cancer are able to recognize, infiltrate, and colonize bone are still unclear. Chemokines are small soluble proteins which under normal physiological conditions mediate chemotactic trafficking of leukocytes to specific tissues in the body. In the context of metastasis, the best characterized role for the chemokine system is in the regulation of primary tumor growth, survival, invasion, and homing to specific secondary sites. However, there is ample evidence that metastatic tumors exploit chemokines to modulate the metastatic niche within bone which ultimately results in osteolytic bone disease. In this review, we examine the role of chemokines in metastatic tumor growth within bone. In particular, the chemokines CCL2, CCL3, IL-8/CXCL8, and CXCL12 are consistently involved in promoting osteoclastogenesis and tumor growth. We will also evaluate the suitability of chemokines as targets for chemotherapy with the use of neutralizing antibodies and chemokine receptor-specific antagonists.

  2. Novel chemokine-like activities of histones in tumor metastasis.

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    Chen, Ruochan; Xie, Yangchun; Zhong, Xiao; Fu, Yongmin; Huang, Yan; Zhen, Yixiang; Pan, Pinhua; Wang, Haichao; Bartlett, David L; Billiar, Timothy R; Lotze, Michael T; Zeh, Herbert J; Fan, Xue-Gong; Tang, Daolin; Kang, Rui

    2016-09-20

    Histones are intracellular nucleosomal components and extracellular damage-associated molecular pattern molecules that modulate chromatin remodeling, as well as the immune response. However, their extracellular roles in cell migration and invasion remain undefined. Here, we demonstrate that histones are novel regulators of tumor metastasis with chemokine-like activities. Indeed, exogenous histones promote both hepatocellular carcinoma (HCC) cell migration and invasion through toll-like receptor (TLR)4, but not TLR2 or the receptor for advanced glycosylation end product. TLR4-mediated activation of nuclear factor-κB (NF-κB) by extracellular signal-regulated kinase (ERK) is required for histone-induced chemokine (e.g., C-C motif ligand 9/10) production. Pharmacological and genetic inhibition of TLR4-ERK-NF-κB signaling impairs histone-induced chemokine production and HCC cell migration. Additionally, TLR4 depletion (by using TLR4-/- mice and TLR4-shRNA) or inhibition of histone release/activity (by administration of heparin and H3 neutralizing antibody) attenuates lung metastasis of HCC cells injected via the tail vein of mice. Thus, histones promote tumor metastasis of HCC cells through the TLR4-NF-κB pathway and represent novel targets for treating patients with HCC.

  3. Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations

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    Leibovich-Rivkin, Tal; Buganim, Yosef; Solomon, Hilla; Meshel, Tsipi; Rotter, Varda; Ben-Baruch, Adit

    2012-01-01

    Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of Ras High /p53 Low -modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFα and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-κB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout

  4. Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis

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    Addison, Christina L; Belperio, John A; Burdick, Marie D; Strieter, Robert M

    2004-01-01

    The Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8), GROα (CXCL1) and ENA-78 (CXCL5), all of which have previously been shown to be important in non-small cell lung carcinoma (NSCLC) tumor growth. We hypothesized that overexpression of DARC by a NSCLC tumor cell line would result in the binding of the angiogenic ELR+ CXC chemokines by the tumor cells themselves, and thus interfere with the stimulation of endothelial cells and induction of angiogenesis by the tumor cell-derived angiogenic chemokines. NSCLC tumor cells that constitutively expressed DARC were generated and their growth characteristics were compared to control transfected cells in vitro and in vivo in SCID animals. We found that tumors derived from DARC-expressing cells were significantly larger in size than tumors derived from control-transfected cells. However, upon histological examination we found that DARC-expressing tumors had significantly more necrosis and decreased tumor cellularity, as compared to control tumors. Expression of DARC by NSCLC cells was also associated with a decrease in tumor-associated vasculature and a reduction in metastatic potential. The expression of DARC in the context of NSCLC tumors may act as a chemokine decoy receptor and interferes with normal tumor growth and chemokine-induced tumor neovascularization

  5. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines

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    Fox Bernard A

    2007-11-01

    Full Text Available Abstract Background The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5 melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. Methods These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN, were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-γ or TNF-α was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO was determined using GRIES reagent. Results We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1α and MIP-1β following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-γ or TNF-α, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC, MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin

  6. Chemokines and chemokine receptors: new insights into cancer-related inflammation.

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    Lazennec, Gwendal; Richmond, Ann

    2010-03-01

    Chemokines are involved in cellular interactions and tropism in situations frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation associated with carcinogenesis has been highlighted. Increasing evidence suggests that chemokines are produced by tumor cells as well as by cells of the tumor microenvironment including cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, tumor-associated macrophages (TAMs) and more recently tumor-associated neutrophils (TANs). In addition to affecting tumor cell proliferation, angiogenesis and metastasis, chemokines also seem to modulate senescence and cell survival. Here, we review recent progress on the roles of chemokines and chemokine receptors in cancer-related inflammation, and discuss the mechanisms underlying chemokine action in cancer that might facilitate the development of novel therapies in the future. Copyright 2010 Elsevier Ltd. All rights reserved.

  7. CXCL17 expression by tumor cells recruits CD11b+Gr1 high F4/80- cells and promotes tumor progression.

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    Aya Matsui

    Full Text Available BACKGROUND: Chemokines are involved in multiple aspects of pathogenesis and cellular trafficking in tumorigenesis. In this study, we report that the latest member of the C-X-C-type chemokines, CXCL17 (DMC/VCC-1, recruits immature myeloid-derived cells and enhances early tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: CXCL17 was preferentially expressed in some aggressive types of gastrointestinal, breast, and lung cancer cells. CXCL17 expression did not impart NIH3T3 cells with oncogenic potential in vitro, but CXCL17-expressing NIH3T3 cells could form vasculature-rich tumors in immunodeficient mice. Our data showed that CXCL17-expressing tumor cells increased immature CD11b(+Gr1(+ myeloid-derived cells at tumor sites in mice and promoted CD31(+ tumor angiogenesis. Extensive chemotactic assays proved that CXCL17-responding cells were CD11b(+Gr1(highF4/80(- cells (≈ 90% with a neutrophil-like morphology in vitro. Although CXCL17 expression could not increase the number of CD11b(+Gr1(+ cells in tumor-burdened SCID mice or promote metastases of low metastatic colon cancer cells, the existence of CXCL17-responding myeloid-derived cells caused a striking enhancement of xenograft tumor formation. CONCLUSIONS/SIGNIFICANCE: These results suggest that aberrant expression of CXCL17 in tumor cells recruits immature myeloid-derived cells and promotes tumor progression through angiogenesis.

  8. Atypical chemokine receptors in cancer: friends or foes?

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    Massara, Matteo; Bonavita, Ornella; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2016-06-01

    The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. © Society for Leukocyte Biology.

  9. Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines.

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    Adalsteinsson, Viktor A; Tahirova, Narmin; Tallapragada, Naren; Yao, Xiaosai; Campion, Liam; Angelini, Alessandro; Douce, Thomas B; Huang, Cindy; Bowman, Brittany; Williamson, Christina A; Kwon, Douglas S; Wittrup, K Dane; Love, J Christopher

    2013-10-01

    Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors.

  10. Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils

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    Ming Yuan

    2016-01-01

    Full Text Available Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4+ and CD8+ T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth.

  11. Chemokines in cancer related inflammation

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    Allavena, Paola; Germano, Giovanni; Marchesi, Federica [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089, Rozzano, Milan (Italy); Mantovani, Alberto, E-mail: alberto.mantovani@humanitasresearch.it [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089, Rozzano, Milan (Italy); Department of Translational Medicine, University of Milan (Italy)

    2011-03-10

    Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis. Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies.

  12. Optogenetic control of chemokine receptor signal and T-cell migration

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    Xu, Yuexin; Hyun, Young-Min; Lim, Kihong; Lee, Hyunwook; Cummings, Ryan J.; Gerber, Scott A.; Bae, Seyeon; Cho, Thomas Yoonsang; Lord, Edith M.; Kim, Minsoo

    2014-01-01

    Adoptive cell transfer of ex vivo-generated immune-promoting or tolerogenic T cells to either enhance immunity or promote tolerance in patients has been used with some success. However, effective trafficking of the transferred cells to the target tissue sites is the main barrier to achieving successful clinical outcomes. Here we developed a strategy for optically controlling T-cell trafficking using a photoactivatable (PA) chemokine receptor. Photoactivatable-chemokine C-X-C motif receptor 4 (PA-CXCR4) transmitted intracellular CXCR4 signals in response to 505-nm light. Localized activation of PA-CXCR4 induced T-cell polarization and directional migration (phototaxis) both in vitro and in vivo. Directing light onto the melanoma was sufficient to recruit PA-CXCR4–expressing tumor-targeting cytotoxic T cells and improved the efficacy of adoptive T-cell transfer immunotherapy, with a significant reduction in tumor growth in mice. These findings suggest that the use of photoactivatable chemokine receptors allows remotely controlled leukocyte trafficking with outstanding spatial resolution in tissues and may be feasible in other cell transfer therapies. PMID:24733886

  13. A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus.

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    Alejo, Alí; Ruiz-Argüello, M Begoña; Ho, Yin; Smith, Vincent P; Saraiva, Margarida; Alcami, Antonio

    2006-04-11

    Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis.

  14. A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus

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    Alejo, Alí; Ruiz-Argüello, M. Begoña; Ho, Yin; Smith, Vincent P.; Saraiva, Margarida; Alcami, Antonio

    2006-01-01

    Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis. PMID:16581912

  15. Chemokines: novel targets for breast cancer metastasis

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    Ali, Simi; Lazennec, Gwendal

    2007-01-01

    Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients. PMID:17717637

  16. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells

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    Li Fan

    2010-04-01

    Full Text Available Abstract Background In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC patients remains poor. Therefore, it is crucial to understand what factors are involved in promoting development of HCC. Evidence is accumulating that members of the chemokine receptor family are viewed as promising therapeutic targets in the fight against cancer. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. However, little is known about the effect of CXCR7 on the process of HCC cell invasion and angiogenesis. The aim of this study is to investigate the expression of CXCR7 in hepatocellular carcinoma tissues and cell lines and to evaluate the role of CXCR7 in tumor growth, angiogenesis and invasion of HCC cells. Methods We constructed CXCR7 expressing shRNA, and CXCR7shRNA was subsequently stably transfected into human HCC cells. We evaluated the effect of CXCR7 inhibition on cell invasion, adhesion, VEGF secretion, tube formation and tumor growth. Immunohistochemistry was done to assess the expression of CXCR7 in human hepatocellular carcinoma tissues and CD31 in tumor of mice. We also evaluated the effect of VEGF stimulation on expression of CXCR7. Results CXCR7 was overexpressed in hepatocellular carcinoma tissues. We showed that high invasive potential HCC cell lines express high levels of CXCR7. In vitro, CXCL12 was found to induce invasion, adhesion, tube formation, and VEGF secretion in SMMC-7721 cells. These biological effects were inhibited by silencing of CXCR7 in SMMC-7721 cells. In addition, we also found that VEGF stimulation can up-regulate CXCR7 expression in SMMC-7721 cells and HUVECs. More importantly, enhanced expression of CXCR7 by VEGF was founctional. In vivo, tumor growth and angiogenesis were suppressed by knockdown of CXCR7 in SMMC-7721 cells. However, silencing of CXCR7 did not affect metastasis of tumor in vivo

  17. Chemokines and Chemokine Receptors: Accomplices for Human Immunodeficiency Virus Infection and Latency

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    Zhuo Wang

    2017-10-01

    Full Text Available Chemokines are small chemotactic cytokines that are involved in the regulation of immune cell migration. Multiple functional properties of chemokines, such as pro-inflammation, immune regulation, and promotion of cell growth, angiogenesis, and apoptosis, have been identified in many pathological and physiological contexts. Human immunodeficiency virus (HIV infection is characterized by persistent inflammation and immune activation during both acute and chronic phases, and the “cytokine storm” is one of the hallmarks of HIV infection. Along with immune activation after HIV infection, an extensive range of chemokines and other cytokines are elevated, thereby generating the so-called “cytokine storm.” In this review, the effects of the upregulated chemokines and chemokine receptors on the processes of HIV infection are discussed. The objective of this review was to focus on the main chemokines and chemokine receptors that have been found to be associated with HIV infection and latency. Elevated chemokines and chemokine receptors have been shown to play important roles in the HIV life cycle, disease progression, and HIV reservoir establishment. Thus, targeting these chemokines and receptors and the other proteins of related signaling pathways might provide novel therapeutic strategies, and the evidence indicates a promising future regarding the development of a functional cure for HIV.

  18. T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-γ Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma

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    Qiang Zou

    2015-12-01

    Full Text Available USP15 is a deubiquitinase that negatively regulates activation of naive CD4+ T cells and generation of IFN-γ-producing T helper 1 (Th1 cells. USP15 deficiency in mice promotes antitumor T cell responses in a transplantable cancer model; however, it has remained unclear how deregulated T cell activation impacts primary tumor development during the prolonged interplay between tumors and the immune system. Here, we find that the USP15-deficient mice are hypersensitive to methylcholantrene (MCA-induced fibrosarcomas. Excessive IFN-γ production in USP15-deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet+ regulatory T cells and CD11b+Gr-1+ myeloid-derived suppressor cells at tumor site. Mixed bone marrow adoptive transfer studies further reveals a T cell-intrinsic role for USP15 in regulating IFN-γ production and tumor development. These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-γ, which promotes an immunosuppressive tumor microenvironment during MCA-induced primary tumorigenesis.

  19. A Multi-targeted Approach to Suppress Tumor-Promoting Inflammation

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    Samadi, Abbas K.; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Bishayee, Anupam; Lokeshwar, Bal L.; Grue, Brendan; Panis, Carolina; Boosani, Chandra S.; Poudyal, Deepak; Stafforini, Diana M.; Bhakta, Dipita; Niccolai, Elena; Guha, Gunjan; Rupasinghe, H.P. Vasantha; Fujii, Hiromasa; Honoki, Kanya; Mehta, Kapil; Aquilano, Katia; Lowe, Leroy; Hofseth, Lorne J.; Ricciardiello, Luigi; Ciriolo, Maria Rosa; Singh, Neetu; Whelan, Richard L.; Chaturvedi, Rupesh; Ashraf, S. Salman; Kumara, HMC Shantha; Nowsheen, Somaira; Mohammed, Sulma I.; Helferich, William G.; Yang, Xujuan

    2015-01-01

    Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-kappaB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes. PMID:25951989

  20. CXC-type chemokines promote myofibroblast phenoconversion and prostatic fibrosis.

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    Mehrnaz Gharaee-Kermani

    Full Text Available Recent studies from our group suggest that extracellular matrix (ECM deposition and fibrosis characterize the peri-urethral prostate tissues of some men suffering from Lower Urinary Tract Symptoms (LUTS and that fibrosis may be a contributing factor to the etiology of LUTS. Fibrosis can generally be regarded as an errant wound-healing process in response to chronic inflammation, and several studies have shown that the aging prostate tissue microenvironment is rich with inflammatory cells and proteins. However, it is unclear whether these same inflammatory proteins, particularly CXC-type chemokines, can mediate myofibroblast phenoconversion and the ECM deposition necessary for the development of prostatic tissue fibrosis. To examine this, immortalized and primary prostate stromal fibroblasts treated with TGF-β1, CXCL5, CXCL8, or CXCL12 were evaluated morphologically by microscopy, by immunofluorescence and qRT-PCR for αSMA, collagen 1, vimentin, calponin, and tenascin protein and transcript expression, and by gel contraction assays for functional myofibroblast phenoconversion. The results of these studies showed that that immortalized and primary prostate stromal fibroblasts are induced to express collagen 1 and 3 and αSMA gene transcripts and proteins and to undergo complete and functional myofibroblast phenoconversion in response to CXC-type chemokines, even in the absence of exogenous TGF-β1. Moreover, CXCL12-mediated myofibroblast phenoconversion can be completely abrogated by inhibition of the CXCL12 receptor, CXCR4. These findings suggest that CXC-type chemokines, which comprise inflammatory proteins known to be highly expressed in the aging prostate, can efficiently and completely mediate myofibroblast phenoconversion and may thereby promote fibrotic changes in prostate tissue architecture associated with the development and progression of male lower urinary tract dysfunction.

  1. The CXCR5 chemokine receptor is expressed by carcinoma cells and promotes growth of colon carcinoma in the liver.

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    Meijer, Joost; Zeelenberg, Ingrid S; Sipos, Bence; Roos, Ed

    2006-10-01

    The chemokine receptor CXCR5 is expressed by B cells and certain T cells and controls their migration into and within lymph nodes. Its ligand BCA-1/CXCL13 is present in lymph nodes and spleen and also in the liver. Surprisingly, we detected CXCR5 in several mouse and human carcinoma cell lines. CXCR5 was particularly prominent in pancreatic carcinoma cell lines and was also detected by immunohistochemistry in 7 of 18 human pancreatic carcinoma tissues. Expression in CT26 colon carcinoma was low in vitro, up-regulated in vivo, and rapidly lost when cells were explanted in vitro. CXCL13 strongly promoted proliferation of CXCR5-transfected CT26 cells in vitro. In the liver, after intrasplenic injection, these CXCR5 transfectants initially grew faster than controls, but the growth rate of control tumors accelerated later to become similar to the transfectants, likely due to the up-regulation of CXCR5. Inhibition of CXCR5 function, by trapping CXCR5 in the endoplasmic reticulum using a CXCL13-KDEL "intrakine," had no effect on initial growth of liver foci but later caused a prolonged growth arrest. In contrast, s.c. and lung tumors of CXCR5- and intrakine-transfected cells grew at similar rates as controls. We conclude that expression of CXCR5 on tumor cells promotes the growth of tumor cells in the liver and, at least for CT26 cells, seems to be required for outgrowth to large liver tumors. Given the limited expression on normal cells, CXCR5 may constitute an attractive target for therapy, particularly for pancreatic carcinoma.

  2. A complex pattern of chemokine receptor expression is seen in osteosarcoma

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    Luettichau, Irene von; Huss, Ralf; Nelson, Peter J; Segerer, Stephan; Wechselberger, Alexandra; Notohamiprodjo, Mike; Nathrath, Michaela; Kremer, Markus; Henger, Anna; Djafarzadeh, Roghieh; Burdach, Stefan

    2008-01-01

    Osteosarcoma is the most frequent bone tumor in childhood and adolescence. Patients with primary metastatic disease have a poor prognosis. It is therefore important to better characterize the biology of this tumor to define new prognostic markers or therapeutic targets for tailored therapy. Chemokines and their receptors have been shown to be involved in the development and progression of malignant tumors. They are thought to be active participants in the biology of osteosarcoma. The function of specific chemokines and their receptors is strongly associated with the biological context and microenvironment of their expression. In this report we characterized the expression of a series of chemokine receptors in the complex environment that defines osteosarcoma. The overall level of chemokine receptor mRNA expression was determined using TaqMan RT-PCR of microdissected archival patient biopsy samples. Expression was then verified at the protein level by immunohistochemistry using a series of receptor specific antibody reagents to elucidate the cellular association of expression. Expression at the RNA level was found for most of the tested receptors. CCR1 expression was found on infiltrating mononuclear and polynuclear giant cells in the tumor. Cells associated with the lining of intratumoral vessels were shown to express CCR4. Infiltrating mononuclear cells and tumor cells both showed expression of the receptor CCR5, while CCR7 was predominantly expressed by the mononuclear infiltrate. CCR10 was only very rarely detected in few scattered infiltrating cells. Our data elucidate for the first time the cellular context of chemokine receptor expression in osteosarcoma. This is an important issue for better understanding potential chemokine/chemokine receptor function in the complex biologic processes that underlie the development and progression of osteosarcoma. Our data support the suggested involvement of chemokines and their receptors in diverse aspects of the biology

  3. The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers.

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    Merav Darash-Yahana

    2009-08-01

    Full Text Available Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.

  4. Chemokines as Cancer Vaccine Adjuvants

    Directory of Open Access Journals (Sweden)

    Agne Petrosiute

    2013-10-01

    Full Text Available We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants.

  5. Differential Expression of Chemokine Receptors and their Roles in Cancer Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Nimmagadda, Sridhar, E-mail: snimmag1@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD (United States)

    2012-05-30

    Chemokine/chemokine receptor interactions play diverse roles in cell migration and homeostasis. Emerging evidence suggests that cancer cells co-opt chemokine networks for survival, proliferation, immune evasion, and metastasis. Most of the chemokine receptors are reported to be involved in tumor progression. Given their extensive implication in cancer progression, several chemokine receptor/ligand axes are considered as potential therapeutic targets. This review provides a survey of chemokine receptor expression in cancer and evaluates the potential of chemokine receptor imaging as a tool for molecular characterization of cancer.

  6. Differential Expression of Chemokine Receptors and their Roles in Cancer Imaging

    International Nuclear Information System (INIS)

    Nimmagadda, Sridhar

    2012-01-01

    Chemokine/chemokine receptor interactions play diverse roles in cell migration and homeostasis. Emerging evidence suggests that cancer cells co-opt chemokine networks for survival, proliferation, immune evasion, and metastasis. Most of the chemokine receptors are reported to be involved in tumor progression. Given their extensive implication in cancer progression, several chemokine receptor/ligand axes are considered as potential therapeutic targets. This review provides a survey of chemokine receptor expression in cancer and evaluates the potential of chemokine receptor imaging as a tool for molecular characterization of cancer.

  7. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hyeon-Jae; Lee, Jin-Hwee [College of Pharmacy, Ajou University, Suwon 443-749 (Korea, Republic of); Jung, Yi-Sook, E-mail: yisjung@ajou.ac.kr [College of Pharmacy, Ajou University, Suwon 443-749 (Korea, Republic of); Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 443-749 (Korea, Republic of)

    2014-05-02

    Highlights: • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced TARC and MDC expression in HaCaT cells. • PKCζ, p38 MAPK, or NF-κB mediate TNF-α/IFN-γ-induced TARC and MDC expression. • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced activation of PKCζ, p38 MAPK, or NF-κB. • (+)-Nootkatone suppresses chemokine expression by inhibiting of PKCζ and p38 pathways. - Abstract: Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.

  8. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells.

    Science.gov (United States)

    Choi, Hyeon-Jae; Lee, Jin-Hwee; Jung, Yi-Sook

    2014-05-02

    Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner.

    Directory of Open Access Journals (Sweden)

    Johanna R Reed

    Full Text Available Tumor formation is an extensive process requiring complex interactions that involve both tumor cell-intrinsic pathways and soluble mediators within the microenvironment. Tumor cells exploit the intrinsic functions of many soluble molecules, including chemokines and their receptors, to regulate pro-tumorigenic phenotypes that are required for growth and progression of the primary tumor. Previous studies have shown that activation of inducible FGFR1 (iFGFR1 in mammary epithelial cells resulted in increased proliferation, migration, and invasion in vitro and tumor formation in vivo. These studies also demonstrated that iFGFR1 activation stimulated recruitment of macrophages to the epithelium where macrophages contributed to iFGFR1-mediated epithelial cell proliferation and angiogenesis. The studies presented here further utilize this model to identify the mechanisms that regulate FGFR1-induced macrophage recruitment. Results from this study elucidate a novel role for the inflammatory chemokine CX3CL1 in FGFR1-induced macrophage migration. Specifically, we illustrate that activation of both the inducible FGFR1 construct in mouse mammary epithelial cells and endogenous FGFR in the triple negative breast cancer cell line, HS578T, leads to expression of the chemokine CX3CL1. Furthermore, we demonstrate that FGFR-induced CX3CL1 is sufficient to recruit CX3CR1-expressing macrophages in vitro. Finally, blocking CX3CR1 in vivo leads to decreased iFGFR1-induced macrophage recruitment, which correlates with decreased angiogenesis. While CX3CL1 is a known target of FGF signaling in the wound healing environment, these studies demonstrate that FGFR activation also leads to induction of CX3CL1 in a tumor setting. Furthermore, these results define a novel role for CX3CL1 in promoting macrophage recruitment during mammary tumor formation, suggesting that the CX3CL1/CX3CR1 axis may represent a potential therapeutic approach for targeting breast cancers associated

  10. Composing a Tumor Specific Bacterial Promoter.

    Directory of Open Access Journals (Sweden)

    Igor V Deyneko

    Full Text Available Systemically applied Salmonella enterica spp. have been shown to invade and colonize neoplastic tissues where it retards the growth of many tumors. This offers the possibility to use the bacteria as a vehicle for the tumor specific delivery of therapeutic molecules. Specificity of such delivery is solely depending on promoter sequences that control the production of a target molecule. We have established the functional structure of bacterial promoters that are transcriptionally active exclusively in tumor tissues after systemic application. We observed that the specific transcriptional activation is accomplished by a combination of a weak basal promoter and a strong FNR binding site. This represents a minimal set of control elements required for such activation. In natural promoters, additional DNA remodeling elements are found that alter the level of transcription quantitatively. Inefficiency of the basal promoter ensures the absence of transcription outside tumors. As a proof of concept, we compiled an artificial promoter sequence from individual motifs representing FNR and basal promoter and showed specific activation in a tumor microenvironment. Our results open possibilities for the generation of promoters with an adjusted level of expression of target proteins in particular for applications in bacterial tumor therapy.

  11. The role of chemokines and chemokine receptors in eosinophil activation during inflammatory allergic reactions

    Directory of Open Access Journals (Sweden)

    Oliveira S.H.P.

    2003-01-01

    Full Text Available Chemokines are important chemotactic cytokines that play a fundamental role in the trafficking of leukocytes to sites of inflammation. They are also potent cell-activating factors, inducing cytokine and histamine release and free radical production, a fact that makes them particularly important in the pathogenesis of allergic inflammation. The action of chemokines is regulated at the level of agonist production and processing as well as at the level of receptor expression and coupling. Therefore, an analysis of the ligands must necessarily consider receptors. Eosinophils are target cells involved in the allergic inflammatory response since they are able to release a wide variety of mediators including CC and CXC chemokines and express their receptors. These mediators could damage the airway epithelial cells and might be important to stimulate other cells inducing an amplification of the allergic response. This review focuses on recently emerging data pertaining to the importance of chemokines and chemokine receptors in promoting eosinophil activation and migration during the allergic inflammatory process. The analysis of the function of eosinophils and their chemokine receptors during allergic inflammation might be a good approach to understanding the determinants of asthma severity and to developing novel therapies.

  12. Elevated chemokine CC-motif receptor-like 2 (CCRL2) promotes cell migration and invasion in glioblastoma.

    Science.gov (United States)

    Yin, Fengqiong; Xu, Zhenhua; Wang, Zifeng; Yao, Hong; Shen, Zan; Yu, Fang; Tang, Yiping; Fu, Dengli; Lin, Sheng; Lu, Gang; Kung, Hsiang-Fu; Poon, Wai Sang; Huang, Yunchao; Lin, Marie Chia-Mi

    2012-12-14

    Chemokine CC-motif receptor-like 2 (CCRL2) is a 7-transmembrane G protein-coupled receptor which plays a key role in lung dendritic cell trafficking to peripheral lymph nodes. The function and expression of CCRL2 in cancer is not understood at present. Here we report that CCRL2 expression level is elevated in human glioma patient samples and cell lines. The magnitude of increase is positively associated with increasing tumor grade, with the highest level observed in grade IV glioblastoma. By gain-of-function and loss-of-function studies, we further showed that CCRL2 did not regulate the growth of human glioblatoma U87 and U373 cells. Importantly, we demonstrated that over-expression of CCRL2 significantly enhanced the migration rate and invasiveness of the glioblastoma cells. Taken together, these results suggest for the first time that elevated CCRL2 in glioma promotes cell migration and invasion. The potential roles of CCRL2 as a novel therapeutic target and biomarker warrant further investigations. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

    Directory of Open Access Journals (Sweden)

    Adriana Albini

    2018-04-01

    Full Text Available The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves not only cancer cells but also various tumor-associated leukocytes (TALs and stromal cells. TALs produce chemokines, cytokines, proteases, structural proteins, and microvescicles. Vascular endothelial growth factor (VEGF and inflammatory chemokines are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In our review, we discuss the regulation of angiogenesis by innate immune cells in the tumor microenvironment, specific features, and roles of major players: macrophages, neutrophils, myeloid-derived suppressor and dendritic cells, mast cells, γδT cells, innate lymphoid cells, and natural killer cells. Anti-VEGF or anti-inflammatory drugs could balance an immunosuppressive microenvironment to an immune permissive one. Anti-VEGF as well as anti-inflammatory drugs could therefore represent partners for combinations with immune checkpoint inhibitors, enhancing the effects of immune therapy.

  14. A radiogallium-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging.

    Science.gov (United States)

    Sano, Kohei; Masuda, Ryo; Hisada, Hayato; Oishi, Shinya; Shimokawa, Kenta; Ono, Masahiro; Fujii, Nobutaka; Saji, Hideo; Mukai, Takahiro

    2014-03-01

    We have developed a novel radiogallium (Ga)-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging. A CXCR4 imaging probe with two CXCR4 antagonists (Ac-TZ14011) on Ga-DOTA core, Ga-DOTA-TZ2, was synthesized, and the affinity and binding to CXCR4 was evaluated in CXCR4 expressing cells in vitro. The affinity of Ga-DOTA-TZ2 for CXCR4 was 20-fold greater than the corresponding monovalent probe, Ga-DOTA-TZ1. (67)Ga-DOTA-TZ2 showed the significantly higher accumulation in CXCR4-expressing tumor cells compared with (67)Ga-DOTA-TZ1, suggesting the bivalent effect enhances its binding to CXCR4. The incorporation of two CXCR4 antagonists to Ga-DOTA could be effective in detecting CXCR4-expressing tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Chemokine Receptor-Specific Antibodies in Cancer Immunotherapy: Achievements and Challenges

    Science.gov (United States)

    Vela, Maria; Aris, Mariana; Llorente, Mercedes; Garcia-Sanz, Jose A.; Kremer, Leonor

    2015-01-01

    The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications. PMID:25688243

  16. Sonic Hedgehog Signaling Promotes Tumor Growth

    National Research Council Canada - National Science Library

    Bushman, Wade

    2007-01-01

    ... of the DOD New Investigator award indicate that Shh signaling promotes tumor growth. This proposal addresses the hypothesis that Sonic hedgehog signaling promotes tumor growth by activating stromal cell gene expression...

  17. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Pimenta, Erica M. [Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States); Barnes, Betsy J., E-mail: barnesbe@njms.rutgers.edu [Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States)

    2014-04-23

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin{sup ®}) and rituximab (Rituxan{sup ®})) and the first approved cancer vaccine, Provenge{sup ®} (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

  18. Role of Tertiary Lymphoid Structures (TLS in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Directory of Open Access Journals (Sweden)

    Erica M. Pimenta

    2014-04-01

    Full Text Available Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin® and rituximab (Rituxan® and the first approved cancer vaccine, Provenge® (sipuleucel-T, investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS within the tumor microenvironment may be used to enhance immunotherapy response.

  19. The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally?

    Science.gov (United States)

    Yoshimura, Teizo

    2018-01-29

    Macrophages are one of the most abundant leukocyte populations infiltrating tumor tissues and can exhibit both tumoricidal and tumor-promoting activities. In 1989, we reported the purification of monocyte chemoattractant protein-1 (MCP-1) from culture supernatants of mitogen-activated peripheral blood mononuclear cells and tumor cells. MCP-1 is a potent monocyte-attracting chemokine, identical to the previously described lymphocyte-derived chemotactic factor or tumor-derived chemotactic factor, and greatly contributes to the recruitment of blood monocytes into sites of inflammatory responses and tumors. Because in vitro-cultured tumor cells often produce significant amounts of MCP-1, tumor cells are considered to be the main source of MCP-1. However, various non-tumor cells in the tumor stroma also produce MCP-1 in response to stimuli. Studies performed in vitro and in vivo have provided evidence that MCP-1 production in tumors is a consequence of complex interactions between tumor cells and non-tumor cells and that both tumor cells and non-tumor cells contribute to the production of MCP-1. Although MCP-1 production was once considered to be a part of host defense against tumors, it is now believed to regulate the vicious cycle between tumor cells and macrophages that promotes the progression of tumors.Cellular and Molecular Immunology advance online publication, 29 January 2018; doi:10.1038/cmi.2017.135.

  20. THE TUMOR MACROENVIRONMENT: CANCER-PROMOTING NETWORKS BEYOND TUMOR BEDS

    OpenAIRE

    Rutkowski, Melanie R.; Svoronos, Nikolaos; Puchalt, Alfredo Perales; Conejo-Garcia, Jose R.

    2015-01-01

    During tumor progression, alterations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion to distal organs, and eventual metastatic disease. Distally produced hormones, commensal microbiota residing within mucosal surfaces, and myeloid cells and even the bone marrow impact the systemic immune system, tumor growth, and metastatic spread. Understanding the reciprocal interactions between the cells and soluble factors within the mac...

  1. Chemokines and Chemokine Receptors in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Wenjing Cheng

    2014-01-01

    Full Text Available Multiple sclerosis is an autoimmune disease with classical traits of demyelination, axonal damage, and neurodegeneration. The migration of autoimmune T cells and macrophages from blood to central nervous system as well as the destruction of blood brain barrier are thought to be the major processes in the development of this disease. Chemokines, which are small peptide mediators, can attract pathogenic cells to the sites of inflammation. Each helper T cell subset expresses different chemokine receptors so as to exert their different functions in the pathogenesis of MS. Recently published results have shown that the levels of some chemokines and chemokine receptors are increased in blood and cerebrospinal fluid of MS patients. This review describes the advanced researches on the role of chemokines and chemokine receptors in the development of MS and discusses the potential therapy of this disease targeting the chemokine network.

  2. Tumor-Infiltrating Immune Cells Promoting Tumor Invasion and Metastasis: Existing Theories

    Directory of Open Access Journals (Sweden)

    Yan-gao Man, Alexander Stojadinovic, Jeffrey Mason, Itzhak Avital, Anton Bilchik, Bjoern Bruecher, Mladjan Protic, Aviram Nissan, Mina Izadjoo, Xichen Zhang, Anahid Jewett

    2013-01-01

    Full Text Available It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness.

  3. Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Yani Zhao

    Full Text Available The Duffy antigen receptor for chemokines (DARC shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear.We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated (125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. (125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression.(125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells.These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization.

  4. Chemokines

    Directory of Open Access Journals (Sweden)

    Richard Horuk

    2007-01-01

    Full Text Available Chemokines are a family of polypeptides that direct the migration of leukocytestoward a site of infection. They play a major role in autoimmune disease and chemokine receptors have recently been found to mediate HIV-1 fusion. In this short review we examine the role of chemokines in host defence and in the pathophysiology of autoimmune diseases. We conclude by discussing various therapeutic approaches that target chemokine receptors and that could be beneficial in disease.

  5. Ionizing radiation in tumor promotion and progression

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.

    1990-08-01

    Chronic exposure to beta radiation has been tested as a tumor promoting or progressing agent. The dorsal skins of groups of 25 female SENCAR mice were chemically initiated with a single exposure to DMBA, and chronic exposure to strontium-90/yttrium-90 beta radiation was tested as a stage 1, stage 2 or complete skin tumor promoter. Exposure of initiated mice to 0.5 gray twice a week for 13 weeks produced no papillomas, indicating no action as a complete promoter. Another similar group of animals was chemically promoted through stage 1 (with TPA) followed by 0.5 gray of beta radiation twice a week for 13 weeks. Again no papillomas developed indicating no action of chronic radiation as a stage 2 tumor promoter. The same radiation exposure protocol in another DMBA initiated group receiving both stage 1 and 2 chemical promotion resulted in a decrease in papilloma frequency, compared to the control group receiving no beta irradiation, indicating a tumor preventing effect of radiation at stage 2 promotion, probably by killing initiated cells. Chronic beta radiation was tested three different ways as a stage 1 tumor promoter. When compared to the appropriate control, beta radiation given after initiation as a stage 1 promoter (0.5 gray twice a week for 13 weeks), after initiation and along with a known stage 1 chemical promoter (1.0 gray twice a week for 2 weeks), or prior to initiation as a stage 1 promoter (0.5 gray twice a week for 4 weeks), each time showed a weak (∼ 15% stimulation) but statistically significant (p<0.01) ability to act as a stage 1 promoter. When tested as a tumor progressing agent delivered to pre-existing papillomas, beta radiation (0.5 gray twice a week for 13 weeks) increased carcinoma frequency from 0.52 to 0.68 carcinoma/animal, but this increase was not statistically significant at the 95% confidence level. We conclude that in the addition to the known initiating, progressing and complete carcinogenic action of acute exposures to ionizing

  6. Targeting chemokine (C-C motif) ligand 2 (CCL2) as an example of translation of cancer molecular biology to the clinic.

    Science.gov (United States)

    Zhang, Jian; Patel, Lalit; Pienta, Kenneth J

    2010-01-01

    Chemokines are a family of small and secreted proteins that play pleiotropic roles in inflammation-related pathological diseases, including cancer. Among the identified 50 human chemokines, chemokine (C-C motif) ligand 2 (CCL2) is of particular importance in cancer development since it serves as one of the key mediators of interactions between tumor and host cells. CCL2 is produced by cancer cells and multiple different host cells within the tumor microenvironment. CCL2 mediates tumorigenesis in many different cancer types. For example, CCL2 has been reported to promote prostate cancer cell proliferation, migration, invasion, and survival, via binding to its functional receptor CCR2. Furthermore, CCL2 induces the recruitment of macrophages and induces angiogenesis and matrix remodeling. Targeting CCL2 has been demonstrated as an effective therapeutic approach in preclinical prostate cancer models, and currently, neutralizing monoclonal antibody against CCL2 has entered into clinical trials in prostate cancer. In this chapter, targeting CCL2 in prostate cancer will be used as an example to show translation of laboratory findings from cancer molecular biology to the clinic. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  8. The Tumor Macroenvironment: Cancer-Promoting Networks Beyond Tumor Beds.

    Science.gov (United States)

    Rutkowski, Melanie R; Svoronos, Nikolaos; Perales-Puchalt, Alfredo; Conejo-Garcia, Jose R

    2015-01-01

    During tumor progression, alterations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion to distal organs, and eventual metastatic disease. Distally produced hormones, commensal microbiota residing within mucosal surfaces, myeloid cells and even the bone marrow impact the systemic immune system, tumor growth, and metastatic spread. Understanding the reciprocal interactions between the cells and soluble factors within the macroenvironment and the primary tumor will enable the design of specific therapies that have the potential to prevent dissemination and metastatic spread. This chapter will summarize recent findings detailing how the primary tumor and systemic tumor macroenvironment coordinate malignant progression. © 2015 Elsevier Inc. All rights reserved.

  9. What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

    Energy Technology Data Exchange (ETDEWEB)

    Kufareva, Irina; Gustavsson, Martin; Zheng, Yi; Stephens, Bryan S.; Handel, Tracy M. (UCSD)

    2017-05-22

    Chemokines and their cell surface G protein–coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

  10. Intracellular coexpression of CXC- and CC– chemokine receptors and their ligands in human melanoma cell lines and dynamic variations after xenotransplantation

    International Nuclear Information System (INIS)

    Pinto, Sandra; Martínez-Romero, Alicia; O’Connor, José-Enrique; Gil-Benso, Rosario; San-Miguel, Teresa; Terrádez, Liria; Monteagudo, Carlos; Callaghan, Robert C

    2014-01-01

    Chemokines have been implicated in tumor progression and metastasis. In melanoma, chemokine receptors have been implicated in organ selective metastasis by regulating processes such as chemoattraction, adhesion and survival. In this study we have analyzed, using flow cytometry, the systems formed by the chemokine receptors CXCR3, CXCR4, CXCR7, CCR7 and CCR10 and their ligands in thirteen human melanoma cell lines (five established from primary tumors and eight established from metastasis from different tissues). WM-115 and WM-266.4 melanoma cell lines (obtained from a primary and a metastatic melanoma respectively) were xenografted in nude mice and the tumors and cell lines derived from them were also analyzed. Our results show that the melanoma cell lines do not express or express in a low degree the chemokine receptors on their cell surface. However, melanoma cell lines show intracellular expression of all the aforementioned receptors and most of their respective ligands. When analyzing the xenografts and the cell lines obtained from them we found variations in the intracellular expression of chemokines and chemokine receptors that differed between the primary and metastatic cell lines. However, as well as in the original cell lines, minute or no expression of the chemokine receptors was observed at the cell surface. Coexpression of chemokine receptors and their ligands was found in human melanoma cell lines. However, this expression is intracellular and receptors are not found at the cell membrane nor chemokines are secreted to the cell medium. The levels of expressed chemokine receptors and their ligands show dynamic variations after xenotransplantation that differ depending on the origin of the cell line (from primary tumor or from metastasis)

  11. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

    Directory of Open Access Journals (Sweden)

    Jessica L Williams

    2014-05-01

    Full Text Available In the adult central nervous system (CNS, chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.

  12. Chronic ionizing radiation exposure as a tumor promoter in mouse skin

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.; Trivedi, A.

    1992-01-01

    We have tested a chronic exposure to 90 Y beta-radiation as a tumor promoter in mouse skin previously exposed to a chemical tumor initiator. Three different tests of radiation as a stage I tumor promoter, in skin subsequently given chemical stage II promotion, all indicated that the beta-radiation acted as a weak stage I skin tumor promoter. It showed no action as either a stage II or complete tumor promoter. (author)

  13. Citrullinated Chemokines in Rheumatoid Arthritis

    Science.gov (United States)

    2016-12-01

    inflammation, thick- ness of the synovial lining layer, and vascularity (16). These observations support the hypothesis that citrulli- nated chemokines may...Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA, et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium...arthritis: regulation of its production in synovial cells by interleukin-1 and tumor necrosis factor. Arthritis Rheum 1993;36:762–71. 35. Hatano Y

  14. Breast Cancer Vaccines Based on Dendritic Cells and the Chemokines

    National Research Council Canada - National Science Library

    Mule, James

    1998-01-01

    The major objective of this project is to establish a new modality for the treatment of breast cancer that employs the combination of chemokine gene-modified fibroblasts with breast tumor-pulsed dendritic cells (DC...

  15. Breast Cancer Vaccines Based on Dendritic Cells and the Chemokines

    National Research Council Canada - National Science Library

    Mule, James

    1997-01-01

    The major objective of this project is to establish a new modality for the treatment of breast cancer that employs the combination of chemokine gene modified fibroblasts with breast tumor pulsed dendritic cells (DC...

  16. Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2).

    Science.gov (United States)

    Dvorak, Kaitlyn M; Pettee, Krista M; Rubinic-Minotti, Kaitlin; Su, Robin; Nestor-Kalinoski, Andrea; Eisenmann, Kathryn M

    2018-01-01

    The tumor microenvironment (TME) promotes tumor cell invasion and metastasis. An important step in the shift to a pro-cancerous microenvironment is the transformation of normal stromal fibroblasts to carcinoma-associated fibroblasts (CAFs). CAFs are present in a majority of solid tumors and can directly promote tumor cell motility via cytokine, chemokine and growth factor secretion into the TME. The exact effects that the TME has upon cytoskeletal regulation in motile tumor cells remain enigmatic. The conserved formin family of cytoskeleton regulating proteins plays an essential role in the assembly and/or bundling of unbranched actin filaments. Mammalian Diaphanous-related formin 2 (mDia2/DIAPH3/Drf3/Dia) assembles a dynamic F-actin cytoskeleton that underlies tumor cell migration and invasion. We therefore sought to understand whether CAF-derived chemokines impact breast tumor cell motility through modification of the formin-assembled F-actin cytoskeleton. In MDA-MB-231 cells, conditioned media (CM) from WS19T CAFs, a human breast tumor-adjacent CAF line, significantly and robustly increased wound closure and invasion relative to normal human mammary fibroblast (HMF)-CM. WS19T-CM also promoted proteasome-mediated mDia2 degradation in MDA-MB-231 cells relative to control HMF-CM and WS21T CAF-CM, a breast CAF cell line that failed to promote robust MDA-MB-231 migration. Cytokine array analysis of CM identified up-regulated secreted factors in WS19T relative to control WS21T CM. We identified CXCL12 as a CM factor influencing loss of mDia2 protein while increasing MDA-MB-231 cell migration. Our data suggest a mechanism whereby CAFs promote tumor cell migration and invasion through CXCL12 secretion to regulate the mDia2-directed cytoskeleton in breast tumor cells.

  17. Tumor Suppression and Promotion by Autophagy

    Directory of Open Access Journals (Sweden)

    Yenniffer Ávalos

    2014-01-01

    Full Text Available Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

  18. Tumor suppression and promotion by autophagy.

    Science.gov (United States)

    Ávalos, Yenniffer; Canales, Jimena; Bravo-Sagua, Roberto; Criollo, Alfredo; Lavandero, Sergio; Quest, Andrew F G

    2014-01-01

    Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

  19. The Role of Cytokines, Chemokines, and Growth Factors in the Pathogenesis of Pityriasis Rosea

    Directory of Open Access Journals (Sweden)

    Francesco Drago

    2015-01-01

    Full Text Available Introduction. Pityriasis rosea (PR is an exanthematous disease related to human herpesvirus- (HHV- 6/7 reactivation. The network of mediators involved in recruiting the infiltrating inflammatory cells has never been studied. Object. To investigate the levels of serum cytokines, growth factors, and chemokines in PR and healthy controls in order to elucidate the PR pathogenesis. Materials and Methods. Interleukin- (IL- 1, IL-6, IL-17, interferon- (IFN- γ, tumor necrosis factor- (TNF- α, vascular endothelial growth factor (VEGF, granulocyte colony stimulating factor (G-CSF, and chemokines, CXCL8 (IL-8 and CXCL10 (IP-10, were measured simultaneously by a multiplex assay in early acute PR patients’ sera and healthy controls. Subsequently, sera from PR patients were analysed at 3 different times (0, 15, and 30 days. Results and discussion. Serum levels of IL-17, IFN-γ, VEGF, and IP-10 resulted to be upregulated in PR patients compared to controls. IL-17 has a key role in host defense against pathogens stimulating the release of proinflammatory cytokines/chemokines. IFN-γ has a direct antiviral activity promoting NK cells and virus specific T cells cytotoxicity. VEGF stimulates vasculogenesis and angiogenesis. IP-10 can induce chemotaxis, apoptosis, cell growth, and angiogenesis. Conclusions. Our findings suggest that these inflammatory mediators may modulate PR pathogenesis in synergistic manner.

  20. NADPH promotes the rapid growth of the tumor

    Directory of Open Access Journals (Sweden)

    Hao Sheng

    2018-04-01

    Full Text Available NADPH oxidase is the main source of intracellular reactive oxygen species (ROS. ROS plays an important role in a variety of tumor types. The ROS mediated by NADPH oxidase increases the expression of hypoxia-inducible factor alpha (HIF-α through multiple signaling pathways in tumor, and HIF-α could be regulated and controlled by downstream multiple targeted genes such as vascular endothelial growth factor, glucose transporter to promote tumor angiogenesis, cell energy metabolism reprogram and tumor metastasis. Meanwhile, HIF-α can also regulate the expression of NADPH oxidase by ROS, thus further promoting development of tumor. In this review, we summarized the functions of NADPH in tumorigenesis and discussed their potential implications in cancer therapy.

  1. Promotion of Tumor Invasion by Cooperation of Granulocytes and Macrophages Activated by Anti-tumor Antibodies

    Directory of Open Access Journals (Sweden)

    Emilio Barbera-Guillem

    1999-11-01

    Full Text Available We investigated the potential role of anti-tumor antibodies and tumor antigens in the formation of immune complexes which promote matrix degradation and angiogenesis. B-cell deficient or B-cell depleted mice showed a reduction in tumor invasion and metastasis. In vitro invasion assays and in vivo models of metastasis showed that anti-sTn antibodies and sTn tumor antigens form complexes which induce granulocytes and macrophages together to mediate tumor invasion and metastasis by processes including extracellular matrix degradation and angiogenesis. These results suggest the existence of a tumor promoting role of a B-cell immune response induced by shed tumor associated antigens of solid, nonlymphoid tumors.

  2. Targeting tumor-associated macrophages by anti-tumor Chinese materia medica.

    Science.gov (United States)

    Pu, Wei-Ling; Sun, Li-Kang; Gao, Xiu-Mei; Rüegg, Curzio; Cuendet, Muriel; Hottiger, Micheal O; Zhou, Kun; Miao, Lin; Zhang, Yun-Sha; Gebauer, Margaret

    2017-10-01

    Tumor-associated macrophages (TAMs) play a key role in all stages of tumorigenesis and tumor progression. TAMs secrete different kinds of cytokines, chemokines, and enzymes to affect the progression, metastasis, and resistance to therapy depending on their state of reprogramming. Therapeutic benefit in targeting TAMs suggests that macrophages are attractive targets for cancer treatment. Chinese materia medica (CMM) is an important approach for treating cancer in China and in the Asian region. According to the theory of Chinese medicine (CM) and its practice, some prescriptions of CM regulate the body's internal environment possibly including the remodeling the tumor microenvironment (TME). Here we briefly summarize the pivotal effects of TAMs in shaping the TME and promoting tumorigenesis, invasion, metastasis and immunosuppression. Furthermore, we illustrate the effects and mechanisms of CMM targeting TAMs in antitumor therapy. Finally, we reveal the CMM's dual-regulatory and multi-targeting functions on regulating TAMs, and hopefully, provide the theoretical basis for CMM clinical practice related to cancer therapy.

  3. Genes that cooperate with tumor promoters in transformation

    International Nuclear Information System (INIS)

    Colburn, N.H.; Smith, B.M.

    1988-01-01

    Tumor-promoting phorbol esters, like growth factors, elicit pleiotropic responses involving biochemical pathways that lead to different biological responses. Genetic variant cell lines that are resistant to mitogenic, differentiation, or transformation responses to tumor promoters have been valuable tools for understanding the molecular bases of these responses. Studies using the mouse epidermal JB6 cell lines that are sensitive or resistant to tumor promoter-induced transformation have yielded new understanding of genetic and signal transduction events involved in neoplastic transformation. The isolation and characterization of cloned mouse promotion sensitivity genes pro-1 and pro-2 is reviewed. A new activity of pro-1 has been identified: when transfected into human cancer prone basal cell nevus syndrome fibroblasts but not normal fibroblasts mouse pro-1 confers lifespan extension of these cells. Recently, we have found tat a pro-1 homolog from a library of nasopharyngeal carcinoma, but not the homolog from a normal human library, is activated for transferring promotion sensitivity. The many genetic variants for responses to tumor promoters have also proved valuable for signal transduction studies. JPB P- cells fail to show the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced syntheses of two proteins of 15 and 16 kD seen in P+ cells. P-, P+, and TPA transformed cells show a progressive decrease in both basal and TPA-inducible levels of a protein kinase C substrate of 80 kD. P- cells are relatively resistant both to anchorage-independent transformation and to a protein band shift induced by the calcium analog lanthanum. It appears that one or more calcium-binding proteins and one or more pro genes may be critical determinants of tumor promoter-induced neoplastic transformation

  4. Chemokine Function in Periodontal Disease and Oral Cavity Cancer

    Science.gov (United States)

    Sahingur, Sinem Esra; Yeudall, W. Andrew

    2015-01-01

    The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor progression. Interaction between cancer cells and their microenvironment is mediated in large part by secreted factors such as chemokines, and serves to enhance the malignant phenotype in oral and other cancers. In this article, we will outline the biological and biochemical mechanisms of chemokine action in host–microbiome interactions in periodontal disease and in oral cancer, and how these may overlap and contribute to pathogenesis. PMID:25999952

  5. Molecular Mechanisms of Mouse Skin Tumor Promotion

    International Nuclear Information System (INIS)

    Rundhaug, Joyce E.; Fischer, Susan M.

    2010-01-01

    Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen-activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-α and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion

  6. Quantitative Methylation Profiles for Multiple Tumor Suppressor Gene Promoters in Salivary Gland Tumors

    Science.gov (United States)

    Durr, Megan L.; Mydlarz, Wojciech K.; Shao, Chunbo; Zahurak, Marianna L.; Chuang, Alice Y.; Hoque, Mohammad O.; Westra, William H.; Liegeois, Nanette J.; Califano, Joseph A.; Sidransky, David; Ha, Patrick K.

    2010-01-01

    Background Methylation profiling of tumor suppressor gene (TSGs) promoters is quickly becoming a powerful diagnostic tool for the early detection, prognosis, and even prediction of clinical response to treatment. Few studies address this in salivary gland tumors (SGTs); hence the promoter methylation profile of various TSGs was quantitatively assessed in primary SGT tissue to determine if tumor-specific alterations could be detected. Methodology DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence-based, quantitative methylation-specific PCR (qMSP). The data were utilized in a binary fashion as well as quantitatively (using a methylation quotient) allowing for better profiling and interpretation of results. Principal Findings The average number of methylation events across the studied genes was highest in salivary duct carcinoma (SDC), with a methylation value of 9.6, compared to the normal 4.5 (ptrend for increasing methylation in APC, Mint 1, PGP9.5, RAR-β, and Timp3. Conclusions/Significance Screening promoter methylation profiles in SGTs showed considerable heterogeneity. The methylation status of certain markers was surprisingly high in even normal salivary tissue, confirming the need for such controls. Several TSGs were found to be associated with malignant SGTs, especially SDC. Further study is needed to evaluate the potential use of these associations in the detection, prognosis, and therapeutic outcome of these rare tumors. PMID:20520817

  7. ELR+ CXC chemokine expression in benign and malignant colorectal conditions

    International Nuclear Information System (INIS)

    Rubie, Claudia; Frick, Vilma Oliveira; Wagner, Mathias; Schuld, Jochen; Gräber, Stefan; Brittner, Brigitte; Bohle, Rainer M; Schilling, Martin K

    2008-01-01

    CXCR2 chemokine ligands CXCL1, CXCL5 and CXCL6 were shown to be involved in chemoattraction, inflammatory responses, tumor growth and angiogenesis. Here, we comparatively analyzed their expression profile in resection specimens from patients with colorectal adenoma (CRA) (n = 30) as well as colorectal carcinoma (CRC) (n = 48) and corresponding colorectal liver metastases (CRLM) (n = 16). Chemokine expression was assessed by microdissection, quantitative real-time PCR (Q-RT-PCR), the enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). In contrast to CXCL6, we demonstrated CXCL1 and CXCL5 mRNA and protein expression to be significantly up-regulated in CRC and CRLM tissue specimens in relation to their matched tumor neighbor tissues. Moreover, both chemokine ligands were demonstrated to be significantly higher expressed in CRC tissues than in CRA tissues thus indicating a progressive increase in the transition from the premalignant condition to the development of the malignant status. Although a comparative analysis of the CXCL1/CXCL5 protein expression profiles in CRC patients revealed that the absolute expression level of CXCL1 was significantly higher in comparison to CXCL5, mRNA- and protein overexpression of CXCL5 in CRC and CRLM tissues was much more pronounced (80- and 60- fold in CRC tissues, respectively) in comparison to CXCL1 (5- and 3.5- fold in CRC tissues, respectively). Our results demonstrate a significant association between CXCL1 and CXCL5 expression with CRC and CRLM suggesting for both chemokine ligands a potential role in the progression from CRA to CRC and thus, in the initiation of CRC

  8. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

    DEFF Research Database (Denmark)

    Holst, P J; Rosenkilde, M M; Manfra, D

    2001-01-01

    sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does...... not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines....

  9. Tumor-Associated Macrophages Recruit CCR6+ Regulatory T Cells and Promote the Development of Colorectal Cancer via Enhancing CCL20 Production in Mice

    Science.gov (United States)

    Li, Qun; Zhang, Weiwei; Ke, Fang; Leng, Qibin; Wang, Hong; Chen, Jinfei; Wang, Honglin

    2011-01-01

    Background Tumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3+ regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown. Methodology/Principal Findings CRC was either induced by N-methyl-N-nitrosourea (MNU) and H. pylori or established by subcutaneous injection of mouse colorectal tumor cell line (CMT93) in mice. CMT93 cells were co-cultured with primary macrophages in a transwell apparatus. Recruitment of FoxP3 green fluorescence protein positive (FoxP3GFP+) Treg-cells was assessed using the IVIS Imaging System or immunofluorescence staining. A role for macrophages in trafficking of Treg-cells and in the development of CRC was investigated in CD11b diphtheria toxin receptor (CD11b-DTR) transgenic C57BL/6J mice in which macrophages can be selectively depleted. Treg-cells remarkably infiltrated solid tumor, and predominantly expressed the homing chemokine receptor (CCR) 6 in the induced CRC model. Both CMT93 cancer cells and macrophages produced a large amount of CCL20, the sole ligand of CCR6 in vitro and in vivo. Injection of recombinant mouse CCL20 into tumor sites promoted its development with a marked recruitment of Treg-cells in the graft CRC model. Conditional macrophage ablation decreased CCL20 levels, blocked Treg-cell recruitment and inhibited tumor growth in CD11b-DTR mice grafted with CMT93. Conclusions/Significance TAMs recruit CCR6+ Treg-cells to tumor mass and promote its development via enhancing the production of CCL20 in a CRC mouse model. PMID:21559338

  10. Chemokines, lymphocytes, and HIV

    Directory of Open Access Journals (Sweden)

    Farber J.M.

    1998-01-01

    Full Text Available Chemokines are members of a family of more than 30 human cytokines whose best-described activities are as chemotactic factors for leukocytes and that are presumed to be important in leukocyte recruitment and trafficking. While many chemokines can act on lymphocytes, the roles of chemokines and their receptors in lymphocyte biology are poorly understood. The recent discoveries that chemokines can suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate co-receptors for HIV-1 entry have lent urgency to studies on the relationships between chemokines and lymphocytes. My laboratory has characterized Mig and Crg-2/IP-10, chemokines that are induced by IFN-g and that specifically target lymphocytes, particularly activated T cells. We have demonstrated that the genes for these chemokines are widely expressed during experimental infections in mice with protozoan and viral pathogens, but that the patterns of mig and crg-2 expression differed, suggesting non-redundant roles in vivo. Our related studies to identify new chemokine receptors from activated lymphocytes resulted in the cloning of STRL22 and STRL33. We and others have shown that STRL22 is a receptor for the CC chemokine MIP-3a, and STRL22 has been re-named CCR6. Although STRL33 remains an orphan receptor, we have shown that it can function as a co-receptor for HIV-1 envelope glycoproteins, and that it is active with a broader range of HIV-1 envelope glycoproteins than the major co-receptors described to date. The ability of STRL33 to function with a wide variety of envelope glycoproteins may become particularly important if therapies are instituted to block other specific co-receptors. We presume that investigations into the roles of chemokines and their receptors in lymphocyte biology will provide information important for understanding the pathogenesis of AIDS and for manipulating immune and inflammatory responses for clinical benefit

  11. Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis.

    Science.gov (United States)

    Wattenberg, Elizabeth V

    2007-01-01

    Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na(+),K(+)-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

  12. The hematopoietic chemokine CXCL12 promotes integration of human endothelial colony forming cell-derived cells into immature vessel networks.

    Science.gov (United States)

    Newey, Sarah E; Tsaknakis, Grigorios; Khoo, Cheen P; Athanassopoulos, Thanassi; Camicia, Rosalba; Zhang, Youyi; Grabowska, Rita; Harris, Adrian L; Roubelakis, Maria G; Watt, Suzanne M

    2014-11-15

    Proangiogenic factors, vascular endothelial growth factor (VEGF), and fibroblast growth factor-2 (FGF-2) prime endothelial cells to respond to "hematopoietic" chemokines and cytokines by inducing/upregulating expression of the respective chemokine/cytokine receptors. Coculture of human endothelial colony forming cell (ECFC)-derived cells with human stromal cells in the presence of VEGF and FGF-2 for 14 days resulted in upregulation of the "hematopoietic" chemokine CXCL12 and its CXCR4 receptor by day 3 of coculture. Chronic exposure to the CXCR4 antagonist AMD3100 in this vasculo/angiogenesis assay significantly reduced vascular tubule formation, an observation recapitulated by delayed AMD3100 addition. While AMD3100 did not affect ECFC-derived cell proliferation, it did demonstrate a dual action. First, over the later stages of the 14-day cocultures, AMD3100 delayed tubule organization into maturing vessel networks, resulting in enhanced endothelial cell retraction and loss of complexity as defined by live cell imaging. Second, at earlier stages of cocultures, we observed that AMD3100 significantly inhibited the integration of exogenous ECFC-derived cells into established, but immature, vascular networks. Comparative proteome profiler array analyses of ECFC-derived cells treated with AMD3100 identified changes in expression of potential candidate molecules involved in adhesion and/or migration. Blocking antibodies to CD31, but not CD146 or CD166, reduced the ECFC-derived cell integration into these extant vascular networks. Thus, CXCL12 plays a key role not only in endothelial cell sensing and guidance, but also in promoting the integration of ECFC-derived cells into developing vascular networks.

  13. IL-33 activates tumor stroma to promote intestinal polyposis.

    Science.gov (United States)

    Maywald, Rebecca L; Doerner, Stephanie K; Pastorelli, Luca; De Salvo, Carlo; Benton, Susan M; Dawson, Emily P; Lanza, Denise G; Berger, Nathan A; Markowitz, Sanford D; Lenz, Heinz-Josef; Nadeau, Joseph H; Pizarro, Theresa T; Heaney, Jason D

    2015-05-12

    Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

  14. Teleost Chemokines and Their Receptors

    Directory of Open Access Journals (Sweden)

    Steve Bird

    2015-11-01

    Full Text Available Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specially zebrafish (Danio rerio, rainbow trout (Oncorhynchus mykiss and catfish (Ictalurus punctatus, outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly.

  15. Interaction of chemokines with their receptors--from initial chemokine binding to receptor activating steps

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Rosenkilde, Mette Marie

    2014-01-01

    and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity......-contributing interactions are attributed to different domains and known to occur in two steps. Here, knowledge on chemokine and receptor domains involved in the first binding-step and the second activation-step is reviewed. A mechanism comprising at least two steps seems consistent; however, several intermediate...... interactions possibly occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly...

  16. A novel fusion protein of IP10-scFv retains antibody specificity and chemokine function

    International Nuclear Information System (INIS)

    Guo Junqing; Chen Liu; Ai Hongwu; Jing Jiannian; Zhou Jiyong; Zhang Chuyu; You Shangyou

    2004-01-01

    We combined the specificity of tumor-specific antibody with the chemokine function of interferon-γ inducible protein 10 (IP-10) to recruit immune effector cells in the vicinity of tumor cells. A novel fusion protein of IP10-scFv was constructed by fusing mouse IP-10 to V H region of single-chain Fv fragment (scFv) against acidic isoferritin (AIF), and expressed in NS0 murine myeloma cells. The IP10-scFv fusion protein was shown to maintain the specificity of the antiAIF scFv with similar affinity constant, and bind to the human hepatocarcinoma SMMC 7721 cells secreting AIF as well as the activated mouse T lymphocytes expressing CXCR3 receptor. Furthermore, the IP10-scFv protein either in solution or bound on the surface of SMMC 7721 cells induced significant chemotaxis of mouse T cells in vitro. The results indicate that the IP10-scFv fusion protein possesses both bioactivities of the tumor-specific antibody and IP-10 chemokine, suggesting its possibility to induce an enhanced immune response against the residual tumor cells in vivo

  17. Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement

    DEFF Research Database (Denmark)

    Czermak, B J; Lentsch, A B; Bless, N M

    1999-01-01

    demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation....... In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions...... increased neutrophil accumulation occurred, as did lung injury. These observations suggest that C5a and MAC function synergistically with a costimulus to enhance chemokine generation and the intensity of the lung inflammatory response....

  18. Investigation of proliferation and migration of tongue squamous cell carcinoma promoted by three chemokines, MIP-3α, MIP-1β, and IP-10

    Directory of Open Access Journals (Sweden)

    Chu H

    2017-08-01

    Full Text Available Hongxing Chu,1,* Bo Jia,1,* Xiaoling Qiu,2 Jie Pan,1 Xiang Sun,1 Zhiping Wang,1 Jianjiang Zhao1 1Department of Oral and Maxillofacial Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China; 2Department of Endodontology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China *These authors contributed equally to this work Abstract: The aim of this work was to investigate the role of chemokines in proliferation and migration of tongue squamous cell carcinoma (TSCC. Out of the 80 cytokines surveyed by a human cytokine antibody array, three chemokines, macrophage inflammatory protein-3α (MIP-3α, macrophage inflammatory protein-1β (MIP-1β, and interferon gamma-induced protein 10 (IP-10, showed elevated expression in TSCC cells (CAL-27 and UM-1, compared to the oral mucosal epithelial cells. Immunohistochemistry confirmed the high level of expression of MIP-3α in the TSCC tissues, especially in the high clinical stages. Furthermore, Western blot and immunofluorescence staining indicated that C-C chemokine receptor type 5, C-C chemokine receptor type 6, and C-X-C motif chemokine receptor 3, which are the receptors for MIP-3α, MIP-1β, and IP-10, respectively, were expressed in the TSCC cells. Viability assay showed MIP-3α, MIP-1β, and IP-10 led to the proliferation of the CAL-27 cells. Interestingly, MIP-1β and IP-10 also induced apoptosis in the TSCC cells. Transwell invasion assay showed MIP-3α and IP-10 could increase the invasive capability of TSCC cells; consistently, the enzymatic activities of matrix metalloproteinase-2 and matrix metalloproteinase-9 increased in the MIP-3α- and IP-10-treated cells. In summary, our results indicate the expression of MIP-3α, MIP-1β, and IP-10 increased in the TSCC cells. The elevated expression of MIP-3α and IP-10 promoted proliferation and migration of TSCC. These chemokines, along with their receptors, could be potential biomarkers and

  19. The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress

    Directory of Open Access Journals (Sweden)

    Stathopoulos Efstathios N

    2010-09-01

    Full Text Available Abstract Introduction Stress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo. Methods For this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis. Results Array analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this

  20. Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis

    NARCIS (Netherlands)

    Haringman, Jasper J.; Oostendorp, Roos L.; Tak, Paul P.

    2005-01-01

    The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as

  1. Infiltrating leukocytes confound the detection of E-cadherin promoter methylation in tumors

    International Nuclear Information System (INIS)

    Lombaerts, Marcel; Middeldorp, Janneke W.; Weide, Esther van der; Philippo, Katja; Wezel, Tom van; Smit, Vincent T.H.B.M.; Cornelisse, Cees J.; Cleton-Jansen, Anne-Marie

    2004-01-01

    Promoter hypermethylation is known to result in transcriptional downregulation of many genes including the CDH1 gene. In this study we set out to determine CDH1 promoter methylation in breast tumors with decreased or absent E-cadherin protein expression and without CDH1 gene mutations by methylation-specific PCR (MSP). Interestingly, some tumor samples with normal E-cadherin expression yielded a methylation-specific PCR product. We hypothesized that other cells than tumor cells contribute to these products. Since in normal breast tissue no CDH1 promoter methylation is detected, infiltrating leukocytes, often present in tumors, might account for these methylation-specific fragments. Indeed, a methylation-specific fragment is found in all twelve leukocyte samples tested. Furthermore, activated T-cells also yielded a methylation-specific fragment. Sequencing of these fragments reveals two distinct methylation profiles. Leukocytes have only partial methylation of some CpGs, while the tumor-associated methylation profile shows complete methylation of most CpGs. Therefore, to assess whether CDH1 methylation is tumor associated, sequencing of MSP products is a prerequisite. Here we show that out of six lobular tumors lacking E-cadherin protein expression, three have tumor-associated CDH1 promoter methylation while in three other tumors no methylation is detected

  2. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, Thomas Birk; Wittenhagen, P

    2007-01-01

    OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were...

  3. Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice.

    Science.gov (United States)

    Sun, Xiujie; Gupta, Kshama; Wu, Bogang; Zhang, Deyi; Yuan, Bin; Zhang, Xiaowen; Chiang, Huai-Chin; Zhang, Chi; Curiel, Tyler J; Bendeck, Michelle P; Hursting, Stephen; Hu, Yanfen; Li, Rong

    2018-02-23

    Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1- KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro , and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Prognostic value of the expression of C-Chemokine Receptor 6 and 7 and their ligands in non-metastatic breast cancer

    International Nuclear Information System (INIS)

    Cassier, Philippe A; Mignotte, Hervé; Bathélémy-Dubois, Clarisse; Caux, Christophe; Lebecque, Serge; Blay, Jean-Yves; Treilleux, Isabelle; Bachelot, Thomas; Ray-Coquard, Isabelle; Bendriss-Vermare, Nathalie; Ménétrier-Caux, Christine; Trédan, Olivier; Goddard-Léon, Sophie; Pin, Jean-Jacques

    2011-01-01

    Chemokines and chemokine receptors are major actors of leukocytes trafficking and some have been shown to play an important role in cancer metastasis. Chemokines CCL19, CCL20 and CCL21 and their receptors CCR6 and CCR7, were assessed as potential biomarkers of metastatic dissemination in primary breast cancer. Biomarker expression levels were evaluated using immunohistochemistry on paraffin-embedded tissue sections of breast cancer (n = 207). CCR6 was expressed by tumor cells in 35% of cases. CCR7 was expressed by spindle shaped stromal cells in 43% of cases but not by tumor cells in this series. CCL19 was the only chemokine found expressed in a significant number of breast cancers and was expressed by both tumor cells and dendritic cells (DC). CCR6, CCL19 and CCR7 expression correlated with histologic features of aggressive disease. CCR6 expression was associated with shorter relapse-free survival (RFS) in univariate and but not in multivariate analysis (p = 0.0316 and 0.055 respectively), and was not associated with shorter overall survival (OS). Expression of CCR7 was not significantly associated with shorter RFS or OS. The presence of CCL19-expressing DC was associated with shorter RFS in univariate and multivariate analysis (p = 0.042 and 0.020 respectively) but not with shorter OS. These results suggest a contribution of CCR6 expression on tumor cells and CCL19-expressing DC in breast cancer dissemination. In our series, unlike what was previously published, CCR7 was exclusively expressed on stromal cells and was not associated with survival

  5. Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yi; Han, Gye Won; Abagyan, Ruben; Wu, Beili; Stevens, Raymond C.; Cherezov, Vadim; Kufareva, Irina; Handel, Tracy M. (USC); (Chinese Aca. Sci.); (UCSD)

    2017-06-01

    CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.

  6. Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor families.

    Science.gov (United States)

    Johnston, Carl J; Williams, Jacqueline P; Okunieff, Paul; Finkelstein, Jacob N

    2002-03-01

    Fibrosis is a common outcome of chronic inflammation or injury. Pulmonary fibrosis may be the result of abnormal repair after an acute inflammatory response. The process of repair initiated by a tissue insult is largely a function of the activation of cells to produce important biological mediators such as cytokines, growth factors and chemokines, which orchestrate most aspects of the inflammatory response. Consequently, altered regulation of the production of inflammatory cell cytokines and chemokines after injury and repair likely contributes to the fibrosis. Our hypothesis is that chronic expression of specific chemokine and chemokine receptors during the fibrotic phase induced by thoracic irradiation may perpetuate the recruitment and activation of lymphocytes and macrophages, which may contribute to the development of fibrosis. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 12.5 Gy to the thorax. Total lung RNA was prepared and hybridized using microarray analysis and RNase protection assays. At 26 weeks postirradiation, messages encoding the chemokines BLC (now known as Scyb13), C10 (now known as Scya6), IP-10 (now known as Scyb10), MCP-1 (now known as Scya2), MCP-3 (now known as Scya7), MIP-1gamma (now known as Scya9), and RANTES (now known as Scya5) and the chemokine receptors Ccr1, Ccr2, Ccr5 and Ccr6 were elevated in fibrosis-sensitive (C57BL/6) mice. In contrast, only the messages encoding SDF-1alpha (now known as Sdf1) and Ccr1 were elevated 26 weeks postirradiation in fibrosis-resistant (C3H/HeJ) mice. Our results point to the CC and CCR family members as the predominant chemokine responders during the development of fibrosis. These studies suggest that monocyte/macrophage and lymphocyte recruitment and activation are key components of radiation-induced fibrosis.

  7. A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors

    Directory of Open Access Journals (Sweden)

    Maria Isabel Carvalho

    2014-01-01

    Full Text Available Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

  8. A novel fusion protein of IP10-scFv retains antibody specificity and chemokine function

    Energy Technology Data Exchange (ETDEWEB)

    Junqing, Guo; Liu, Chen; Hongwu, Ai; Jiannian, Jing; Jiyong, Zhou; Chuyu, Zhang; Shangyou, You

    2004-07-23

    We combined the specificity of tumor-specific antibody with the chemokine function of interferon-{gamma} inducible protein 10 (IP-10) to recruit immune effector cells in the vicinity of tumor cells. A novel fusion protein of IP10-scFv was constructed by fusing mouse IP-10 to V{sub H} region of single-chain Fv fragment (scFv) against acidic isoferritin (AIF), and expressed in NS0 murine myeloma cells. The IP10-scFv fusion protein was shown to maintain the specificity of the antiAIF scFv with similar affinity constant, and bind to the human hepatocarcinoma SMMC 7721 cells secreting AIF as well as the activated mouse T lymphocytes expressing CXCR3 receptor. Furthermore, the IP10-scFv protein either in solution or bound on the surface of SMMC 7721 cells induced significant chemotaxis of mouse T cells in vitro. The results indicate that the IP10-scFv fusion protein possesses both bioactivities of the tumor-specific antibody and IP-10 chemokine, suggesting its possibility to induce an enhanced immune response against the residual tumor cells in vivo.

  9. COX-2 and Prostaglandin EP3/EP4 Signaling Regulate the Tumor Stromal Proangiogenic Microenvironment via CXCL12-CXCR4 Chemokine Systems

    Science.gov (United States)

    Katoh, Hiroshi; Hosono, Kanako; Ito, Yoshiya; Suzuki, Tatsunori; Ogawa, Yasufumi; Kubo, Hidefumi; Kamata, Hiroki; Mishima, Toshiaki; Tamaki, Hideaki; Sakagami, Hiroyuki; Sugimoto, Yukihiko; Narumiya, Shuh; Watanabe, Masahiko; Majima, Masataka

    2010-01-01

    Bone marrow (BM)–derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)−2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3−/− mice and EP4−/− mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4+ fibroblasts, CXCL12+, and/or CXCR4+ stromal cells as well. Immunofluorescent analyses revealed that CXCL12+CXCR4+S100A4+ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE2-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins. PMID:20110411

  10. Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter.

    Directory of Open Access Journals (Sweden)

    Jianqing Pan

    Full Text Available Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373. Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.

  11. Inhibition of hepatocyte gap junctional intercellular communication by tumor promoters

    International Nuclear Information System (INIS)

    Ruch, R.J.

    1988-01-01

    The mechanisms by which tumor promoters enhance neoplasia are poorly understood. One effect common to most tumor promoters is their ability to inhibit the cell-to-cell exchange of small molecules and ions through gap junctions, i.e., gap junctional intercellular communication (IC). IC maybe necessary for normal growth control and the loss of IC may predispose cells to enhanced growth. In the present studies, the effects of liver tumor promoters and other agents on IC between rodent hepatocytes in primary culture has been studied. IC was detected between hepatocytes: (1) autoradiographically following the passage and incorporation of [5- 3 H]uridine nucleotides from pre-labeled donor hepatocytes to non-labeled, adjacent recipient hepatocytes and (2) by fluorescence microscopy after microinjection of fluorescent Lucifer Yellow CH dye into hepatocytes and visualizing dye spread into adjacent hepatocytes

  12. Chemokines and chemokine receptors expression in the lesions of patients with American cutaneous leishmaniasis

    Directory of Open Access Journals (Sweden)

    Nilka Luisa Diaz

    2013-06-01

    Full Text Available American cutaneous leishmaniasis (ACL presents distinct active clinical forms with different grades of severity, known as localised (LCL, intermediate (ICL and diffuse (DCL cutaneous leishmaniasis. LCL and DCL are associated with a polarised T-helper (Th1 and Th2 immune response, respectively, whereas ICL, or chronic cutaneous leishmaniasis, is associated with an exacerbated immune response and a mixed cytokine expression profile. Chemokines and chemokine receptors are involved in cellular migration and are critical in the inflammatory response. Therefore, we evaluated the expression of the chemokines CXCL10, CCL4, CCL8, CCL11 and CXCL8 and the chemokine receptors CCR3, CXCR3, CCR5 and CCR7 in the lesions of patients with different clinical forms of ACL using immunohistochemistry. LCL patients exhibited a high density of CXCL10+, CCL4+ and CCL8+ cells, indicating an important role for these chemokines in the local Th1 immune response and the migration of CXCR3+ cells. LCL patients showed a higher density of CCR7+ cells than ICL or DCL patients, suggesting major dendritic cell (DC migration to lymph nodes. Furthermore, DCL was associated with low expression levels of Th1-associated chemokines and CCL11+ epidermal DCs, which contribute to the recruitment of CCR3+ cells. Our findings also suggest an important role for epidermal cells in the induction of skin immune responses through the production of chemokines, such as CXCL10, by keratinocytes.

  13. Probing Biased Signaling in Chemokine Receptors

    DEFF Research Database (Denmark)

    Amarandi, Roxana Maria; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie

    2016-01-01

    The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptors...... of others has been termed signaling bias and can accordingly be grouped into ligand bias, receptor bias, and tissue bias. Bias has so far been broadly overlooked in the process of drug development. The low number of currently approved drugs targeting the chemokine system, as well as the broad range...... of failed clinical trials, reflects the need for a better understanding of the chemokine system. Thus, understanding the character, direction, and consequence of biased signaling in the chemokine system may aid the development of new therapeutics. This review describes experiments to assess G protein...

  14. Profiling Heparin-Chemokine Interactions Using Synthetic Tools

    Science.gov (United States)

    de Paz, Jose L.; Moseman, E. Ashley; Noti, Christian; Polito, Laura; von Andrian, Ulrich H.; Seeberger, Peter H.

    2009-01-01

    Glycosaminoglycans (GAGs), such as heparin or heparan sulfate, are required for the in vivo function of chemokines. Chemokines play a crucial role in the recruitment of leukocyte subsets to sites of inflammation and lymphocytes trafficking. GAG-chemokine interactions mediate cell migration and determine which leukocyte subsets enter tissues. Identifying the exact GAC sequences that bind to particular chemokines is key to understand chemokine function at the molecular level and develop strategies to interfere with chemokine-mediated processes. Here, we characterize the heparin binding profiles of eight chemokines (CCL21, IL-8, CXCL12, CXCL13, CCL19, CCL25, CCL28, and CXCL16) by employing heparin microarrays containing a small library of synthetic heparin oligosaccharides. The chemokines differ significantly in their interactions with heparin oligosaccharides: While some chemokines, (e.g., CCL21) strongly bind to a hexasaccharide containing the GlcNSO3(6-OSO3)-IdoA(2-OSO3) repeating unit, CCL19 does not bind and CXCL12 binds only weakly. The carbohydrate microarray binding results were validated by surface plasmon resonance experiments. In vitro chemotaxis assays revealed that dendrimers coated with the fully sulfated heparin hexasaccharide inhibit lymphocyte migration toward CCL21. Migration toward CXCL12 or CCL19 was not affected. These in vitro homing assays indicate that multivalent synthetic heparin dendrimers inhibit the migration of lymphocytes toward certain chemokine gradients by blocking the formation of a chemokine concentration gradient on GAG endothelial chains. These findings are in agreement with preliminary in vivo measurements of circulating lymphocytes. The results presented here contribute to the understanding of GAG-chemokine interactions, a first step toward the design of novel drugs that modulate chemokine activity. PMID:18030990

  15. Chemokines in teleost fish species.

    Science.gov (United States)

    Alejo, Alí; Tafalla, Carolina

    2011-12-01

    Chemokines are chemoattractant cytokines defined by the presence of four conserved cysteine residues which in mammals can be divided into four subfamilies depending on the arrangement of the first two conserved cysteines in their sequence: CXC (α), CC (β), C and CX(3)C classes. Evolutionarily, fish can be considered as an intermediate step between species which possess only innate immunity (invertebrates) and species with a fully developed acquired immune network such as mammals. Therefore, the functionality of their different immune cell types and molecules is sometimes also intermediate between innate and acquired responses. The first chemokine gene identified in a teleost was a rainbow trout (Oncorhynchus mykiss) chemokine designated as CK1 in 1998. Since then, many different chemokine genes have been identified in several fish species, but their role in homeostasis and immune response remains largely unknown. Extensive genomic duplication events and the fact that chemokines evolve more quickly than other immune genes, make it very difficult to establish true orthologues between fish and mammalian chemokines that would help us with the ascription of immune roles. In this review, we describe the current state of knowledge of chemokine biology in teleost fish, focusing mainly on which genes have been identified so far and highlighting the most important aspects of their expression regulation, due to the great lack of functional information available for them. As the number of chemokine genes begins to close down for some teleost species, there is an important need for functional assays that may elucidate the role of each of these molecules within the fish immune response. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Chemokine (C-X-C) ligand 1 (CXCL1) protein expression is increased in aggressive bladder cancers

    International Nuclear Information System (INIS)

    Miyake, Makito; Lawton, Adrienne; Goodison, Steve; Urquidi, Virginia; Gomes-Giacoia, Evan; Zhang, Ge; Ross, Shanti; Kim, Jeongsoon; Rosser, Charles J

    2013-01-01

    Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may regulate tumor epithelial-stromal interactions that facilitate tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, but limited studies to date have described CXCL1 protein expression in human bladder cancer (BCa). CXCL1 protein expression was examined in 152 bladder tissue specimens (142 BCa) by immunohistochemical staining. The expression of CXCL1 was scored by assigning a combined score based on the proportion of cells staining and intensity of staining. CXCL1 expression patterns were correlated with clinicopathological features and follow-up data. CXCL1 protein expression was present in cancerous tissues, but was entirely absent in benign tissue. CXCL1 combined immunostaining score was significantly higher in high-grade tumors relative to low-grade tumors (p = 0.012). Similarly, CXCL1 combined immunostaining score was higher in high stage tumors (T2-T4) than in low stage tumors (Ta-T1) (p < 0.0001). An increase in the combined immunostaining score of CXCL1 was also associated with reduced disease-specific survival. To date, this is the largest study describing increased CXCL1 protein expression in more aggressive phenotypes in human BCa. Further studies are warranted to define the role CXCL1 plays in bladder carcinogenesis and progression

  17. Genomic organization, annotation, and ligand-receptor inferences of chicken chemokines and chemokine receptor genes based on comparative genomics

    Directory of Open Access Journals (Sweden)

    Sze Sing-Hoi

    2005-03-01

    Full Text Available Abstract Background Chemokines and their receptors play important roles in host defense, organogenesis, hematopoiesis, and neuronal communication. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this report, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to systematically identify chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Results Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. All of the chicken chemokines contained a conserved CC, CXC, CX3C, or XC motif, whereas all the chemokine receptors had seven conserved transmembrane helices, four extracellular domains with a conserved cysteine, and a conserved DRYLAIV sequence in the second intracellular domain. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. Conclusion The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. All identified chicken chemokines and their cognate receptors were identified in the chicken genome except CCR9, whose ligand was not identified in this study. The organization of these genes suggests that there were a substantial number of these genes present before divergence between aves and mammals and more gene duplications of CC, CXC, CCR, and CXCR subfamilies in mammals than in aves after the divergence.

  18. Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination.

    Science.gov (United States)

    Karim, Hawra; Kim, Sung Hoon; Lapato, Andrew S; Yasui, Norio; Katzenellenbogen, John A; Tiwari-Woodruff, Seema K

    2018-06-12

    Estrogen receptor β (ERβ) ligands promote remyelination in mouse models of multiple sclerosis. Recent work using experimental autoimmune encephalomyelitis (EAE) has shown that ERβ ligands induce axon remyelination, but impact peripheral inflammation to varying degrees. To identify if ERβ ligands initiate a common immune mechanism in remyelination, central and peripheral immunity and pathology in mice given ERβ ligands at peak EAE were assessed. All ERβ ligands induced differential expression of cytokines and chemokines, but increased levels of CXCL1 in the periphery and in astrocytes. Oligodendrocyte CXCR2 binds CXCL1 and has been implicated in normal myelination. In addition, despite extensive immune cell accumulation in the CNS, all ERβ ligands promoted extensive remyelination in mice at peak EAE. This finding highlights a component of the mechanism by which ERβ ligands mediate remyelination. Hence, interplay between the immune system and central nervous system may be responsible for the remyelinating effects of ERβ ligands. Our findings of potential neuroprotective benefits arising from the presence of CXCL1 could have implications for improved therapies for multiple sclerosis. Copyright © 2018 the Author(s). Published by PNAS.

  19. Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

    Directory of Open Access Journals (Sweden)

    Julie A Wallace

    Full Text Available Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.

  20. Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival.

    Science.gov (United States)

    Pišlar, Anja; Perišić Nanut, Milica; Kos, Janko

    2015-12-01

    Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression.

    Science.gov (United States)

    Han, Yanmei; Liu, Qiuyan; Hou, Jin; Gu, Yan; Zhang, Yi; Chen, Zhubo; Fan, Jia; Zhou, Weiping; Qiu, Shuangjian; Zhang, Yonghong; Dong, Tao; Li, Ning; Jiang, Zhengping; Zhu, Ha; Zhang, Qian; Ma, Yuanwu; Zhang, Lianfeng; Wang, Qingqing; Yu, Yizhi; Li, Nan; Cao, Xuetao

    2018-04-19

    Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119 + CD45 - CD71 + phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Hedgehog signaling in tumor cells facilitates osteoblast-enhanced osteolytic metastases.

    Directory of Open Access Journals (Sweden)

    Shamik Das

    Full Text Available The remodeling process in bone yields numerous cytokines and chemokines that mediate crosstalk between osteoblasts and osteoclasts and also serve to attract and support metastatic tumor cells. The metastatic tumor cells disturb the equilibrium in bone that manifests as skeletal complications. The Hedgehog (Hh pathway plays an important role in skeletogenesis. We hypothesized that the Hh pathway mediates an interaction between tumor cells and osteoblasts and influences osteoblast differentiation in response to tumor cells. We have determined that breast tumor cells have an activated Hh pathway characterized by upregulation of the ligand, IHH and transcription factor GLI1. Breast cancer cells interact with osteoblasts and cause an enhanced differentiation of pre-osteoblasts to osteoblasts that express increased levels of the osteoclastogenesis factors, RANKL and PTHrP. There is sustained expression of osteoclast-promoting factors, RANKL and PTHrP, even after the osteoblast differentiation ceases and apoptosis sets in. Moreover, tumor cells that are deficient in Hh signaling are compromised in their ability to induce osteoblast differentiation and consequently are inefficient in causing osteolysis. The stimulation of osteoblast differentiation sets the stage for osteoclast differentiation and overall promotes osteolysis. Thus, in the process of developing newer therapeutic strategies against breast cancer metastasis to bone it would worthwhile to keep in mind the role of the Hh pathway in osteoblast differentiation in an otherwise predominant osteolytic phenomenon.

  3. The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice

    NARCIS (Netherlands)

    Bongers, Gerold; Maussang, David; Muniz, Luciana R; Noriega, Vanessa M; Fraile-Ramos, Alberto; Barker, Nick; Marchesi, Federica; Thirunarayanan, Nanthakumar; Vischer, Henry F; Qin, Lihui; Mayer, Lloyd; Harpaz, Noam; Leurs, Rob; Furtado, Glaucia C; Clevers, Hans; Tortorella, Domenico; Smit, Martine J; Lira, Sergio A

    2010-01-01

    US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28 mice)

  4. Curcumin and Turmeric Modulate the Tumor-Promoting Effects of Iron In Vitro.

    Science.gov (United States)

    Messner, Donald J; Robinson, Todd; Kowdley, Kris V

    2017-04-01

    Free or loosely chelated iron has tumor-promoting properties in vitro. Curcumin, a polyphenol derived from the food spice turmeric (Curcuma longa), is a potent antioxidant that binds iron. The primary aim of this study was to investigate whether curcuminoids prevent tumor-promoting effects of iron in T51B cells, a non-neoplastic rat liver epithelial cell line. Purified curcuminoids (curcumin) or a standardized turmeric extract similarly reduced oxidative stress and cytotoxicity associated with iron overload (IC 50 values near 10 μM, P turmeric for 16 wk in culture; subsequently assayed by soft agar colony formation) was nearly complete at 20 μM of total curcuminoids (P turmeric extract were taken up better by cells, had a longer half-life, and appeared more effective in blocking tumor promotion (P < 0.01), suggesting enhanced curcuminoid delivery to cells in culture. The primary finding that curcuminoids can inhibit tumor promotion caused by iron in T51B cells is tempered by evidence for an underlying increase in neoplastic transformation at lower concentrations.

  5. MicroRNA-17-92 cluster promotes the proliferation and the chemokine production of keratinocytes: implication for the pathogenesis of psoriasis.

    Science.gov (United States)

    Zhang, Weigang; Yi, Xiuli; An, Yawen; Guo, Sen; Li, Shuli; Song, Pu; Chang, Yuqian; Zhang, Shaolong; Gao, Tianwen; Wang, Gang; Li, Chunying

    2018-05-11

    Keratinocytes are the main epidermal cell type that constitutes the skin barrier against environmental damages, which emphasizes the balance between the growth and the death of keratinocytes in maintaining skin homeostasis. Aberrant proliferation of keratinocytes and the secretion of inflammatory factors from keratinocytes are related to the formation of chronic inflammatory skin diseases like psoriasis. MicroRNA-17-92 (miRNA-17-92 or miR-17-92) is a miRNA cluster that regulates cell growth and immunity, but the role of miR-17-92 cluster in keratinocytes and its relation to skin diseases have not been well investigated. In the present study, we initially found that miR-17-92 cluster promoted the proliferation and the cell-cycle progression of keratinocytes via suppressing cyclin-dependent kinase inhibitor 2B (CDKN2B). Furthermore, miR-17-92 cluster facilitated the secretion of C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) from keratinocytes by inhibiting suppressor of cytokine signaling 1 (SOCS1), which enhanced the chemotaxis for T lymphocytes formed by keratinocytes. In addition, we detected increased expression of miR-17-92 cluster in psoriatic lesions and the level of lesional miR-17-92 cluster was positively correlated with the disease severity in psoriasis patients. At last, miR-17-92 cluster was increased in keratinocytes by cytokines through the activation of signal transducers and activators of transcription 1 (STAT1) signaling pathway. Our findings demonstrate that cytokine-induced overexpression of miR-17-92 cluster can promote the proliferation and the immune function of keratinocytes, and thus may contribute to the development of inflammatory skin diseases like psoriasis, which implicates miR-17-92 cluster as a potential therapeutic target for psoriasis and other skin diseases with similar inflammatory pathogenesis.

  6. Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation.

    Science.gov (United States)

    Ahirwar, Dinesh K; Nasser, Mohd W; Ouseph, Madhu M; Elbaz, Mohamad; Cuitiño, Maria C; Kladney, Raleigh D; Varikuti, Sanjay; Kaul, Kirti; Satoskar, Abhay R; Ramaswamy, Bhuvaneswari; Zhang, Xiaoli; Ostrowski, Michael C; Leone, Gustavo; Ganju, Ramesh K

    2018-05-03

    The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.

  7. Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promoters.

    Science.gov (United States)

    Fujiki, H; Suganuma, M; Yoshizawa, S; Kanazawa, H; Sugimura, T; Manam, S; Kahn, S M; Jiang, W; Hoshina, S; Weinstein, I B

    1989-01-01

    Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin-1, and calyculin A, have potent tumor-promoting activity in two-stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation at the second nucleotide of codon 61 (CAA----CTA) in the c-Ha-ras gene, determined by the polymerase chain reaction procedure and DNA sequencing. Three potent 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, TPA, teleocidin, and aplysiatoxin, showed the same effects. These results provide strong evidence that this mutation in the c-Ha-ras gene is due to a direct effect of DMBA rather than a selective effect of specific tumor promoters.

  8. Andrographolide attenuates LPS-stimulated up-regulation of C-C and C-X-C motif chemokines in rodent cortex and primary astrocytes.

    Science.gov (United States)

    Wong, Siew Ying; Tan, Michelle G K; Banks, William A; Wong, W S Fred; Wong, Peter T-H; Lai, Mitchell K P

    2016-02-09

    Andrographolide is the major bioactive compound isolated from Andrographis paniculata, a native South Asian herb used medicinally for its anti-inflammatory properties. In this study, we aimed to assess andrographolide's potential utility as an anti-neuroinflammatory therapeutic. The effects of andrographolide on lipopolysaccharide (LPS)-induced chemokine up-regulation both in mouse cortex and in cultured primary astrocytes were measured, including cytokine profiling, gene expression, and, in cultured astrocytes, activation of putative signaling regulators. Orally administered andrographolide significantly attenuated mouse cortical chemokine levels from the C-C and C-X-C subfamilies. Similarly, andrographolide abrogated a range of LPS-induced chemokines as well as tumor necrosis factor (TNF)-α in astrocytes. In astrocytes, the inhibitory actions of andrographolide on chemokine and TNF-α up-regulation appeared to be mediated by nuclear factor-κB (NF-κB) or c-Jun N-terminal kinase (JNK) activation. These results suggest that andrographolide may be useful as a therapeutic for neuroinflammatory diseases, especially those characterized by chemokine dysregulation.

  9. Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration

    Directory of Open Access Journals (Sweden)

    Yvona Ward

    2018-04-01

    Full Text Available Summary: Tumor cells initiate platelet activation leading to the secretion of bioactive molecules, which promote metastasis. Platelet receptors on tumors have not been well-characterized, resulting in a critical gap in knowledge concerning platelet-promoted metastasis. We identify a direct interaction between platelets and tumor CD97 that stimulates rapid bidirectional signaling. CD97, an adhesion G protein-coupled receptor (GPCR, is an overexpressed tumor antigen in several cancer types. Purified CD97 extracellular domain or tumor cell-associated CD97 stimulated platelet activation. CD97-initiated platelet activation led to granule secretion, including the release of ATP, a mediator of endothelial junction disruption. Lysophosphatidic acid (LPA derived from platelets induced tumor invasiveness via proximal CD97-LPAR heterodimer signaling, coupling coincident tumor cell migration and vascular permeability to promote transendothelial migration. Consistent with this, CD97 was necessary for tumor cell-induced vascular permeability in vivo and metastasis formation in preclinical models. These findings support targeted blockade of tumor CD97 as an approach to ameliorate metastatic spread. : Tumor-initiated platelet activation promotes tissue invasion of cancer cells and metastasis. Ward et al. demonstrate that a common tumor-associated antigen, CD97, accounts for platelet activation and participates directly in LPA-mediated signal transduction leading to tumor cell invasion. CD97 promotes vascular extravasation and metastasis in pre-clinical models. Keywords: platelets, metastasis, transendothelial migration, circulating tumor cells, CD97, adhesion GPCR, LPA

  10. Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity.

    Science.gov (United States)

    Karin, Nathan; Razon, Hila

    2018-09-01

    Chemokines are mostly known for their chemotactic properties, and less for their ability to direct the biological function of target cells, including T cells. The current review focuses on a key chemokine named CXCL10 and its role in directing the migratory propertied and biological function of CD4+ and CD8+ T cells in the context of cancer and inflammatory autoimmunity. CXCR3 is a chemokine receptor that is abundant on CD4+ T cells, CD8+ T cells and NK cells. It has three known ligands: CXCL9, CXCL10 and CXCL11. Different studies, including those coming form our laboratory, indicated that aside of attracting CD8+ and CD4+ effector T cells to tumor sites and sites of inflammation CXCL10 directs the polarization and potentiates the biological function of these cells. This makes CXCL10 a "key driver chemokine" and a valid target for therapy of autoimmune diseases such as Inflammatory Bowl's Disease, Multiple Sclerosis, Rheumatoid arthritis and others. As for cancer this motivated different groups, including our group to develop CXCL10 based therapies for cancer due to its ability to enhance T-dependent anti cancer immunity. The current review summarizes these findings and their potential translational implication. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Structures of Orf Virus Chemokine Binding Protein in Complex with Host Chemokines Reveal Clues to Broad Binding Specificity.

    Science.gov (United States)

    Couñago, Rafael M; Knapp, Karen M; Nakatani, Yoshio; Fleming, Stephen B; Corbett, Michael; Wise, Lyn M; Mercer, Andrew A; Krause, Kurt L

    2015-07-07

    The chemokine binding protein (CKBP) from orf virus (ORFV) binds with high affinity to chemokines from three classes, C, CC, and CXC, making it unique among poxvirus CKBPs described to date. We present its crystal structure alone and in complex with three CC chemokines, CCL2, CCL3, and CCL7. ORFV CKBP possesses a β-sandwich fold that is electrostatically and sterically complementary to its binding partners. Chemokines bind primarily through interactions involving the N-terminal loop and a hydrophobic recess on the ORFV CKBP β-sheet II surface, and largely polar interactions between the chemokine 20s loop and a negatively charged surface groove located at one end of the CKBP β-sheet II surface. ORFV CKBP interacts with leukocyte receptor and glycosaminoglycan binding sites found on the surface of bound chemokines. SEC-MALLS and chromatographic evidence is presented supporting that ORFV CKBP is a dimer in solution over a broad range of protein concentrations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists.

    Science.gov (United States)

    Szpakowska, Martyna; Meyrath, Max; Reynders, Nathan; Counson, Manuel; Hanson, Julien; Steyaert, Jan; Chevigné, Andy

    2018-07-01

    The atypical chemokine receptor ACKR3/CXCR7 plays crucial roles in numerous physiological processes but also in viral infection and cancer. ACKR3 shows strong propensity for activation and, unlike classical chemokine receptors, can respond to chemokines from both the CXC and CC families as well as to the endogenous peptides BAM22 and adrenomedullin. Moreover, despite belonging to the G protein coupled receptor family, its function appears to be mainly dependent on β-arrestin. ACKR3 has also been shown to continuously cycle between the plasma membrane and the endosomal compartments, suggesting a possible role as a scavenging receptor. So far, the molecular basis accounting for these atypical binding and signalling properties remains elusive. Noteworthy, ACKR3 extracellular domains bear three disulphide bridges. Two of them lie on top of the two main binding subpockets and are conserved among chemokine receptors, and one, specific to ACKR3, forms an intra-N terminus four-residue-loop of so far unknown function. Here, by mutational and functional studies, we examined the impact of the different disulphide bridges for ACKR3 folding, ligand binding and activation. We showed that, in contrast to most classical chemokine receptors, none of the extracellular disulphide bridges was essential for ACKR3 function. However, the disruption of the unique ACKR3 N-terminal loop drastically reduced the binding of CC chemokines whereas it only had a mild impact on CXC chemokine binding. Mutagenesis also uncovered that chemokine and endogenous non-chemokine ligands interact and activate ACKR3 according to distinct binding modes characterized by different transmembrane domain subpocket occupancy and N-terminal loop contribution, with BAM22 mimicking the binding mode of CC chemokine N terminus. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis

    Directory of Open Access Journals (Sweden)

    Giulia Fregni

    2018-03-01

    Full Text Available Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis. Keywords: Tumor-associated MSCs, lung cancer, metastasis, GREM1, LOXL2, ADAMTS12, ITGA11

  14. Soy protein isolate inhibits hepatic tumor promotion in mice fed a high-fat liquid diet.

    Science.gov (United States)

    Mercer, Kelly E; Pulliam, Casey F; Pedersen, Kim B; Hennings, Leah; Ronis, Martin Jj

    2017-03-01

    Alcoholic and nonalcoholic fatty liver diseases are risk factors for development of hepatocellular carcinoma, but the underlying mechanisms are poorly understood. On the other hand, ingestion of soy-containing diets may oppose the development of certain cancers. We previously reported that replacing casein with a soy protein isolate reduced tumor promotion in the livers of mice with alcoholic liver disease after feeding a high fat ethanol liquid diet following initiation with diethylnitrosamine. Feeding soy protein isolate inhibited processes that may contribute to tumor promotion including inflammation, sphingolipid signaling, and Wnt/β-catenin signaling. We have extended these studies to characterize liver tumor promotion in a model of nonalcoholic fatty liver disease produced by chronic feeding of high-fat liquid diets in the absence of ethanol. Mice treated with diethylnitrosamine on postnatal day 14 were fed a high-fat liquid diet made with casein or SPI as the sole protein source for 16 weeks in adulthood. Relative to mice fed normal chow, a high fat/casein diet led to increased tumor promotion, hepatocyte proliferation, steatosis, and inflammation. Replacing casein with soy protein isolate counteracted these effects. The high fat diets also resulted in a general increase in transcripts for Wnt/β-catenin pathway components, which may be an important mechanism, whereby hepatic tumorigenesis is promoted. However, soy protein isolate did not block Wnt signaling in this nonalcoholic fatty liver disease model. We conclude that replacing casein with soy protein isolate blocks development of steatosis, inflammation, and tumor promotion in diethylnitrosamine-treated mice fed high fat diets. Impact statement The impact of dietary components on cancer is a topic of great interest for both the general public and the scientific community. Liver cancer is currently the second leading form of cancer deaths worldwide. Our study has addressed the effect of the protein

  15. Role of Chemokine Network in the Development and Progression of Ovarian Cancer: A Potential Novel Pharmacological Target

    Directory of Open Access Journals (Sweden)

    Federica Barbieri

    2010-01-01

    Full Text Available Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development.

  16. Scleroderma dermal microvascular endothelial cells exhibit defective response to pro-angiogenic chemokines

    Science.gov (United States)

    Rabquer, Bradley J.; Ohara, Ray A.; Stinson, William A.; Campbell, Phillip L.; Amin, M. Asif; Balogh, Beatrix; Zakhem, George; Renauer, Paul A.; Lozier, Ann; Arasu, Eshwar; Haines, G. Kenneth; Kahaleh, Bashar; Schiopu, Elena; Khanna, Dinesh; Koch, Alisa E.

    2016-01-01

    Objectives. Angiogenesis plays a critical role in SSc (scleroderma). The aim of this study was to examine the expression of growth-regulated protein-γ (Gro-γ/CXCL3), granulocyte chemotactic protein 2 (GCP-2/CXCL6) and their receptor CXCR2 in endothelial cells (ECs) isolated from SSc skin and determine whether these cells mount an angiogenic response towards pro-angiogenic chemokines. The downstream signalling pathways as well as the pro-angiogenic transcription factor inhibitor of DNA-binding protein 1 (Id-1) were also examined. Methods. Skin biopsies were obtained from patients with dcSSc. ECs were isolated via magnetic positive selection. Angiogenesis was measured by EC chemotaxis assay. Results. Gro-γ/CXCL3 and GCP-2/CXCL6 were minimally expressed in both skin types but elevated in SSc serum. Pro-angiogenic chemokine mRNA was greater in SSc ECs than in normal ECs. SSc ECs did not migrate to vascular endothelial growth factor (VEGF), Gro-γ/CXCL3, GCP-2/CXCL6 or CXCL16. The signalling pathways stimulated by these chemokines were also dysregulated. Id-1 mRNA in SSc ECs was lower compared with normal ECs, and overexpression of Id-1 in SSc ECs increased their ability to migrate towards VEGF and CXCL16. Conclusion. Our results show that SSc ECs are unable to respond to pro-angiogenic chemokines despite their increased expression in serum and ECs. This might be due to the differences in the signalling pathways activated by these chemokines in normal vs SSc ECs. In addition, the lower expression of Id-1 also decreases the angiogenic response. The inability of pro-angiogenic chemokines to promote EC migration provides an additional mechanism for the impaired angiogenesis that characterizes SSc. PMID:26705326

  17. Alteration of keratinocyte differentiation and senescence by the tumor promoter dioxin

    International Nuclear Information System (INIS)

    Ray, Soma S.; Swanson, Hollie I.

    2003-01-01

    Exposure to the environmental contaminant dioxin, elicits a variety of responses, which includes tumor promotion, embryotoxicity/teratogenesis, and carcinogenesis in both animals and humans. Many of the effects of dioxin are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated bHLH (basic helix-loop-helix)/PAS transcription factor. We initiated this study to determine whether dioxin's tumor-promoting activities may lie in its ability to alter proliferation, differentiation, and/or senescence using normal human epidermal keratinocytes (HEKs). Here, we report that dioxin appears to accelerate differentiation as measured by flow cytometry and by increased expression of the differentiation markers involucrin and filaggrin. In addition, dioxin appears to increase proliferation as indicated by an increase in NADH/NADPH production and changes in cell cycle. Finally, dioxin decreases SA (senescence associated) β-galactosidase staining, an indicator of senescence, in the differentiating keratinocytes. These changes were accompanied by decreases in the expression levels of key cell cycle regulatory proteins p53, p16 INK4a , and p14 ARF . Our findings support the idea that dioxin may exert its tumor-promoting actions, in part, by downregulating the expression levels of key tumor suppressor proteins, which may impair the cell's ability to maintain its appropriate cellular status

  18. Industasis, a promotion of tumor formation by nontumorigenic stray cells

    Czech Academy of Sciences Publication Activity Database

    Pajer, Petr; Karafiát, Vít; Pečenka, Vladimír; Průková, Dana; Dudlová, J.; Plachý, Jiří; Kašparová, P.; Dvořák, Michal

    2009-01-01

    Roč. 69, č. 11 (2009), s. 4605-4612 ISSN 0008-5472 R&D Projects: GA ČR GA204/06/1728; GA MŠk(CZ) LC06061; GA AV ČR IAA500520608 Institutional research plan: CEZ:AV0Z50520514 Keywords : tumor promotion * lung tumors * Fyn-related kinase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.543, year: 2009

  19. Chapter 8. Activation mechanisms of chemokine receptors

    DEFF Research Database (Denmark)

    Jensen, Pia C; Rosenkilde, Mette M

    2009-01-01

    binding. Attempts to unravel the activation mechanism of 7TM receptors have led to the conclusion that activation involves movements of the transmembrane segments VI and VII in particular, as recently gathered in the Global Toggle Switch Model. However, to understand the activation mechanism completely......, more research has to be done in this field. Chemokine receptors are interesting tools in this matter. First, the chemokine system has a high degree of promiscuity that allows several chemokines to target one receptor in different ways, as well as a single chemokine ligand to target several receptors...

  20. SMM-chemokines: a class of unnatural synthetic molecules as chemical probes of chemokine receptor biology and leads for therapeutic development.

    Science.gov (United States)

    Kumar, Santosh; Choi, Won-Tak; Dong, Chang-Zhi; Madani, Navid; Tian, Shaomin; Liu, Dongxiang; Wang, Youli; Pesavento, James; Wang, Jun; Fan, Xuejun; Yuan, Jian; Fritzsche, Wayne R; An, Jing; Sodroski, Joseph G; Richman, Douglas D; Huang, Ziwei

    2006-01-01

    Chemokines and their receptors play important roles in numerous physiological and pathological processes. To develop natural chemokines into receptor probes and inhibitors of pathological processes, the lack of chemokine-receptor selectivity must be overcome. Here, we apply chemical synthesis and the concept of modular modifications to generate unnatural synthetically and modularly modified (SMM)-chemokines that have high receptor selectivity and affinity, and reduced toxicity. A proof of the concept was shown by transforming the nonselective viral macrophage inflammatory protein-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for human immunodeficiency virus (HIV)-1 entry. These new analogs provided insights into receptor binding and signaling mechanisms and acted as potent HIV-1 inhibitors. These results support the concept of SMM-chemokines for studying and controlling the function of other chemokine receptors.

  1. Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines.

    Science.gov (United States)

    Choi, Won-Tak; Kaul, Marcus; Kumar, Santosh; Wang, Jun; Kumar, I M Krishna; Dong, Chang-Zhi; An, Jing; Lipton, Stuart A; Huang, Ziwei

    2007-03-09

    As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120(IIIB), and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

  2. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

    Science.gov (United States)

    Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N.; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S.

    2012-01-01

    Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15–transduced NKT cells. PMID:22565311

  3. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity.

    Science.gov (United States)

    Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S

    2012-06-01

    Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKT cells.

  4. Studies on the tumor initiation/promotion potential of six middle distillates (MDs) in mouse skin.

    Science.gov (United States)

    Jungen, H; Mellert, W; Wenzel-Hartung, R

    1995-08-01

    Six middle distillates (MDs) were tested for tumor initiating/promoting activity after application to the skin of 30 male CD-1 (ICR) BR mice per group. As the control, 7,12-dimethylbenz[a]-anthracene (DMBA) was used for initiation followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion. For assessing the tumor-initiating activity, 50 microliters of neat MDs was administered for 5 days with subsequent TPA promotion. In the promotion bioassay, after DMBA initiation 50 microliters of the neat MDs was administered twice weekly until Week 28. For the examination of complete carcinogenic activity, one MD was given without DMBA initiation. Hyperkeratosis, hyperplasia, and dermal inflammation, occurring during the initiation with the MDs, were completely reversible during the 2-week treatment-free period after initiation. Similar skin findings were observed during promotion with the MDs. Regarding the number of affected animals and the severity of the response, TPA was more irritating than the MDs. The initiation study revealed skin tumors for the DMBA/TPA control (30/30), MD 57,389 (14/30), MD 57,396 (5/30), MD 57,383 (4/30) and MD 57,324 (2/30). The promotion study revealed tumor induction by MDs 57,389 (9/30), 57,324 (1/30), 57,393 (1/30), and 57,396 (1/30). Two of 30 animals treated with MD 57,389 developed tumors without DMBA initiation thus indicating that it also is a complete carcinogen. MD 57,399 caused neither initiating nor promoting effects. The tumors observed were diagnosed histopathologically predominantly as squamous cell papillomas.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Tumor-promoting phorbol esters effect alkalinization of canine renal proximal tubular cells

    International Nuclear Information System (INIS)

    Mellas, J.; Hammerman, M.R.

    1986-01-01

    We have demonstrated the presence of specific receptors for tumor-promoting phorbol esters in the plasma membrane of the canine renal proximal tubular cell. These compounds affect proximal tubular metabolism in vitro. For example, we have shown that they inhibit gluconeogenesis in canine renal proximal tubular segments. Tumor-promoting phorbol esters have been shown to effect alkalinization of non-renal cells, by enhancing Na + -H + exchange across the plasma membrane. To determine whether the actions of tumor-promoting phorbol esters in proximal tubular segments might be mediated by a similar process, we incubated suspensions of segments from dog kidney with these compounds and measured changes in intracellular pH using [ 14 C]-5,5-dimethoxazoladine-2-4-dione (DMO) and flow dialysis. Incubation of segments with phorbol 12,13 dibutyrate, but not inactive phorbol ester, 4 γ phorbol, effected alkalinization of cells within the segments in a concentration-dependent manner. Alkalinization was dependent upon the presence of extracellular [Na + ] > intracellular [Na + ], was prevented by amiloride and was demonstrable in the presence of SITS. Our findings suggest that tumor-promoting esters stimulate the Na + -H + exchanger known to be present in the brush border membrane of the renal proximal tubular cell. It is possible that the stimulation reflects a mechanism by which phorbol esters affect metabolic processes in these cells

  6. Systematic review of the neurobiological relevance of chemokines to psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Michael eStuart

    2015-09-01

    Full Text Available Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance. Much recent research has focused on the role of cytokines in the pathophysiology of psychiatric disorders; however the related family of immune proteins designated chemokines has been relatively neglected. Chemokines were originally identified as having chemotactic function on immune cells, however recent evidence has begun to elucidate novel, brain-specific functions of these proteins of relevance to the mechanisms of psychiatric disorders. A systematic review of both human and animal literature in the PubMed and Google Scholar databases was undertaken. After application of all inclusion and exclusion criteria, 157 references were remained for the review. Some early mechanistic evidence does associate select chemokines with the neurobiological processes, including neurogenesis, modulation of the neuroinflammatory response, regulation of the HPA axis, and modulation of neurotransmitter systems. This early evidence however does not clearly demonstrate any specificity for a certain psychiatric disorder, but is primarily relevant to mechanisms which are shared across disorders. Notable exceptions include CCL11 which has recently been shown to impair hippocampal function in aging - of distinct relevance to Alzheimer’s disease and depression in the elderly, and prenatal exposure to CXCL8 that may disrupt early neurodevelopmental periods predisposing to schizophrenia. Pro-inflammatory chemokines, such as CCL2, CCL7, CCL8, CCL12, CCL13, have been shown to drive chemotaxis of pro-inflammatory cells to the inflamed or injured CNS. Likewise, CX3CL has been implicated in promoting glial cells activation, proinflammatory cytokines secretion, expression of ICAM-1 and recruitment of CD4+ T-cells into the CNS during neuroinflammatory processes. With further translational research, chemokines may present novel diagnostic and/or therapeutic targets in

  7. Systematic Review of the Neurobiological Relevance of Chemokines to Psychiatric Disorders.

    Science.gov (United States)

    Stuart, Michael J; Singhal, Gaurav; Baune, Bernhard T

    2015-01-01

    Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance. Much recent research has focused on the role of cytokines in the pathophysiology of psychiatric disorders; however, the related family of immune proteins designated chemokines has been relatively neglected. Chemokines were originally identified as having chemotactic function on immune cells; however, recent evidence has begun to elucidate novel, brain-specific functions of these proteins of relevance to the mechanisms of psychiatric disorders. A systematic review of both human and animal literature in the PubMed and Google Scholar databases was undertaken. After application of all inclusion and exclusion criteria, 157 references were remained for the review. Some early mechanistic evidence does associate select chemokines with the neurobiological processes, including neurogenesis, modulation of the neuroinflammatory response, regulation of the hypothalamus-pituitary-adrenal axis, and modulation of neurotransmitter systems. This early evidence however does not clearly demonstrate any specificity for a certain psychiatric disorder, but is primarily relevant to mechanisms which are shared across disorders. Notable exceptions include CCL11 that has recently been shown to impair hippocampal function in aging - of distinct relevance to Alzheimer's disease and depression in the elderly, and pre-natal exposure to CXCL8 that may disrupt early neurodevelopmental periods predisposing to schizophrenia. Pro-inflammatory chemokines, such as CCL2, CCL7, CCL8, CCL12, and CCL13, have been shown to drive chemotaxis of pro-inflammatory cells to the inflamed or injured CNS. Likewise, CX3CL has been implicated in promoting glial cells activation, pro-inflammatory cytokines secretion, expression of ICAM-1, and recruitment of CD4+ T-cells into the CNS during neuroinflammatory processes. With further translational research, chemokines may present novel diagnostic and

  8. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Tani, M; Jensen, J

    1999-01-01

    Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether...

  9. Chemokines: structure, receptors and functions. A new target for inflammation and asthma therapy?

    Directory of Open Access Journals (Sweden)

    F. A. A. van Acker

    1996-01-01

    Full Text Available Five to 10% of the human population have a disorder of the respiratory tract called ‘asthma’. It has been known as a potentially dangerous disease for over 2000 years, as it was already described by Hippocrates and recognized as a disease entity by Egyptian and Hebrew physicians. At the beginning of this decade, there has been a fundamental change in asthma management. The emphasis has shifted from symptom relief with bronchodilator therapies (e.g. β2-agonists to a much earlier introduction of anti-inflammatory treatment (e.g. corticosteroids. Asthma is now recognized to be a chronic inflammatory disease of the airways, involving various inflammatory cells and their mediators. Although asthma has been the subject of many investigations, the exact role of the different inflammatory cells has not been elucidated completely. Many suggestions have been made and several cells have been implicated in the pathogenesis of asthma, such as the eosinophils, the mast cells, the basophils and the lymphocytes. To date, however, the relative importance of these cells is not completely understood. The cell type predominantly found in the asthmatic lung is the eosinophil and the recruitment of these eosinophils can be seen as a characteristic of asthma. In recent years much attention is given to the role of the newly identified chemokines in asthma pathology. Chemokines are structurally and functionally related 8–10 kDa peptides that are the products of distinct genes clustered on human chromosomes 4 and 17 and can be found at sites of inflammation. They form a superfamily of proinflammatory mediators that promote the recruitment of various kinds of leukocytes and lymphocytes. The chemokine superfamily can be divided into three subgroups based on overall sequence homology. Although the chemokines have highly conserved amino acid sequences, each of the chemokines binds to and induces the chemotaxis of particular classes of white blood cells. Certain

  10. NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

    Science.gov (United States)

    Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

    2016-01-01

    Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915

  11. Anti-chemokine small molecule drugs: a promising future?

    Science.gov (United States)

    Proudfoot, Amanda E I; Power, Christine A; Schwarz, Matthias K

    2010-03-01

    Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry. Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review. In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future. In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.

  12. Sesquiterpene lactones isolated from indigenous Middle Eastern plants inhibit tumor promoter-induced transformation of JB6 cells

    Directory of Open Access Journals (Sweden)

    Saikali Melody

    2012-07-01

    Full Text Available Abstract Background Sesquiterpene lactones (SL are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. Considering that several SL-derived drugs are currently in cancer clinical trials, we have tested two SL molecules, 3-β-methoxy-iso-seco-tanapartholide (β-tan isolated from Achillea falcata and salograviolide A (Sal A isolated from Centaurea ainetensis, for their anti-tumor properties. We used the mouse epidermal JB6P + cells as a model for tumor promotion and cellular transformation. Key players that are involved in cellular transformation and tumorigenesis are the AP-1 and NF-κB transcription factors; therefore, we assessed how β-tan and Sal A modulate their signaling pathways in JB6P + cells. Methods The effects of β-tan and Sal A on the growth of normal and neoplastic keratinocytes and on the tumor promotion-responsive JB6P + cells were determined using the MTT assay. Anchorage-independent cell growth transformation assays were used to evaluate the anti-tumor promoting properties of these SL molecules in JB6P + cells and dual luciferase reporter assays and western blot analysis were used to investigate their effects on tumor promoter-induced AP-1 and NF-κB activities and protein levels of key AP-1 and NF-кB target genes. Results β-tan and Sal A selectively inhibited tumor promoter-induced cell growth and transformation of JB6P + cells at concentrations that do not affect JB6P + and primary keratinocytes basal cell growth. In addition, both molecules reduced basal and tumor promoter-induced NF-κB transcriptional activities, differentially regulated basal and tumor promoter-induced AP-1 transcriptional activities, and modulated key players of the AP-1 and NF-κB signaling pathways. Conclusions These results highlight the anti-tumor promoting properties of β-tan and Sal A. These SL molecules isolated from two plant species native to

  13. Sesquiterpene lactones isolated from indigenous Middle Eastern plants inhibit tumor promoter-induced transformation of JB6 cells.

    Science.gov (United States)

    Saikali, Melody; Ghantous, Akram; Halawi, Racha; Talhouk, Salma N; Saliba, Najat A; Darwiche, Nadine

    2012-07-09

    Sesquiterpene lactones (SL) are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. Considering that several SL-derived drugs are currently in cancer clinical trials, we have tested two SL molecules, 3-β-methoxy-iso-seco-tanapartholide (β-tan) isolated from Achillea falcata and salograviolide A (Sal A) isolated from Centaurea ainetensis, for their anti-tumor properties. We used the mouse epidermal JB6P + cells as a model for tumor promotion and cellular transformation. Key players that are involved in cellular transformation and tumorigenesis are the AP-1 and NF-κB transcription factors; therefore, we assessed how β-tan and Sal A modulate their signaling pathways in JB6P + cells. The effects of β-tan and Sal A on the growth of normal and neoplastic keratinocytes and on the tumor promotion-responsive JB6P + cells were determined using the MTT assay. Anchorage-independent cell growth transformation assays were used to evaluate the anti-tumor promoting properties of these SL molecules in JB6P + cells and dual luciferase reporter assays and western blot analysis were used to investigate their effects on tumor promoter-induced AP-1 and NF-κB activities and protein levels of key AP-1 and NF-кB target genes. β-tan and Sal A selectively inhibited tumor promoter-induced cell growth and transformation of JB6P + cells at concentrations that do not affect JB6P + and primary keratinocytes basal cell growth. In addition, both molecules reduced basal and tumor promoter-induced NF-κB transcriptional activities, differentially regulated basal and tumor promoter-induced AP-1 transcriptional activities, and modulated key players of the AP-1 and NF-κB signaling pathways. These results highlight the anti-tumor promoting properties of β-tan and Sal A. These SL molecules isolated from two plant species native to the Middle East may provide opportunities for complementary

  14. Senescence from glioma stem cell differentiation promotes tumor growth

    International Nuclear Information System (INIS)

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  15. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  16. CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells.

    Science.gov (United States)

    Wang, Li-Hong; Lin, Chih-Yang; Liu, Shih-Chia; Liu, Guan-Ting; Chen, Yen-Ling; Chen, Jih-Jung; Chan, Chia-Han; Lin, Ting-Yi; Chen, Chi-Kuan; Xu, Guo-Hong; Chen, Shiou-Sheng; Tang, Chih-Hsin; Wang, Shih-Wei

    2016-06-14

    Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumor lymphangiogenesis and lymphatic metastasis. Chemokine CCL5 has been reported to facilitate angiogenesis and metastasis in chondrosarcoma. However, the effect of chemokine CCL5 on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has largely remained a mystery. In this study, we showed a clinical correlation between CCL5 and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that CCL5 promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium (CM) from CCL5-overexpressed cells significantly induced tube formation of human lymphatic endothelial cells (LECs). Mechanistic investigations showed that CCL5 activated VEGF-C-dependent lymphangiogenesis by down-regulating miR-507. Moreover, inhibiting CCL5 dramatically reduced VEGF-C and lymphangiogenesis in the chondrosarcoma xenograft animal model. Collectively, we document for the first time that CCL5 induces tumor lymphangiogenesis by the induction of VEGF-C in human cancer cells. Our present study reveals miR-507/VEGF-C signaling as a novel mechanism in CCL5-mediated tumor lymphangiogenesis. Targeting both CCL5 and VEGF-C pathways might serve as the potential therapeutic strategy to block cancer progression and metastasis in chondrosarcoma.

  17. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2016-10-01

    cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression...impact of pharmacological inhibition of Cxcl5 and Cxcr2 on MDSCs using the transwell migration assay 26 . First, anti-Cxcl5 neutralizing antibody...and MRI . (B) Generation of the CPPSML chimera model. (C) Fluorescence microscopy and H&E image of snap frozen prostate tumor from chimera showing that

  18. The inflammatory cytokine TNFα cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells

    International Nuclear Information System (INIS)

    Leibovich-Rivkin, Tal; Liubomirski, Yulia; Meshel, Tsipi; Abashidze, Anastasia; Brisker, Daphna; Solomon, Hilla; Rotter, Varda; Weil, Miguel; Ben-Baruch, Adit

    2014-01-01

    In the present study we determined the relative contribution of two processes to breast cancer progression: (1) Intrinsic events, such as activation of the Ras pathway and down-regulation of p53; (2) The inflammatory cytokines TNFα and IL-1β, shown in our published studies to be highly expressed in tumors of >80% of breast cancer patients with recurrent disease. Using MCF-7 human breast tumor cells originally expressing WT-Ras and WT-p53, we determined the impact of the above-mentioned elements and cooperativity between them on the expression of CXCL8 (ELISA, qRT-PCR), a member of a “cancer-related chemokine cluster” that we have previously identified. Then, we determined the mechanisms involved (Ras-binding-domain assays, Western blot, luciferase), and tested the impact of Ras + TNFα on angiogenicity (chorioallantoic membrane assays) and on tumor growth at the mammary fat pad of mice and on metastasis, in vivo. Using Ras G12V that recapitulates multiple stimulations induced by receptor tyrosine kinases, we found that Ras G12V alone induced CXCL8 expression at the mRNA and protein levels, whereas down-regulation of p53 did not. TNFα and IL-1β potently induced CXCL8 expression and synergized with Ras G12V , together leading to amplified CXCL8 expression. Testing the impact of WT-Ras, which is the common form in breast cancer patients, we found that WT-Ras was not active in promoting CXCL8; however, TNFα has induced the activation of WT-Ras: joining these two elements has led to cooperative induction of CXCL8 expression, via the activation of MEK, NF-κB and AP-1. Importantly, TNFα has led to increased expression of WT-Ras in an active GTP-bound form, with properties similar to those of Ras G12V . Jointly, TNFα + Ras activities have given rise to increased angiogenesis and to elevated tumor cell dissemination to lymph nodes. TNFα cooperates with Ras in promoting the metastatic phenotype of MCF-7 breast tumor cells, and turns WT-Ras into a tumor

  19. Microbiological exploitation of the chemokine system

    DEFF Research Database (Denmark)

    Holst, Peter Johannes; Rosenkilde, Mette Marie

    2003-01-01

    Several viruses encode chemokine elements in their genome. This review focuses on the roles of such elements in the ongoing battle between the virus and the host. The biological and pharmacological characterizations of several of these chemokine elements have highlighted their importance in the m...

  20. Chemokine Involvement in Fetal and Adult Wound Healing

    Science.gov (United States)

    Balaji, Swathi; Watson, Carey L.; Ranjan, Rajeev; King, Alice; Bollyky, Paul L.; Keswani, Sundeep G.

    2015-01-01

    Significance: Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired and characterized by scar formation. The biologic basis of the fetal regenerative phenotype can serve as a roadmap to recapitulating regenerative repair in adult wounds. Reduced leukocyte infiltration, likely mediated, in part, through changes in the chemokine milieu, is a fundamental feature of fetal wound healing. Recent Advances: The contributions of chemokines to wound healing are a topic of active investigation. Recent discoveries have opened the possibility of targeting chemokines therapeutically to treat disease processes and improve healing capability, including the possibility of achieving a scarless phenotype in postnatal wounds. Critical Issues: Successful wound healing is a complex process, in which there is a significant interplay between multiple cell types, signaling molecules, growth factors, and extracellular matrix. Chemokines play a crucial role in this interplay and have been shown to have different effects in various stages of the healing process. Understanding how these chemokines are locally produced and regulated during wound healing and how the chemokine milieu differs in fetal versus postnatal wounds may help us identify ways in which we can target chemokine pathways. Future Directions: Further studies on the role of chemokines and their role in the healing process will greatly advance the potential for using these molecules as therapeutic targets. PMID:26543680

  1. Distinct chemokine receptor and cytokine expression profile in secondary progressive MS

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F

    2001-01-01

    Chemokines, small chemotactic cytokines, have been implicated in active relapsing-remitting MS (RRMS). However, the role of chemokines and chemokine receptors has not been specifically studied in secondary progressive MS (SPMS).......Chemokines, small chemotactic cytokines, have been implicated in active relapsing-remitting MS (RRMS). However, the role of chemokines and chemokine receptors has not been specifically studied in secondary progressive MS (SPMS)....

  2. Chemokines and Chemokine Receptors in Susceptibility to HIV-1 Infection and Progression to AIDS

    Directory of Open Access Journals (Sweden)

    Animesh Chatterjee

    2012-01-01

    Full Text Available A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.

  3. Radiation-induced irreparable heritable changes in cells promoting their tumoral transformation

    International Nuclear Information System (INIS)

    Kuzin, A.M.; Vagabova, M.Eh.; Yurov, S.S.

    1988-01-01

    In experiments with model plant tumors (Kalanchoe-ti plasmid Agrobat. tumefaciens C-58D) it was shown that exposure of the recepient plant to low-level γ-radiation of Gy induced changes in cells that were not repaired over two months promoting tumoral transformations in them. Those changes were shown to persist in the offspring of the exposed somatic cells

  4. System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity.

    Directory of Open Access Journals (Sweden)

    Megha Rajaram

    Full Text Available Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8 or minimally (STC1 significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti

  5. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis | Center for Cancer Research

    Science.gov (United States)

    We demonstrate a novel tumor-promoting role of myeloid immune suppressor Gr+CD11b+ cells, which are evident in cancer patients and tumor-bearing animals. These cells constitute approximately 5% of total cells in tumors. Tumors coinjected with Gr+CD11b+ cells exhibited increased vascular density, vascular maturation, and decreased necrosis. These immune cells produce high

  6. Transforming Growth Factor-β and Interleukin-1β Signaling Pathways Converge on the Chemokine CCL20 Promoter.

    Science.gov (United States)

    Brand, Oliver J; Somanath, Sangeeta; Moermans, Catherine; Yanagisawa, Haruhiko; Hashimoto, Mitsuo; Cambier, Stephanie; Markovics, Jennifer; Bondesson, Andrew J; Hill, Arthur; Jablons, David; Wolters, Paul; Lou, Jianlong; Marks, James D; Baron, Jody L; Nishimura, Stephen L

    2015-06-05

    CCL20 is the only chemokine ligand for the chemokine receptor CCR6, which is expressed by the critical antigen presenting cells, dendritic cells. Increased expression of CCL20 is likely involved in the increased recruitment of dendritic cells observed in fibroinflammatory diseases such as chronic obstructive pulmonary disease (COPD). CCL20 expression is increased by the proinflammatory cytokine IL-1β. We have determined that IL-1β-dependent CCL20 expression is also dependent on the multifunctional cytokine TGF-β. TGF-β is expressed in a latent form that must be activated to function, and activation is achieved through binding to the integrin αvβ8 (itgb8). Here we confirm correlative increases in αvβ8 and IL-1β with CCL20 protein in lung parenchymal lysates of a large cohort of COPD patients. How IL-1β- and αvβ8-mediated TGF-β activation conspire to increase fibroblast CCL20 expression remains unknown, because these pathways have not been shown to directly interact. We evaluate the 5'-flanking region of CCL20 to determine that IL-1β-driven CCL20 expression is dependent on αvβ8-mediated activation of TGF-β. We identify a TGF-β-responsive element (i.e. SMAD) located on an upstream enhancer of the human CCL20 promoter required for efficient IL-1β-dependent CCL20 expression. By chromatin immunoprecipitation, this upstream enhancer complexes with the p50 subunit of NF-κB on a NF-κB-binding element close to the transcriptional start site of CCL20. These interactions are confirmed by electromobility shift assays in nuclear extracts from human lung fibroblasts. These data define a mechanism by which αvβ8-dependent activation of TGF-β regulates IL-1β-dependent CCL20 expression in COPD. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Effect of tumor promoters on ultraviolet light-induced mutation and mitotic recombination in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Kunz, B.A.; Hannan, M.A.; Haynes, R.H.

    1980-01-01

    Recently, it has been suggested that mitotic recombination is involved in tumor promotion. On this basis, one might expect tumor promoters to be recombinagenic. D7 is a diploid strain of yeast in which both mutation and mitotic recombination can be measured. We have used this strain to assay the known tumor promoters, iodacetate, anthralin, and 12-0-tetradecanoylphorbol-13-acetate, and the cocarcinogen, catechol, for mutagenicity, recombinagenicity, and the ability to enhance ultraviolet light (UV)-induced genetic events. In the absence of preirradiation with UV, iodoacetate was found to be recombinagenic whereas catechol was mutagenic; however, in both cases, the effects were small. Iodoacetate, anthralin, and catechol potentiated UV-induced mitotic crossing-over, aberrant colony formation, and mutation, while catechol also increased UV-induced gene conversion. We were unable to detect any mutagenic or recombinagenic effect of 12-0-tetradecanoyl-phorbol-13-acetate in either whole cells or spheroplasts. Our results do not indicate any consistent correlation between tumor-promoting activity and the ability of an agent to induce mitotic recombination in yeast. However, the ability to potentiate UV-induced mutation and mitotic recombination may reflect the cocarcinogenic activity of certain promoters

  8. International Union of Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

    Science.gov (United States)

    Bachelerie, Francoise; Ben-Baruch, Adit; Burkhardt, Amanda M.; Combadiere, Christophe; Farber, Joshua M.; Graham, Gerard J.; Horuk, Richard; Sparre-Ulrich, Alexander Hovard; Locati, Massimo; Luster, Andrew D.; Mantovani, Alberto; Matsushima, Kouji; Nibbs, Robert; Nomiyama, Hisayuki; Power, Christine A.; Proudfoot, Amanda E. I.; Rosenkilde, Mette M.; Rot, Antal; Sozzani, Silvano; Thelen, Marcus; Yoshie, Osamu; Zlotnik, Albert

    2014-01-01

    Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human

  9. CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Heyu [Central Laboratory, Peking University School of Stomatology, Beijing (China); Nan, Xu [Center for Human Disease Genomics, Department of Immunology, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing (China); Li, Xuefen [Central Laboratory, Peking University School of Stomatology, Beijing (China); Chen, Yan; Zhang, Jianyun [Department of Oral Pathology, Peking University School of Stomatology, Beijing (China); Sun, Lisha [Central Laboratory, Peking University School of Stomatology, Beijing (China); Han, Wenlin [Center for Human Disease Genomics, Department of Immunology, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing (China); Li, Tiejun, E-mail: litiejun22@vip.sina.com [Department of Oral Pathology, Peking University School of Stomatology, Beijing (China)

    2014-05-02

    Highlights: • Down-regulation of CMTM5 expression in OSCC tissues was found. • The promoter methylation status of CMTM5 was measured. • CMTM5-v1 inhibited cell proliferation and migration and induced apoptosis. • CMTM5 might act as a putative tumor suppressor gene in OSCC. - Abstract: Oral squamous cell carcinoma (OSCC) is one of the most common types of malignancies in the head and neck region. CKLF-like MARVEL transmembrane domain-containing member 5 (CMTM5) has been recently implicated as a tumor suppressor gene in several cancer types. Herein, we examined the expression and function of CMTM5 in oral squamous cell carcinoma. CMTM5 was down-regulated in oral squamous cell lines and tumor samples from patients with promoter methylation. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored CMTM5 expression. In the OSCC cell lines CAL27 and GNM, the ectopic expression of CMTM5-v1 strongly inhibited cell proliferation and migration and induced apoptosis. In addition, CMTM5-v1 inhibited tumor formation in vivo. Therefore, CMTM5 might act as a putative tumor suppressor gene through promoter methylation in oral squamous cell carcinoma.

  10. CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Zhang, Heyu; Nan, Xu; Li, Xuefen; Chen, Yan; Zhang, Jianyun; Sun, Lisha; Han, Wenlin; Li, Tiejun

    2014-01-01

    Highlights: • Down-regulation of CMTM5 expression in OSCC tissues was found. • The promoter methylation status of CMTM5 was measured. • CMTM5-v1 inhibited cell proliferation and migration and induced apoptosis. • CMTM5 might act as a putative tumor suppressor gene in OSCC. - Abstract: Oral squamous cell carcinoma (OSCC) is one of the most common types of malignancies in the head and neck region. CKLF-like MARVEL transmembrane domain-containing member 5 (CMTM5) has been recently implicated as a tumor suppressor gene in several cancer types. Herein, we examined the expression and function of CMTM5 in oral squamous cell carcinoma. CMTM5 was down-regulated in oral squamous cell lines and tumor samples from patients with promoter methylation. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored CMTM5 expression. In the OSCC cell lines CAL27 and GNM, the ectopic expression of CMTM5-v1 strongly inhibited cell proliferation and migration and induced apoptosis. In addition, CMTM5-v1 inhibited tumor formation in vivo. Therefore, CMTM5 might act as a putative tumor suppressor gene through promoter methylation in oral squamous cell carcinoma

  11. CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis.

    Science.gov (United States)

    Dondossola, Eleonora; Rangel, Roberto; Guzman-Rojas, Liliana; Barbu, Elena M; Hosoya, Hitomi; St John, Lisa S; Molldrem, Jeffrey J; Corti, Angelo; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2013-12-17

    Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13(+) bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have identified CD11b(+)CD13(+) myeloid cells as the immune subpopulation directly regulating tumor blood vessel development. Finally, we show that these cells are specifically localized within the tumor microenvironment and produce proangiogenic soluble factors. Thus, CD11b(+)CD13(+) myeloid cells constitute a population of bone marrow-derived cells that promote tumor progression and metastasis and are potential candidates for the development of targeted antiangiogenic drugs.

  12. Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response.

    Science.gov (United States)

    Newton, Jared M; Flores-Arredondo, Jose H; Suki, Sarah; Ware, Matthew J; Krzykawska-Serda, Martyna; Agha, Mahdi; Law, Justin J; Sikora, Andrew G; Curley, Steven A; Corr, Stuart J

    2018-02-22

    Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.

  13. Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression.

    Science.gov (United States)

    Isakov, Noah

    2018-02-01

    The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell cycle and differentiation, morphogenesis, and cell survival and death. Mutation and/or dysregulation of AGC kinases can lead to malignant cell transformation and contribute to the pathogenesis of many human diseases. Members of one subgroup of AGC kinases, the protein kinase C (PKC), have been singled out as critical players in carcinogenesis, following their identification as the intracellular receptors of phorbol esters, which exhibit tumor-promoting activities. This observation attracted the attention of researchers worldwide and led to intense investigations on the role of PKC in cell transformation and the potential use of PKC as therapeutic drug targets in cancer diseases. Studies demonstrated that many cancers had altered expression and/or mutation of specific PKC genes. However, the causal relationships between the changes in PKC gene expression and/or mutation and the direct cause of cancer remain elusive. Independent studies in normal cells demonstrated that activation of PKC is essential for the induction of cell activation and proliferation, differentiation, motility, and survival. Based on these observations and the general assumption that PKC isoforms play a positive role in cell transformation and/or cancer progression, many PKC inhibitors have entered clinical trials but the numerous attempts to target PKC in cancer has so far yielded only very limited success. More recent studies demonstrated that PKC function as tumor suppressors, and suggested that future clinical efforts should focus on restoring, rather than inhibiting, PKC activity. The present manuscript provides some historical perspectives on the tumor promoting function of PKC, reviewing some of the observations linking PKC to cancer progression, and discusses the role of PKC in the pathogenesis of cancer diseases and its

  14. Diet-induced obesity promotes colon tumor development in azoxymethane-treated mice.

    Directory of Open Access Journals (Sweden)

    Iina Tuominen

    Full Text Available Obesity is an important risk factor for colon cancer in humans, and numerous studies have shown that a high fat diet enhances colon cancer development. As both increased adiposity and high fat diet can promote tumorigenesis, we examined the effect of diet-induced obesity, without ongoing high fat diet, on colon tumor development. C57BL/6J male mice were fed regular chow or high fat diet for 8 weeks. Diets were either maintained or switched resulting in four experimental groups: regular chow (R, high fat diet (H, regular chow switched to high fat diet (RH, and high fat diet switched to regular chow (HR. Mice were then administered azoxymethane to induce colon tumors. Tumor incidence and multiplicity were dramatically smaller in the R group relative to all groups that received high fat diet at any point. The effect of obesity on colon tumors could not be explained by differences in aberrant crypt foci number. Moreover, diet did not alter colonic expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, which were measured immediately after azoxymethane treatment. Crypt apoptosis and proliferation, which were measured at the same time, were increased in the HR relative to all other groups. Our results suggest that factors associated with obesity - independently of ongoing high fat diet and obesity - promote tumor development because HR group animals had significantly more tumors than R group, and these mice were fed the same regular chow throughout the entire carcinogenic period. Moreover, there was no difference in the number of aberrant crypt foci between these groups, and thus the effect of obesity appears to be on subsequent stages of tumor development when early preneoplastic lesions transition into adenomas.

  15. Extravascular red blood cells and hemoglobin promote tumor growth and therapeutic resistance as endogenous danger signals.

    Science.gov (United States)

    Yin, Tao; He, Sisi; Liu, Xiaoling; Jiang, Wei; Ye, Tinghong; Lin, Ziqiang; Sang, Yaxiong; Su, Chao; Wan, Yang; Shen, Guobo; Ma, Xuelei; Yu, Min; Guo, Fuchun; Liu, Yanyang; Li, Ling; Hu, Qiancheng; Wang, Yongsheng; Wei, Yuquan

    2015-01-01

    Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-κB pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1β release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance. Copyright © 2014 by The American Association of Immunologists, Inc.

  16. Hypoxia promotes tumor growth in linking angiogenesis to immune escape

    Directory of Open Access Journals (Sweden)

    Salem eCHOUAIB

    2012-02-01

    Full Text Available Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection and contains many overlapping mechanisms to evade antigen specific immunotherapy. Obviously, tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival and metastasis. Among the hypoxia-induced genes, hypoxia-inducible factor (HIF-1 and vascular endothelial growth factor (VEGF play a determinant role in promoting tumor cell growth and survival. In this regard, hypoxia is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.

  17. Chemokine Signaling in Allergic Contact Dermatitis: Toward Targeted Therapies.

    Science.gov (United States)

    Smith, Jeffrey S; Rajagopal, Sudarshan; Atwater, Amber Reck

    2018-06-22

    Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immune system, but also by natural killer and innate lymphoid cells within the innate immune system. The chemokine receptor system, consisting of chemokine peptides and chemokine G protein-coupled receptors, is a critical regulator of inflammatory processes such as ACD. Specific chemokine signaling pathways are selectively up-regulated in ACD, most prominently CXCR3 and its endogenous chemokines CXCL9, CXCL10, and CXCL11. Recent research demonstrates that these 3 chemokines are not redundant and indeed activate distinct intracellular signaling profiles such as those activated by heterotrimeric G proteins and β-arrestin adapter proteins. Such differential signaling provides an attractive therapeutic target for novel ACD therapies and other inflammatory diseases.

  18. Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

    International Nuclear Information System (INIS)

    Costa, Vera L; Henrique, Rui; Ribeiro, Franclim R; Pinto, Mafalda; Oliveira, Jorge; Lobo, Francisco; Teixeira, Manuel R; Jerónimo, Carmen

    2007-01-01

    Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors. A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP) in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC), 13 papillary (pRCC), 10 chromophobe (chRCC), and 10 oncocytomas) and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters. Significant differences in methylation levels among the four subtypes of renal tumors were found for CDH1 (p = 0.0007), PTGS2 (p = 0.002), and RASSF1A (p = 0.0001). CDH1 hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (p = 0.00016 and p = 0.0034, respectively), whereas PTGS2 methylation levels were significantly higher in ccRCC compared to pRCC (p = 0.004). RASSF1A methylation levels were significantly higher in pRCC than in normal tissue (p = 0.035). In pRCC, CDH1 and RASSF1A methylation levels were inversely correlated with tumor stage (p = 0.031) and nuclear grade (p = 0.022), respectively. The major subtypes of renal epithelial neoplasms display differential aberrant CDH1, PTGS2, and RASSF1A promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses

  19. The Serum Concentrations of Chemokine CXCL12 and Its Specific Receptor CXCR4 in Patients with Esophageal Cancer

    Directory of Open Access Journals (Sweden)

    Marta Łukaszewicz-Zając

    2016-01-01

    Full Text Available Objectives. Recent investigations have suggested that upregulated levels of inflammatory biomarkers, such as chemokines, may be associated with development of many malignancies, including esophageal cancer (EC. Based on our knowledge, this study is the first to assess the serum concentration of chemokine CXCL12 and its specific receptor CXCR4 in the diagnosis of EC patients. Material and Methods. The present study included 79 subjects: 49 patients with EC and 30 healthy volunteers. The serum concentrations of CXCL12 and CXCR4 and classical tumor markers such as carcinoembryonal antigen (CEA and squamous cell cancer antigen (SCC-Ag were measured using immunoenzyme assays, while C-reactive protein (CRP levels were assessed by immunoturbidimetric method. Moreover, diagnostic criteria of all proteins tested and the survival of EC patients were assessed. Results. The serum concentrations of CXCL12 were significantly higher, while those of its receptor CXCR4 were significantly lower in EC patients compared to healthy controls. The diagnostic sensitivity, negative predictive value, and accuracy of CXCR4 were the highest among all analyzed proteins and increased for combined analysis with classical tumor markers and CRP levels. Conclusion. Our findings suggest that serum CXCR4 may improve the diagnosis of EC patients, especially in combination with classical tumor markers.

  20. Disruption of Lysosome Function Promotes Tumor Growth and Metastasis in Drosophila *

    OpenAIRE

    Chi, Congwu; Zhu, Huanhu; Han, Min; Zhuang, Yuan; Wu, Xiaohui; Xu, Tian

    2010-01-01

    Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the RasV12 cells....

  1. Chemokines and their receptors in central nervous system disease

    NARCIS (Netherlands)

    Biber, K; de Jong, EK; van Weering, HRJ; Boddeke, HWGM

    Almost a decade ago, it was discovered that the human deficiency virus (HIV) makes use of chemokine receptors to infect blood cells. This appreciation of the clinical relevance of specific chemokine receptors has initiated a considerable boost in the field of chemokine research. It is clear today

  2. Capacity of wild-type and chemokine-armed parvovirus H-1PV for inhibiting neo-angiogenesis.

    Science.gov (United States)

    Lavie, Muriel; Struyf, Sofie; Stroh-Dege, Alexandra; Rommelaere, Jean; Van Damme, Jo; Dinsart, Christiane

    2013-12-01

    Anti-angiogenic therapy has been recognized as a powerful potential strategy for impeding the growth of various tumors. However no major therapeutic effects have been observed to date, mainly because of the emergence of several resistance mechanisms. Among novel strategies to target tumor vasculature, some oncolytic viruses open up new prospects. In this context, we addressed the question whether the rodent parvovirus H-1PV can target endothelial cells. We show that cultures of human normal (HUVEC) and immortalized (KS-IMM) endothelial cells sustain an abortive viral cycle upon infection with H-1PV and are sensitive to H-1PV cytotoxicity. H-1PV significantly inhibits infected KS-IMM tumor growth. This effect may be traced back by the virus ability to both kill proliferating endothelial cells and inhibit VEGF production Recombinant H-1PV vectors can also transduce tumor cells with chemokines endowed with anti-angiogenesis properties, and warrant further validation for the treatment of highly vascularized tumors. © 2013 Elsevier Inc. All rights reserved.

  3. Reduced Fc∊RI-Mediated Release of Asthma-Promoting Cytokines and Chemokines from Human Basophils during Omalizumab Therapy

    Science.gov (United States)

    Oliver, Janet M.; Tarleton, Christy A.; Gilmartin, Laura; Archibeque, Tereassa; Qualls, Clifford R.; Diehl, Lorena; Wilson, Bridget S.; Schuyler, Mark

    2010-01-01

    Background Treating asthmatics with the humanized IgE-scavenging antibody, omalizumab (rhuMAb-E25, Xolair®), reduces airways inflammation and asthma symptoms. Previously, omalizumab was shown to cause a dramatic and reversible loss of cell surface high-affinity IgE receptors, Fc∊RI, from the peripheral blood basophils of asthmatics. The consequences of receptor loss for the Fc∊RI-mediated synthesis and release of cytokines implicated in allergic asthma have not been examined. Methods Fifteen asthmatic volunteers each received omalizumab for 12 weeks. Peripheral blood basophils were isolated before, during, 2 weeks after and 6 months after omalizumab. Basophils were assayed for the basal and anti-IgE-stimulated release of cytokines, chemokines and histamine. Pooled data were analyzed by repeated measures ANOVA and by paired t tests. Results Anti-IgE-stimulated human basophils synthesize and release Th2 cytokines (IL-4, IL-13) and chemokines (IL-8, RANTES). The anti-IgE-stimulated release of IL-4, IL-13 and IL-8 was reduced during omalizumab treatment and returned to pretreatment levels after omalizumab withdrawal. Omalizumab did not alter basophil histamine levels or basal and anti-IgE-stimulated histamine release. Conclusions Omalizumab may reduce asthma symptoms in part by suppressing the Fc∊RI-mediated production by basophils of Th2 cytokines and selected chemokines. Anti-IgE-stimulated basophil cytokine synthesis appears more sensitive than histamine release to the loss of Fc∊RI caused by omalizumab treatment. PMID:19844128

  4. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization

    International Nuclear Information System (INIS)

    Jang, Ji-Young; Lee, Jong-Kuen; Jeon, Yoon-Kyung; Kim, Chul-Woo

    2013-01-01

    Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-β) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-β and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-β; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. Our data demonstrate that EGCG up-regulates miR-16 in

  5. Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor–microenvironment interactions

    International Nuclear Information System (INIS)

    Ben-Baruch, A

    2003-01-01

    A comprehensive overview of breast cancer development and progression suggests that the process is influenced by intrinsic properties of the tumor cells, as well as by microenvironmental factors. Indeed, in breast carcinoma, an intensive interplay exists between the tumor cells on one hand, and inflammatory cells/cytokines/chemokines on the other. The purpose of the present review is to outline the reciprocal interactions that exist between these different elements, and to shed light on their potential involvement in breast cancer development and progression

  6. Virally encoded chemokines and chemokine receptors in the role of viral infections

    DEFF Research Database (Denmark)

    Holst, Peter J; Lüttichau, Hans R; Schwartz, Thue W

    2003-01-01

    of these or potent ways to alter an efficient antiviral response to a weak Th2-driven response. Examples here are the chemokine scavenging by US28, attractance of Th2 cells and regulatory cells by vMIP1-3 and the selective engaging of CCR8 by MC148. Important insights into viral pathology and possible targets...... for antiviral therapies have been provided by UL33, UL78 and in particular ORF74 and the chances are that many more will follow. In HHV8 vMIP-2 and the chemokine-binding proteins potent anti-inflammatory agents have been provided. These have already had their potential demonstrated in animal models and may...

  7. Macrophage Transactivation for Chemokine Production Identified as a Negative Regulator of Granulomatous Inflammation Using Agent-Based Modeling

    Directory of Open Access Journals (Sweden)

    Daniel Moyo

    2018-03-01

    Full Text Available Cellular activation in trans by interferons, cytokines, and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and/or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling, and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation.

  8. The role of dermal irritation in the skin tumor promoting activity of petroleum middle distillates.

    Science.gov (United States)

    Nessel, C S; Freeman, J J; Forgash, R C; McKee, R H

    1999-05-01

    Petroleum middle distillates (PMDs), a class of hydrocarbons which boil between 350-700 degrees F, are tumor promoters in mouse skin. The promotional activity is produced under conditions that also result in local changes, including chronic irritation and epidermal hyperplasia. The present study was conducted by comparing equal weekly doses of irritating and minimally or nonirritating test materials, to assess whether tumor promotion was a secondary response to these effects. Four PMDs, C10-C14 normal paraffins (NP), lightly refined paraffinic oil (LRPO), Jet Fuel A (JF), and steam-cracked gas oil (SCGO), were evaluated. Test materials were applied undiluted (2x/week) or as 28.6% (7x/week) or 50% (4x/week) concentrations in mineral oil for 52 weeks following initiation with dimethylbenzanthracene (DMBA). When applied undiluted, all materials produced moderate irritation and significant increase in tumor incidence. When NP, LRPO, or JF were applied in mineral oil diluent, skin irritation was generally ameliorated and few, if any, tumors were produced. SCGO was irritating and produced a significant increase in tumor frequency when administered in mineral-oil diluent. These data indicate that the promotional activity of straight-run PMDs is likely related to chronic irritation at the application site and not to dose. Thus, when used appropriately in the absence of prolonged irritation, these materials should not present a tumorigenic hazard to humans.

  9. Chemokines and chemokine receptors in inflammation of the nervous system

    DEFF Research Database (Denmark)

    Huang, D; Han, Yong-Chang; Rani, M R

    2000-01-01

    This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis...

  10. Peroxisome proliferator-activated receptor α agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    International Nuclear Information System (INIS)

    Antonelli, Alessandro; Ferrari, Silvia Martina; Frascerra, Silvia; Corrado, Alda; Pupilli, Cinzia; Bernini, Giampaolo; Benvenga, Salvatore; Ferrannini, Ele; Fallahi, Poupak

    2011-01-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR)α activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPARα and PPARγ activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN)γ and tumor necrosis factor (TNF)α. IFNγ stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNFα alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFNγ and TNFα had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPARα activators inhibited the secretion of both chemokines (stimulated with IFNγ and TNFα) at a level higher (for CXCL10, about 60-72%) than PPARγ agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFNγ and TNFα in GD and normal thyrocytes. Furthermore we first show that PPARα activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

  11. Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

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    Oliveira Jorge

    2007-07-01

    Full Text Available Abstract Background Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors. Methods A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC, 13 papillary (pRCC, 10 chromophobe (chRCC, and 10 oncocytomas and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters. Results Significant differences in methylation levels among the four subtypes of renal tumors were found for CDH1 (p = 0.0007, PTGS2 (p = 0.002, and RASSF1A (p = 0.0001. CDH1 hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (p = 0.00016 and p = 0.0034, respectively, whereas PTGS2 methylation levels were significantly higher in ccRCC compared to pRCC (p = 0.004. RASSF1A methylation levels were significantly higher in pRCC than in normal tissue (p = 0.035. In pRCC, CDH1 and RASSF1A methylation levels were inversely correlated with tumor stage (p = 0.031 and nuclear grade (p = 0.022, respectively. Conclusion The major subtypes of renal epithelial neoplasms display differential aberrant CDH1, PTGS2, and RASSF1A promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.

  12. Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression*

    Science.gov (United States)

    Coke, Christopher J.; Scarlett, Kisha A.; Chetram, Mahandranauth A.; Jones, Kia J.; Sandifer, Brittney J.; Davis, Ahriea S.; Marcus, Adam I.

    2016-01-01

    The G-protein-coupled chemokine receptor CXCR4 generates signals that lead to cell migration, cell proliferation, and other survival mechanisms that result in the metastatic spread of primary tumor cells to distal organs. Numerous studies have demonstrated that CXCR4 can form homodimers or can heterodimerize with other G-protein-coupled receptors to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor. Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells. Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2 and ultimately reduced cancer cell functions such as calcium mobilization and cellular chemotaxis. Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells as well as CXCR4-mediated migration of immune cells, it is plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4. Taken together, the data illustrate a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function and perhaps tumor progression. PMID:26841863

  13. Tumor-associated endothelial cells display GSTP1 and RARβ2 promoter methylation in human prostate cancer

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    Pohida Thomas J

    2006-03-01

    Full Text Available Abstract Background A functional blood supply is essential for tumor growth and proliferation. However, the mechanism of blood vessel recruitment to the tumor is still poorly understood. Ideally, a thorough molecular assessment of blood vessel cells would be critical in our comprehension of this process. Yet, to date, there is little known about the molecular makeup of the endothelial cells of tumor-associated blood vessels, due in part to the difficulty of isolating a pure population of endothelial cells from the heterogeneous tissue environment. Methods Here we describe the use of a recently developed technique, Expression Microdissection, to isolate endothelial cells from the tumor microenvironment. The methylation status of the dissected samples was evaluated for GSTP1 and RARβ2 promoters via the QMS-PCR method. Results Comparing GSTP1 and RARβ2 promoter methylation data, we show that 100% and 88% methylation is detected, respectively, in the tumor areas, both in epithelium and endothelium. Little to no methylation is observed in non-tumor tissue areas. Conclusion We applied an accurate microdissection technique to isolate endothelial cells from tissues, enabling DNA analysis such as promoter methylation status. The observations suggest that epigenetic alterations may play a role in determining the phenotype of tumor-associated vasculature.

  14. White Adipose Tissue Cells Are Recruited by Experimental Tumors and Promote Cancer Progression in Mouse Models

    Science.gov (United States)

    Zhang, Yan; Daquinag, Alexes; Traktuev, Dmitry O.; Amaya-Manzanares, Felipe; Simmons, Paul J.; March, Keith L.; Pasqualini, Renata; Arap, Wadih; Kolonin, Mikhail G.

    2010-01-01

    The connection between obesity and accelerated cancer progression has been established, but the mediating mechanisms are not well understood. We have shown that stromal cells from white adipose tissue (WAT) cooperate with the endothelium to promote blood vessel formation through the secretion of soluble trophic factors. Here, we hypothesize that WAT directly mediates cancer progression by serving as a source of cells that migrate to tumors and promote neovascularization. To test this hypothesis, we have evaluated the recruitment of WAT-derived cells by tumors and the effect of their engraftment on tumor growth by integrating a transgenic mouse strain engineered for expansion of traceable cells with established allograft and xenograft cancer models. Our studies show that entry of adipose stromal and endothelial cells into systemic circulation leads to their homing to and engraftment into tumor stroma and vasculature, respectively. We show that recruitment of adipose stromal cells by tumors is sufficient to promote tumor growth. Finally, we show that migration of stromal and vascular progenitor cells from WAT grafts to tumors is also associated with acceleration of cancer progression. These results provide a biological insight for the clinical association between obesity and cancer, thus outlining potential avenues for preventive and therapeutic strategies. PMID:19491274

  15. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth

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    Roland El Ghazal

    2016-05-01

    Full Text Available In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1 in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4–deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  16. Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM.

    Science.gov (United States)

    Ge, Haitao; Mu, Luyan; Jin, Linchun; Yang, Changlin; Chang, Yifan Emily; Long, Yu; DeLeon, Gabriel; Deleyrolle, Loic; Mitchell, Duane A; Kubilis, Paul S; Lu, Dunyue; Qi, Jiping; Gu, Yunhe; Lin, Zhiguo; Huang, Jianping

    2017-10-01

    Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM. © 2017 UICC.

  17. The role of chronic acanthosis and subacute inflammation in tumor promotion in CD-1 mice by petroleum middle distillates.

    Science.gov (United States)

    Skisak, C

    1991-07-01

    An initiation-promotion bioassay using CD-1 mice was conducted to examine the role of chronic acanthosis and inflammation in tumor promotion by petroleum middle distillates (MD). Test groups were initiated with 7,12-dimethylbenz[a]anthracene (DMBA). Promotion with MD consisted of twice weekly treatments for 25 weeks with either 25 or 50 microliters, 50 microliters + daily treatment with 15 micrograms dexamethasone, 50 microliters + postapplication washings, or 100 microliters. Three mice from each group were euthanized at 21-day intervals (24 total per group). The skin from interim euthanized mice was examined histopathologically for tumors, acanthosis, and subacute inflammation. Tumor incidence at study termination was as follows: 25 microliters (45%), 50 microliters (43%), 50 microliters + dexamethasone (0%), 50 microliters + washing (70%), and 100 microliters (81%). A correlation of greater than 0.93 was observed at all intervals between tumor incidence and cumulative group mean degrees of acanthosis in interim euthanized mice. The correlation between subacute inflammation at early through midstudy interval weeks and tumor incidence at study termination was poor. These results support the hypothesis that induction of a lasting, albeit mild, hyperplasia is an essential, but not sufficient requirement for tumor promotion. Furthermore, subacute inflammation does not appear to be a significant factor in tumor promotion by petroleum MD.

  18. Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms.

    Science.gov (United States)

    Yan, Hongxia; Zhang, Ping; Kong, Xue; Hou, Xianglian; Zhao, Li; Li, Tianhang; Yuan, Xiaozhou; Fu, Hongjun

    2017-04-01

    In malignant melanoma, tumor-associated macrophages play multiple roles in promoting tumor growth, such as inducing the transformation of melanocytes under ultraviolet irradiation, increasing angiogenesis in melanomas, and suppressing antitumor immunity. Because granzyme B- and perforin-expressing Tr1 cells could specifically eliminate antigen-presenting cells of myeloid origin, we examined whether Tr1 cells in melanoma could eliminate tumor-promoting macrophages and how the interaction between Tr1 cells and macrophages could affect the growth of melanoma cells. Tr1 cells were characterized by high interleukin 10 secretion and low Foxp3 expression and were enriched in the CD4 + CD49b + LAG-3 + T-cell fraction. Macrophages derived from peripheral blood monocytes in the presence of modified melanoma-conditioned media demonstrated tumor-promoting capacity, exemplified by improving the proliferation of cocultured A375 malignant melanoma cells. But when primary Tr1 cells were present in the macrophage-A375 coculture, the growth of A375 cells was abrogated. The conventional CD25 + Treg cells, however, were unable to inhibit macrophage-mediated increase in tumor cell growth. Further analyses showed that Tr1 cells did not directly eliminate A375 cells, but mediated the killing of tumor-promoting macrophages through the secretion of granzyme B and perforin. The tumor-infiltrating interleukin 10 + Foxp3 - CD4 + T cells expressed very low levels of granzyme B and perforin, possibly suggested the downregulation of Tr1 cytotoxic capacity in melanoma tumors. Together, these data demonstrated an antitumor function of Tr1 cells through the elimination of tumor-promoting macrophages, which was not shared by conventional Tregs.

  19. Role of Conserved Disulfide Bridges and Aromatic Residues in Extracellular Loop 2 of Chemokine Receptor CCR8 for Chemokine and Small Molecule Binding

    DEFF Research Database (Denmark)

    Barington, Line; Rummel, Pia C; Lückmann, Michael

    2016-01-01

    and aromatic residues in extracellular loop 2 (ECL2) for ligand binding and activation in the chemokine receptor CCR8. We used IP3 accumulation and radioligand binding experiments to determine the impact of receptor mutagenesis on both chemokine and small molecule agonist and antagonist binding and action...... in CCR8. We find that the 7 transmembrane (7TM) receptor conserved disulfide bridge (7TM bridge) linking transmembrane helix (TM)III and ECL2 is crucial for chemokine and small molecule action, whereas the chemokine receptor conserved disulfide bridge between the N terminus and TMVII is needed only...

  20. The β-chemokines CCL2 and CCL7 are two novel differentiation factors for midbrain dopaminergic precursors and neurons

    International Nuclear Information System (INIS)

    Edman, Linda C.; Mira, Helena; Arenas, Ernest

    2008-01-01

    β-chemokines are secreted factors that regulate diverse functions in the adult brain, such as neuro-immune responses and neurotransmission, but their function in the developing brain is largely unknown. We recently found that the orphan nuclear receptor, Nurr1, up regulates CCL2 and CCL7 in neural stem cells, suggesting a possible function of β-chemokines in midbrain development. Here we report that two β-chemokines, CCL2 and CCL7, and two of their receptors, CCR1 and CCR2, are expressed and developmentally regulated in the ventral midbrain (VM). Moreover, we found that the expression of CCL7 was down regulated in the Nurr1 knockout mice, linking CCL7 to dopamine (DA) neuron development. When the function of CCL2 and CCL7 was examined, we found that they selectively enhanced the differentiation of Nurr1+ precursors into DA neurons, but not their survival or progenitor proliferation in primary precursor cultures. Moreover, both CCL2 and CCL7 promoted neuritogenesis in midbrain DA neuron cultures. Thus, our results show for the first time a function of β-chemokines in the developing brain and identify β-chemokines as novel class of pro-differentiation factors for midbrain DA neurons. These data also suggest that β-chemokines may become useful tools to enhance the differentiation of DA cell preparations for cell replacement therapy and drug discovery in Parkinson's disease (PD)

  1. Development of Novel Promiscuous Anti-Chemokine Peptibodies for Treating Autoimmunity and Inflammation

    Directory of Open Access Journals (Sweden)

    Michal Abraham

    2017-11-01

    Full Text Available Chemokines and their receptors play critical roles in the progression of autoimmunity and inflammation. Typically, multiple chemokines are involved in the development of these pathologies. Indeed, targeting single chemokines or chemokine receptors has failed to achieve significant clinical benefits in treating autoimmunity and inflammation. Moreover, the binding of host atypical chemokine receptors to multiple chemokines as well as the binding of chemokine-binding proteins secreted by various pathogens can serve as a strategy for controlling inflammation. In this work, promiscuous chemokine-binding peptides that could bind and inhibit multiple inflammatory chemokines, such as CCL2, CCL5, and CXCL9/10/11, were selected from phage display libraries. These peptides were cloned into human mutated immunoglobulin Fc-protein fusions (peptibodies. The peptibodies BKT120Fc and BKT130Fc inhibited the ability of inflammatory chemokines to induce the adhesion and migration of immune cells. Furthermore, BKT120Fc and BKT130Fc also showed a significant inhibition of disease progression in a variety of animal models for autoimmunity and inflammation. Developing a novel class of antagonists that can control the courses of diseases by selectively blocking multiple chemokines could be a novel way of generating effective therapeutics.

  2. Disruption of lysosome function promotes tumor growth and metastasis in Drosophila.

    Science.gov (United States)

    Chi, Congwu; Zhu, Huanhu; Han, Min; Zhuang, Yuan; Wu, Xiaohui; Xu, Tian

    2010-07-09

    Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.

  3. Involvement of the nuclear factor-κB signaling pathway in the regulation of CXC chemokine receptor-4 expression in neuroblastoma cells induced by tumor necrosis factor-α.

    Science.gov (United States)

    Zhi, Yunlai; Lu, Hongting; Duan, Yuhe; Sun, Weisheng; Guan, Ge; Dong, Qian; Yang, Chuanmin

    2015-02-01

    Metastasis is a hallmark of malignant neuroblastoma and is the main reason for therapeutic failure and recurrence of the tumor. The CXC chemokine receptor-4 (CXCR4), a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1α (SDF-1α), is expressed in various types of tumor. This receptor mediates the homing of tumor cells to specific organs that express the ligand, CXCL12, for this receptor and plays an important role in tumor growth, invasion, metastasis and angiogenesis. In the present study, the inflammatory cytokine, tumor necrosis factor‑α (TNF‑α) upregulated CXCR4 expression in neuroblastoma cells and increased migration to the CXCR4 ligand SDF‑1α. In addition, this effect was dependent upon NF-κB transcriptional activity, as blocking the NF-κB pathway with pyrrolidinedithiocarbamic acid ammonium salt suppressed TNF-α‑induced upregulation of CXCR4 expression and reduced the migration towards the CXCR4 ligand, SDF-1α. Treating neuroblastoma cells with TNF-α resulted in the activation of nuclear factor-kappa B (NF-κB) and subsequently, the translocation of NF-κB from the cytoplasm to the nucleus. Using immunohistochemistry, NF‑κB and CXCR4 were significantly correlated with each other (P=0.0052, Fisher's exact test) in a cohort of neuroblastoma samples (n=80). The present study indicates that the inflammatory cytokine, TNF-α, partially functions through the NF‑κB signaling pathway to upregulate CXCR4 expression to foster neuroblastoma cell metastasis. These findings indicate that effective inhibition of neuroblastoma metastasis should be directed against the inflammatory cytokine-induced NF‑κB/CXCR4/SDF‑1α signaling pathway.

  4. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.

    Directory of Open Access Journals (Sweden)

    Debbie Liao

    2009-11-01

    Full Text Available Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer.We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+ T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression.Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.

  5. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.

    Science.gov (United States)

    Liao, Debbie; Luo, Yunping; Markowitz, Dorothy; Xiang, Rong; Reisfeld, Ralph A

    2009-11-23

    Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.

  6. Structure and function of A41, a vaccinia virus chemokine binding protein.

    Directory of Open Access Journals (Sweden)

    Mohammad W Bahar

    2008-01-01

    Full Text Available The vaccinia virus (VACV A41L gene encodes a secreted 30 kDa glycoprotein that is nonessential for virus replication but affects the host response to infection. The A41 protein shares sequence similarity with another VACV protein that binds CC chemokines (called vCKBP, or viral CC chemokine inhibitor, vCCI, and strains of VACV lacking the A41L gene induced stronger CD8+ T-cell responses than control viruses expressing A41. Using surface plasmon resonance, we screened 39 human and murine chemokines and identified CCL21, CCL25, CCL26 and CCL28 as A41 ligands, with Kds of between 8 nM and 118 nM. Nonetheless, A41 was ineffective at inhibiting chemotaxis induced by these chemokines, indicating it did not block the interaction of these chemokines with their receptors. However the interaction of A41 and chemokines was inhibited in a dose-dependent manner by heparin, suggesting that A41 and heparin bind to overlapping sites on these chemokines. To better understand the mechanism of action of A41 its crystal structure was solved to 1.9 A resolution. The protein has a globular beta sandwich structure similar to that of the poxvirus vCCI family of proteins, but there are notable structural differences, particularly in surface loops and electrostatic charge distribution. Structural modelling suggests that the binding paradigm as defined for the vCCI-chemokine interaction is likely to be conserved between A41 and its chemokine partners. Additionally, sequence analysis of chemokines binding to A41 identified a signature for A41 binding. The biological and structural data suggest that A41 functions by forming moderately strong (nM interactions with certain chemokines, sufficient to interfere with chemokine-glycosaminoglycan interactions at the cell surface (microM-nM and thereby to destroy the chemokine concentration gradient, but not strong enough to disrupt the (pM chemokine-chemokine receptor interactions.

  7. T-Cadherin Expression in Melanoma Cells Stimulates Stromal Cell Recruitment and Invasion by Regulating the Expression of Chemokines, Integrins and Adhesion Molecules

    Directory of Open Access Journals (Sweden)

    Kseniya A. Rubina

    2015-07-01

    Full Text Available T-cadherin is a glycosyl-phosphatidylinositol (GPI anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells.

  8. Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages

    Directory of Open Access Journals (Sweden)

    Hirokazu Nakatsumi

    2017-11-01

    Full Text Available C-C chemokine ligand 2 (CCL2 plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF-κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1 as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB and that CCL2 produced by this pathway contributes to tumor progression.

  9. Human astrocytes: secretome profiles of cytokines and chemokines.

    Directory of Open Access Journals (Sweden)

    Sung S Choi

    Full Text Available Astrocytes play a key role in maintenance of neuronal functions in the central nervous system by producing various cytokines, chemokines, and growth factors, which act as a molecular coordinator of neuron-glia communication. At the site of neuroinflammation, astrocyte-derived cytokines and chemokines play both neuroprotective and neurotoxic roles in brain lesions of human neurological diseases. At present, the comprehensive profile of human astrocyte-derived cytokines and chemokines during inflammation remains to be fully characterized. We investigated the cytokine secretome profile of highly purified human astrocytes by using a protein microarray. Non-stimulated human astrocytes in culture expressed eight cytokines, including G-CSF, GM-CSF, GROα (CXCL1, IL-6, IL-8 (CXCL8, MCP-1 (CCL2, MIF and Serpin E1. Following stimulation with IL-1β and TNF-α, activated astrocytes newly produced IL-1β, IL-1ra, TNF-α, IP-10 (CXCL10, MIP-1α (CCL3 and RANTES (CCL5, in addition to the induction of sICAM-1 and complement component 5. Database search indicated that most of cytokines and chemokines produced by non-stimulated and activated astrocytes are direct targets of the transcription factor NF-kB. These results indicated that cultured human astrocytes express a distinct set of NF-kB-target cytokines and chemokines in resting and activated conditions, suggesting that the NF-kB signaling pathway differentially regulates gene expression of cytokines and chemokines in human astrocytes under physiological and inflammatory conditions.

  10. Impact of periodontitis on chemokines in smokers.

    Science.gov (United States)

    Haytural, O; Yaman, D; Ural, E C; Kantarci, A; Demirel, Korkud

    2015-06-01

    The aim of this study was to investigate the chemokine expression profiles in gingival crevicular fluid (GCF) and serum in patients with advanced chronic periodontitis and to assess the impact of smoking on local and systemic levels of chemokines. Thirty patients with chronic periodontitis (CP; 20 smokers and 10 non-smokers) and 20 periodontally healthy subjects (10 smokers and 10 non-smokers) were recruited. Clinical parameters included the plaque index (PI), gingival index (GI), and bleeding on probing (BOP). Macrophage inflammatory protein-1 alpha (MIP-1α), macrophage inflammatory protein-1 beta (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), and regulated on activation normal T cell expressed and secreted chemokine (RANTES) were measured in gingival crevicular fluid (GCF) and serum using a multiplex immunoassay. MIP-1α levels were significantly lower (10.15 ± 1.48; p = 0.039) while MIP-1β levels were significantly higher (42.05 ± 8.21; p = 0.005) in sera from non-smoker patients with CP compared to non-smoker healthy subjects. MCP-1 concentration in sera was significantly higher in smoker periodontitis patients (8.89 ± 1.65) compared to non-smoker patients with periodontitis (8.14 ± 0.97; p = 0.004). MIP-1α and RANTES were significantly higher in GCF of the patients with CP (p = 0.001) while there were no statistically significant correlations between the GCF levels of these analytes and the smoking status. Periodontal inflammation increases the chemokine concentrations in the GCF while smoking suppresses chemokine levels in serum suggesting that different local and systemic mechanisms are involved during the response to periodontitis in smokers. Understanding the local and systemic chemokine responses in smokers will enable the development of biologically-based treatment methods for chronic periodontitis.

  11. CXCR4-mediated osteosarcoma growth and pulmonary metastasis is promoted by mesenchymal stem cells through VEGF.

    Science.gov (United States)

    Zhang, Peng; Dong, Ling; Yan, Kang; Long, Hua; Yang, Tong-Tao; Dong, Ming-Qing; Zhou, Yong; Fan, Qing-Yu; Ma, Bao-An

    2013-10-01

    Chemokines and chemokine receptor 4 (CXCR4) play an important role in metastasis. CXCR4 is also expressed in the human osteosarcoma cell line 9607-F5M2 (F5M2), which has a high tumorigenic ability and potential for spontaneous pulmonary metastasis. Mesenchymal stem cells (MSCs) contribute to the formation of the tumor stroma and promote metastasis. However, mechanisms underlying the promotion of osteosarcoma growth and pulmonary metastasis by MSCs are still elusive. Our study co-injected the human MSCs and F5M2 cells into the caudal vein of nude mice. The total number of tumor nodules per lung was significantly increased in the F5M2+MSC group compared to the other groups (control, F5M2 cells alone and MSCs alone) at week six. Moreover, a high number of Dil-labeled MSCs was present also at the osteosarcoma metastasis sites in the lung. Using Transwell assays, we found that F5M2 cells migrate towards MSCs, while the CXCR4 inhibitor AMD3100 decreased the migration potential of F5M2 cells towards MSCs. Furthermore, upon treatment with F5M2-conditioned medium, MSCs expressed and secreted higher levels of VEGF as determined by immunohistochemistry, western blotting and ELISA, respectively. Importantly, co-cultured with F5M2 cells, MSCs expressed and secreted higher VEGF levels, while AMD3100 dramatically decreased the VEGF secretion by MSCs. However, CXCR4 expression on F5M2 cells was not significantly increased in the co-culture system. Additionally, VEGF increased the proliferation of both MSCs and F5M2 cells. These findings suggest that CXCR4-mediated osteosarcoma growth and pulmonary metastasis are promoted by MSCs through VEGF.

  12. The progress of tumor gene-radiotherapy induced by Egr-1 promoter

    International Nuclear Information System (INIS)

    Guo Rui; Li Biao

    2010-01-01

    The promoter of early growth response gene-1 (Egr-1) is a cis-acting element of Egr-1, and its activity is regulated by inducers such as ionizing radiation, free radical. In designated gene-radiotherapy system, radiation combined with therapeutic gene (such as tumor necrosis factor-α gene, suicide gene) can spatially and temporally regulate therapeutic gene expression in the irradiated field, produced a marked effect, while little systemic toxicities were observed. The combination of radiotherapy and gene therapy is promising in tumor therapy. (authors)

  13. Degradation of Jatropha curcas phorbol esters derived from Jatropha oil cake and their tumor-promoting activity.

    Science.gov (United States)

    Nakao, Motoyuki; Hasegawa, Go; Yasuhara, Tadashi; Ishihara, Yoko

    2015-04-01

    Large amount of oil cake is generated during biodiesel production from Jatropha seeds. Although Jatropha oil cake is rich in plant nutrients, presence of toxic phorbol esters restricts the usage of oil cake as a fertilizer. The objective of this study is to evaluate the components and tumor promoting activity of phorbol esters in Jatropha oil cake-supplemented soil and plants grown in the treated soil. Contents and their biological activity of Jatropha phorbol esters in soil and plants were sequentially analyzed by high-performance liquid chromatography (HPLC) and in vitro cell transformation assay, respectively. Disappearance of Jatropha phorbol-ester-specific peaks were followed with HPLC during incubation of Jatropha oil cake with soil for five weeks. Along with the degradation of Jatropha phorbol ester in soil, tumor-promoting activity in the sample was also attenuated and ultimately disappeared. Jatropha phorbol esters and tumor promoting activity were not detected from mustard spinach grown in the Jatropha oil cake-supplemented soil. In addition, the esterase KM109 degrades DHPB (see definition below; Jatropha phorbol ester) and reduced its tumor-promoting activity. From these data, we conclude: (1) components and tumor promoting activity of Jatropha phorbol esters in the oil cake disappeared completely by incubation with soil for five-week, (2) Jatropha phorbol esters did not transfer into plants grown in the Jatropha oil cake-supplemented soil, and (3) DHPB can be degraded by esterase from soil bacterium. These observations are useful for utilization of Jatropha oil cake as a fertilizer. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. CCL5 promotes vascular endothelial growth factor expression and induces angiogenesis by down-regulating miR-199a in human chondrosarcoma cells.

    Science.gov (United States)

    Liu, Guan-Ting; Huang, Yuan-Li; Tzeng, Huey-En; Tsai, Chun-Hao; Wang, Shih-Wei; Tang, Chih-Hsin

    2015-02-28

    Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis. Angiogenesis is a critical step in tumor growth and metastasis. Chemokine CCL5 (previously called RANTES) has been shown to facilitate tumor progression and metastasis. However, the relationship of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study, CCL5 increased VEGF expression and also promoted chondrosarcoma medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. MicroRNA analysis was performed in CCL5-treated chondrosarcoma cells versus control cells to investigate the mechanism of CCL5-mediated promotion of chondrosarcoma angiogenesis. Among the miRNAs regulated by CCL5, miR-199a was the most downregulated miRNA after CCL5 treatment. In addition, co-transfection with miR-199a mimic reversed the CCL5-mediated VEGF expression and angiogenesis in vitro and in vivo. Moreover, overexpression of CCL5 increased tumor-associated angiogenesis and tumor growth by downregulating miR-199a in the xenograft tumor angiogenesis model. Taken together, these results demonstrated that CCL5 promotes VEGF-dependent angiogenesis in human chondrosarcoma cells by downregulating miR-199a. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Computer-assisted molecular modeling of tumor promoters: rationale for the activity of phorbol esters, teleocidin B, and aplysiatoxin

    International Nuclear Information System (INIS)

    Jeffrey, A.M.; Liskamp, R.M.J.

    1986-01-01

    In the two-stage model of skin carcinogenesis, it is believed that initiators bind to DNA and that tumor promoters such as phorbol 12-tetradecanoate 13-acetate (TPA) bind noncovalently to membrane-associated high-affinity receptors, probably protein kinase C. Two other types of potent tumor-promoting substances, aplysiatoxin and teleocidin, appear to act also by binding to and activating protein kinase C, even though their chemical structures are quite different. Therefore, the authors have undertaken computer modeling of the special relationship of various functional groups in these three chemical classes of tumor promoters in an attempt to explain how these diverse structures bind to the same receptor molecule. They propose a stereochemical model in which the oxygens in TPA at C-3, C-4, C-9, and C-20 (O-3, O-4, O-9, and O-20) correspond to the O-11, N-13, N-1, and O-24 positions in teleocidin and the O-27, O-3, O-11, and O-30 oxygens in aplysiatoxin, respectively. In this model all distances with respect to overlap of the corresponding atoms are <1 A. In addition, all three types of molecules have their hydrophobic moieties oriented in the similar position. This model is further discussed with respect to other compounds showing various degrees of activity as tumor promoters, including mezerein, ingenol, and 4α-TPA. The model explains how chemically diverse structures can have similar biological activity as tumor promoters and provides a basis for designing both agonists and antagonists of tumor promoters

  16. Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4- and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes

    DEFF Research Database (Denmark)

    Janssens, Rik; Mortier, Anneleen; Boff, Daiane

    2017-01-01

    The chemokine CXCL12 or stromal cell-derived factor 1/SDF-1 attracts hematopoietic progenitor cells and mature leukocytes through the G protein-coupled CXC chemokine receptor 4 (CXCR4). In addition, it interacts with atypical chemokine receptor 3 (ACKR3 or CXCR7) and glycosaminoglycans. CXCL12 ac...

  17. Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression.

    Science.gov (United States)

    Yue, Xuetian; Zhang, Cen; Zhao, Yuhan; Liu, Juan; Lin, Alan W; Tan, Victor M; Drake, Justin M; Liu, Lianxin; Boateng, Michael N; Li, Jun; Feng, Zhaohui; Hu, Wenwei

    2017-08-15

    Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53. © 2017 Yue et al.; Published by Cold Spring Harbor Laboratory Press.

  18. Peptides Derived from Type IV Collagen, CXC Chemokines, and Thrombospondin-1 Domain-Containing Proteins Inhibit Neovascularization and Suppress Tumor Growth in MDA-MB-231 Breast Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Jacob E. Koskimaki

    2009-12-01

    Full Text Available Angiogenesis or neovascularization, the process of new blood vessel formation from preexisting microvasculature, involves interactions among several cell types including parenchymal, endothelial cells, and immune cells. The formation of new vessels is tightly regulated by a balance between endogenous proangiogenic and antiangiogenic factors to maintain homeostasis in tissue; tumor progression and metastasis in breast cancer have been shown to be angiogenesis-dependent. We previously introduced a systematic methodology to identify putative endogenous antiangiogenic peptides and validated these predictions in vitro in human umbilical vein endothelial cell proliferation and migration assays. These peptides are derived from several protein families including type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins. On the basis of the results from the in vitro screening, we have evaluated the ability of one peptide selected from each family named pentastatin-1, chemokinostatin-1, and properdistatin, respectively, to suppress angiogenesis in an MDA-MB-231 human breast cancer orthotopic xenograft model in severe combined immunodeficient mice. Peptides were administered intraperitoneally once per day. We have demonstrated significant suppression of tumor growth in vivo and subsequent reductions in microvascular density, indicating the potential of these peptides as therapeutic agents for breast cancer.

  19. Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression.

    Science.gov (United States)

    Coke, Christopher J; Scarlett, Kisha A; Chetram, Mahandranauth A; Jones, Kia J; Sandifer, Brittney J; Davis, Ahriea S; Marcus, Adam I; Hinton, Cimona V

    2016-05-06

    The G-protein-coupled chemokine receptor CXCR4 generates signals that lead to cell migration, cell proliferation, and other survival mechanisms that result in the metastatic spread of primary tumor cells to distal organs. Numerous studies have demonstrated that CXCR4 can form homodimers or can heterodimerize with other G-protein-coupled receptors to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor. Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells. Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2 and ultimately reduced cancer cell functions such as calcium mobilization and cellular chemotaxis. Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells as well as CXCR4-mediated migration of immune cells, it is plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4. Taken together, the data illustrate a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function and perhaps tumor progression. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Capacity of wild-type and chemokine-armed parvovirus H-1PV for inhibiting neo-angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Lavie, Muriel [Tumor Virology Division, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany); Struyf, Sofie [Laboratory of Molecular Immunology, Rega Institute for Medical Research, K.U. Leuven, Leuven (Belgium); Stroh-Dege, Alexandra; Rommelaere, Jean [Tumor Virology Division, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany); Van Damme, Jo [Laboratory of Molecular Immunology, Rega Institute for Medical Research, K.U. Leuven, Leuven (Belgium); Dinsart, Christiane, E-mail: c.dinsart@dkfz.de [Tumor Virology Division, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany)

    2013-12-15

    Anti-angiogenic therapy has been recognized as a powerful potential strategy for impeding the growth of various tumors. However no major therapeutic effects have been observed to date, mainly because of the emergence of several resistance mechanisms. Among novel strategies to target tumor vasculature, some oncolytic viruses open up new prospects. In this context, we addressed the question whether the rodent parvovirus H-1PV can target endothelial cells. We show that cultures of human normal (HUVEC) and immortalized (KS-IMM) endothelial cells sustain an abortive viral cycle upon infection with H-1PV and are sensitive to H-1PV cytotoxicity. H-1PV significantly inhibits infected KS-IMM tumor growth. This effect may be traced back by the virus ability to both kill proliferating endothelial cells and inhibit VEGF production Recombinant H-1PV vectors can also transduce tumor cells with chemokines endowed with anti-angiogenesis properties, and warrant further validation for the treatment of highly vascularized tumors. - Highlights: • The oncolytic parvovirus H-1PV can target endothelial cells. • Abortive viral cycle upon infection of endothelial cells with H-1PV. • Inhibition of VEGF expression and KS-IMM tumor growth by H-1PV.

  1. Capacity of wild-type and chemokine-armed parvovirus H-1PV for inhibiting neo-angiogenesis

    International Nuclear Information System (INIS)

    Lavie, Muriel; Struyf, Sofie; Stroh-Dege, Alexandra; Rommelaere, Jean; Van Damme, Jo; Dinsart, Christiane

    2013-01-01

    Anti-angiogenic therapy has been recognized as a powerful potential strategy for impeding the growth of various tumors. However no major therapeutic effects have been observed to date, mainly because of the emergence of several resistance mechanisms. Among novel strategies to target tumor vasculature, some oncolytic viruses open up new prospects. In this context, we addressed the question whether the rodent parvovirus H-1PV can target endothelial cells. We show that cultures of human normal (HUVEC) and immortalized (KS-IMM) endothelial cells sustain an abortive viral cycle upon infection with H-1PV and are sensitive to H-1PV cytotoxicity. H-1PV significantly inhibits infected KS-IMM tumor growth. This effect may be traced back by the virus ability to both kill proliferating endothelial cells and inhibit VEGF production Recombinant H-1PV vectors can also transduce tumor cells with chemokines endowed with anti-angiogenesis properties, and warrant further validation for the treatment of highly vascularized tumors. - Highlights: • The oncolytic parvovirus H-1PV can target endothelial cells. • Abortive viral cycle upon infection of endothelial cells with H-1PV. • Inhibition of VEGF expression and KS-IMM tumor growth by H-1PV

  2. β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer.

    Science.gov (United States)

    Yu, Xiaomu; Xu, Maoyi; Li, Na; Li, Zongjuan; Li, Hongye; Shao, Shujuan; Zou, Kun; Zou, Lijuan

    2017-08-19

    Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    Energy Technology Data Exchange (ETDEWEB)

    Antonelli, Alessandro, E-mail: a.antonelli@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Ferrari, Silvia Martina, E-mail: sm.ferrari@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Frascerra, Silvia, E-mail: lafrasce@gmail.com [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Corrado, Alda, E-mail: dala_res@hotmail.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Pupilli, Cinzia, E-mail: c.pupilli@dfc.unifi.it [Endocrinology Unit, Azienda Ospedaliera Careggi and University of Florence, Viale Morgagni 85, I-50134, Florence (Italy); Bernini, Giampaolo, E-mail: g.bernini@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Benvenga, Salvatore, E-mail: s.benvenga@me.nettuno.it [Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti 1, I-98122, Messina (Italy); Ferrannini, Ele, E-mail: eferrannini@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Fallahi, Poupak, E-mail: poupak@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)

    2011-07-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

  4. MicroRNA-96 Promotes Tumor Invasion in Colorectal Cancer via RECK.

    Science.gov (United States)

    Iseki, Yasuhito; Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Fukuoka, Tatsunari; Matsutani, Shinji; Hirakawa, Kosei; Ohira, Masaichi

    2018-04-01

    miR-96 is reported to inhibit reversion cysteine-rich Kazal motif (RECK), which is associated with tumor invasion, in solid cancer types (e.g. breast cancer, non-small cell lung cancer, esophageal cancer). The purpose of this study is to clarify whether miR-96 is similarly associated with tumor invasion in colorectal cancer. We performed western blotting to investigate the expression of RECK when miR-96 mimics or inhibitors were transferred into HCT-116 colorectal cancer cells. The RECK mRNA level was assessed by a reverse transcription polymerase chain reaction. An invasion assay was used to evaluate tumor invasion. The expression of RECK was inhibited by the transfection of miR-96 mimics. RECK mRNA level was reduced by miR-96 mimics and increased by miR-96 inhibitor. In the invasion assay, miR-96 mimics were shown to promote tumor invasion. miR-96 may be associated with tumor invasion through inhibition of RECK expression in colorectal cancer. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  5. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    International Nuclear Information System (INIS)

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-01-01

    findings revealed that OGCs in the tumor environment promoted tumor growth and lymphangiogenesis, at least in part, by secreting VEGF-C

  6. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, Rory R; von Hundelshausen, Philipp; Nesmelova, Irina V

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXC...

  7. NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion.

    Science.gov (United States)

    Li, Liwen; Han, Lei; Sun, Fan; Zhou, Jingjiao; Ohaegbulam, Kim C; Tang, Xudong; Zang, Xingxing; Steinbrecher, Kris A; Qu, Zhaoxia; Xiao, Gutian

    2018-01-01

    Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8 + cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

  8. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals

    Directory of Open Access Journals (Sweden)

    A. Alicia Koblansky

    2016-03-01

    Full Text Available NOD-like receptor (NLR proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1−/− mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB, mitogen-activated protein kinase (MAPK, signal transducer and activator of transcription 3 (STAT3, and interleukin 6 (IL-6. The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+ genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+ colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1−/−Apcmin/+ mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.

  9. A study of chemokines, chemokine receptors and interleukin-6 in patients with panic disorder, personality disorders and their co-morbidity.

    Science.gov (United States)

    Ogłodek, Ewa A; Szota, Anna M; Just, Marek J; Szromek, Adam R; Araszkiewicz, Aleksander

    2016-08-01

    Stress may induce inflammatory changes in the immune system and activate pro-inflammatory cytokines and their receptors by activating the hypothalamic-pituitary-adrenal axis. 460 hospitalized patients with panic disorders (PD) and/or personality disorders (P) were studied. The study group comprised subjects with PD, avoidant personality disorder (APD), borderline personality disorder (BPD), obsessive-compulsive personality disorder (OCPD), and concomitant (PD+APD; PD+BPD; PD+OCPD). Each study group consisted of 60 subjects (30 females and 30 males). The control group included 20 females and 20 males without any history of mental disorder. ELISA was used to assess the levels of chemokines: CCL-5/RANTES (regulated on activation, normal T-cell expressed and secreted), CXCL-12/SDF-1 (stromal derived factor), their receptors CXCR-5 (C-C chemokine receptor type-5), CXCR-4 (chemokine C-X-C motif receptor-4), and IL-6. Statistically significant differences in the levels of CCL-5 and CCR-5 were revealed between all study groups. The greatest differences were found between the groups with PD+OCPD and PD+APD. Moreover, concomitance of PD with P significantly increased the level of chemokines and their receptors in all study groups versus the subjects with P alone. The results of the study show differences between the groups. To be specific, inflammatory markers were more elevated in the study groups than the controls. Therefore, chemokines and chemokine receptors may be used as inflammatory markers in patients with PD co-existent with P to indicate disease severity. PD was found to be a factor in maintaining inflammatory activity in the immune system in patients with P. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  10. Maternal Plasma and Amniotic Fluid Chemokines Screening in Fetal Down Syndrome

    Directory of Open Access Journals (Sweden)

    Piotr Laudanski

    2014-01-01

    Full Text Available Objective. Chemokines exert different inflammatory responses which can potentially be related to certain fetal chromosomal abnormalities. The aim of the study was to determine the concentration of selected chemokines in plasma and amniotic fluid of women with fetal Down syndrome. Method. Out of 171 amniocentesis, we had 7 patients with confirmed fetal Down syndrome (15th–18th weeks of gestation. For the purpose of our control, we chose 14 women without confirmed chromosomal aberration. To assess the concentration of chemokines in the blood plasma and amniotic fluid, we used a protein macroarray, which allows the simultaneous determination of 40 chemokines per sample. Results. We showed significant decrease in the concentration of 4 chemokines, HCC-4, IL-28A, IL-31, and MCP-2, and increase in the concentration of CXCL7 (NAP-2 in plasma of women with fetal Down syndrome. Furthermore, we showed decrease in concentration of 3 chemokines, ITAC, MCP-3, MIF, and increase in concentration of 4 chemokines, IP-10, MPIF-1, CXCL7, and 6Ckine, in amniotic fluid of women with fetal Down syndrome. Conclusion. On the basis of our findings, our hypothesis is that the chemokines may play role in the pathogenesis of Down syndrome. Defining their potential as biochemical markers of Down syndrome requires further investigation on larger group of patients.

  11. S100A9 interaction with TLR4 promotes tumor growth.

    Directory of Open Access Journals (Sweden)

    Eva Källberg

    Full Text Available By breeding TRAMP mice with S100A9 knock-out (S100A9(-/- animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/- and TLR4(-/-, but not in RAGE(-/- animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b(+ cells. Lastly, treatment of mice with a small molecule (ABR-215050 that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.

  12. S100A9 Interaction with TLR4 Promotes Tumor Growth

    Science.gov (United States)

    Källberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Björk, Per; Wikström, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas

    2012-01-01

    By breeding TRAMP mice with S100A9 knock-out (S100A9−/−) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9−/− and TLR4−/−, but not in RAGE−/− animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies. PMID:22470535

  13. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients

    DEFF Research Database (Denmark)

    Meyer, C N; Svenson, M; Schade Larsen, C

    2000-01-01

    of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both...... chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta...

  14. T-Cadherin Expression in Melanoma Cells Stimulates Stromal Cell Recruitment and Invasion by Regulating the Expression of Chemokines, Integrins and Adhesion Molecules

    International Nuclear Information System (INIS)

    Rubina, Kseniya A.; Surkova, Ekaterina I.; Semina, Ekaterina V.; Sysoeva, Veronika Y.; Kalinina, Natalia I.; Poliakov, Alexei A.; Treshalina, Helena M.; Tkachuk, Vsevolod A.

    2015-01-01

    T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate that T-cadherin overexpression leads to the increase in the expression of anti-angiogenic molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells

  15. T-Cadherin Expression in Melanoma Cells Stimulates Stromal Cell Recruitment and Invasion by Regulating the Expression of Chemokines, Integrins and Adhesion Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Rubina, Kseniya A., E-mail: rkseniya@mail.ru; Surkova, Ekaterina I.; Semina, Ekaterina V.; Sysoeva, Veronika Y.; Kalinina, Natalia I. [Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av., 31/5, Moscow 119192 (Russian Federation); Poliakov, Alexei A. [Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA (United Kingdom); Treshalina, Helena M. [Federal State Budgetary Scietific Institution «N.N. Blokhin Russian Cancer Research Center» (FSBSI “N.N.Blokhin RCRC”), Kashirskoe Shosse 24, Moscow 115478 (Russian Federation); Tkachuk, Vsevolod A. [Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av., 31/5, Moscow 119192 (Russian Federation)

    2015-07-21

    T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate that T-cadherin overexpression leads to the increase in the expression of anti-angiogenic molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells.

  16. The herpesvirus 8-encoded chemokine vMIP-II, but not the poxvirus-encoded chemokine MC148, inhibits the CCR10 receptor

    DEFF Research Database (Denmark)

    Lüttichau, H R; Lewis, I C; Gerstoft, J

    2001-01-01

    The viral chemokine antagonist vMIP-II encoded by human herpesvirus 8 (HHV8) and MC148 encoded by the poxvirus - Molluscum contagiosum - were tested against the newly identified chemokine receptor CCR10. As the CCR10 ligand ESkine / CCL27 had the highest identity to MC148 and because both...

  17. Comparing the outcomes of two strategies for colorectal tumor detection: policy-promoted screening program versus health promotion service.

    Science.gov (United States)

    Wu, Ping-Hsiu; Lin, Yu-Min; Liao, Chao-Sheng; Chang, Hung-Chuen; Chen, Yu-Hung; Yang, Kuo-Ching; Shih, Chia-Hui

    2013-06-01

    The Taiwanese government has proposed a population-based colorectal tumor detection program for the average-risk population. This study's objectives were to understand the outcomes of these screening policies and to evaluate the effectiveness of the program. We compared two databases compiled in one medical center. The "policy-promoted cancer screening" (PPS) database was built on the basis of the policy of the Taiwan Bureau of National Health Insurance for cancer screening. The "health promotion service" (HPS) database was built to provide health check-ups for self-paid volunteers. Both the PPS and HPS databases employ the immunochemical fecal occult blood test (iFOBT) and colonoscopy for colorectal tumor screening using different strategies. A comparison of outcomes between the PPS and HPS included: (1) quality indicators-compliance rate, cecum reaching rate, and tumor detection rate; and (2) validity indicators-sensitivity, specificity, positive, and negative predictive values for detecting colorectal neoplasms. A total of 10,563 and 1481 individuals were enrolled in PPS and HPS, respectively. Among quality indicators, there was no statistically significant difference in the cecum reaching rate between PPS and HPS. The compliance rates were 56.1% for PPS and 91.8% for HPS (p performance. Copyright © 2013. Published by Elsevier B.V.

  18. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumor types are associated with increased TERT expression and telomerase activation

    Science.gov (United States)

    Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun; Diplas, Bill H.; Yang, Rui; Killela, Patrick J.; Liang, Junbo; Meng, Qun; Ye, Zai-Yuan; Wang, Wei; Jiang, Xiao-Ting; Xu, Li; He, Xiang-Lei; Zhao, Zhong-Sheng; Xu, Wen-Juan; Wang, Hui-Ju; Ma, Ying-Yu; Xia, Ying-Jie; Li, Li; Zhang, Ru-Xuan; Jin, Tao; Zhao, Zhong-Kuo; Xu, Ji; Yu, Sheng; Wu, Fang; Wang, Si-Zhen; Jiao, Yu-Chen; Yan, Hai; Tao, Hou-Quan

    2015-01-01

    Background Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers. Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations. This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumor types and 799 tumor tissues from Chinese cancer patients. Thymic epithelial tumors, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by RT-qPCR, telomerase activity by the TRAP assay, and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in GIST, thymic epithelial tumors, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets. PMID:25843513

  19. Virus-encoded chemokine receptors--putative novel antiviral drug targets

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M

    2005-01-01

    Large DNA viruses, in particular herpes- and poxviruses, have evolved proteins that serve as mimics or decoys for endogenous proteins in the host. The chemokines and their receptors serve key functions in both innate and adaptive immunity through control of leukocyte trafficking, and have...... receptors belong to the superfamily of G-protein coupled 7TM receptors that per se are excellent drug targets. At present, non-peptide antagonists have been developed against many chemokine receptors. The potentials of the virus-encoded chemokine receptors as drug targets--ie. as novel antiviral strategies...

  20. Targeting herpesvirus reliance of the chemokine system

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Kledal, Thomas N

    2006-01-01

    the infection. However, since both virus and host exist, the organisms struggle must reach an ecological equilibrium. Among the best-studied interactions between viruses and the host immune system are those between herpesviruses and their hosts. Herpesviruses are known to devote a significant part...... of their large genomes on immuno-modulatory genes, some encoding chemokines or chemokine receptors. These genes, which may be dispensable for viral replication in vitro, are highly important for viral growth in vivo, for viral dissemination and disease progression. Indeed, all beta and gamma-herpesviruses have...... chemokine receptors seems to be their constitutive activity. The biological function of the constitutive activity is still unclear, but it has become clear that the receptors are involved in important parts of the viral lifecycle in vivo, and that the receptor signaling is involved in gamma-herpesvirus...

  1. CCR5 signalling, but not DARC or D6 regulatory, chemokine receptors are targeted by herpesvirus U83A chemokine which delays receptor internalisation via diversion to a caveolin-linked pathway.

    Science.gov (United States)

    Catusse, Julie; Clark, David J; Gompels, Ursula A

    2009-07-30

    Herpesviruses have evolved chemokines and chemokine receptors, which modulate the recruitment of human leukocytes during the inflammatory response to infection. Early post-infection, human herpesvirus 6A (HHV-6A) infected cells express the chemokine receptor U51A and chemokine U83A which have complementary effects in subverting the CC-chemokine family thereby controlling anti-viral leukocyte recruitment. Here we show that, to potentiate this activity, the viral chemokine can also avoid clearance by scavenger chemokine receptors, DARC and D6, which normally regulate an inflammatory response. Conversely, U83A delays internalisation of its signalling target receptor CCR5 with diversion to caveolin rich membrane domains. This mechanism can redirect displaced human chemokines to DARC and D6 for clearance of the anti-viral inflammatory response, leaving the viral chemokine unchecked. Cell models for competitive binding assays were established using radiolabeled human chemokines and cold U83A on CCR5, DARC or D6 expressing cells. Flow cytometry was used to assess specific chemotaxis of CCR5 bearing cells to U83A, and internalisation of CCR5 specific chemokine CCL4 after stimulation with U83A. Internalisation analyses were supported by confocal microscopy of internalisation and co-localisation of CCR5 with caveosome marker caveolin-1, after virus or human chemokine stimulation. U83A displaced efficiently human chemokines from CCR5, with a high affinity of 0.01nM, but not from DARC or D6. Signalling via CCR5 resulted in specific chemoattraction of primary human leukocytes bearing CCR5. However, U83A effective binding and signalling to CCR5 resulted in delayed internalisation and recycling up to 2 hours in the absence of continual re-stimulation. This resulted in diversion to a delayed caveolin-linked pathway rather than the rapid clathrin mediated endocytosis previously shown with human chemokines CCL3 or CCL4. U83A diverts human chemokines from signalling, but not

  2. CCR5 signalling, but not DARC or D6 regulatory, chemokine receptors are targeted by herpesvirus U83A chemokine which delays receptor internalisation via diversion to a caveolin-linked pathway

    Directory of Open Access Journals (Sweden)

    Gompels Ursula A

    2009-07-01

    Full Text Available Abstract Background Herpesviruses have evolved chemokines and chemokine receptors, which modulate the recruitment of human leukocytes during the inflammatory response to infection. Early post-infection, human herpesvirus 6A (HHV-6A infected cells express the chemokine receptor U51A and chemokine U83A which have complementary effects in subverting the CC-chemokine family thereby controlling anti-viral leukocyte recruitment. Here we show that, to potentiate this activity, the viral chemokine can also avoid clearance by scavenger chemokine receptors, DARC and D6, which normally regulate an inflammatory response. Conversely, U83A delays internalisation of its signalling target receptor CCR5 with diversion to caveolin rich membrane domains. This mechanism can redirect displaced human chemokines to DARC and D6 for clearance of the anti-viral inflammatory response, leaving the viral chemokine unchecked. Methods Cell models for competitive binding assays were established using radiolabeled human chemokines and cold U83A on CCR5, DARC or D6 expressing cells. Flow cytometry was used to assess specific chemotaxis of CCR5 bearing cells to U83A, and internalisation of CCR5 specific chemokine CCL4 after stimulation with U83A. Internalisation analyses were supported by confocal microscopy of internalisation and co-localisation of CCR5 with caveosome marker caveolin-1, after virus or human chemokine stimulation. Results U83A displaced efficiently human chemokines from CCR5, with a high affinity of 0.01nM, but not from DARC or D6. Signalling via CCR5 resulted in specific chemoattraction of primary human leukocytes bearing CCR5. However, U83A effective binding and signalling to CCR5 resulted in delayed internalisation and recycling up to 2 hours in the absence of continual re-stimulation. This resulted in diversion to a delayed caveolin-linked pathway rather than the rapid clathrin mediated endocytosis previously shown with human chemokines CCL3 or CCL4

  3. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    approximately halfway into the solution. All animals were tested at 60, 15 and 0 min before drug injection. For each animal , the first reading was discarded...approval (December 31, 2015), hiring new personnel, conducting baseline testing for procedures not involving animals , testing equipment, developing...treatment; Analgesia; Nociception; Antinociception; Inflammation; Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain

  4. Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion.

    Science.gov (United States)

    Coffelt, Seth B; Chen, Yung-Yi; Muthana, Munitta; Welford, Abigail F; Tal, Andrea O; Scholz, Alexander; Plate, Karl H; Reiss, Yvonne; Murdoch, Craig; De Palma, Michele; Lewis, Claire E

    2011-04-01

    Angiopoietin 2 (ANGPT2) is a proangiogenic cytokine whose expression is often upregulated by endothelial cells in tumors. Expression of its receptor, TIE2, defines a highly proangiogenic subpopulation of myeloid cells in circulation and tumors called TIE2-expressing monocytes/macrophages (TEMs). Genetic depletion of TEMs markedly reduces tumor angiogenesis in various tumor models, emphasizing their essential role in driving tumor progression. Previously, we demonstrated that ANGPT2 augments the expression of various proangiogenic genes, the potent immunosuppressive cytokine, IL-10, and a chemokine for regulatory T cells (Tregs), CCL17 by TEMs in vitro. We now show that TEMs also express higher levels of IL-10 than TIE2(-) macrophages in tumors and that ANGPT2-stimulated release of IL-10 by TEMs suppresses T cell proliferation, increases the ratio of CD4(+) T cells to CD8(+) T cells, and promotes the expansion of CD4(+)CD25(high)FOXP3(+) Tregs. Furthermore, syngeneic murine tumors expressing high levels of ANGPT2 contained not only high numbers of TEMs but also increased numbers of Tregs, whereas genetic depletion of tumor TEMs resulted in a marked reduction in the frequency of Tregs in tumors. Taken together, our data suggest that ANGPT2-stimulated TEMs represent a novel, potent immunosuppressive force in tumors.

  5. 3D profile-based approach to proteome-wide discovery of novel human chemokines.

    Directory of Open Access Journals (Sweden)

    Aurelie Tomczak

    Full Text Available Chemokines are small secreted proteins with important roles in immune responses. They consist of a conserved three-dimensional (3D structure, so-called IL8-like chemokine fold, which is supported by disulfide bridges characteristic of this protein family. Sequence- and profile-based computational methods have been proficient in discovering novel chemokines by making use of their sequence-conserved cysteine patterns. However, it has been recently shown that some chemokines escaped annotation by these methods due to low sequence similarity to known chemokines and to different arrangement of cysteines in sequence and in 3D. Innovative methods overcoming the limitations of current techniques may allow the discovery of new remote homologs in the still functionally uncharacterized fraction of the human genome. We report a novel computational approach for proteome-wide identification of remote homologs of the chemokine family that uses fold recognition techniques in combination with a scaffold-based automatic mapping of disulfide bonds to define a 3D profile of the chemokine protein family. By applying our methodology to all currently uncharacterized human protein sequences, we have discovered two novel proteins that, without having significant sequence similarity to known chemokines or characteristic cysteine patterns, show strong structural resemblance to known anti-HIV chemokines. Detailed computational analysis and experimental structural investigations based on mass spectrometry and circular dichroism support our structural predictions and highlight several other chemokine-like features. The results obtained support their functional annotation as putative novel chemokines and encourage further experimental characterization. The identification of remote homologs of human chemokines may provide new insights into the molecular mechanisms causing pathologies such as cancer or AIDS, and may contribute to the development of novel treatments. Besides

  6. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    International Nuclear Information System (INIS)

    De Veirman, Kim; Rao, Luigia; De Bruyne, Elke; Menu, Eline; Van Valckenborgh, Els; Van Riet, Ivan; Frassanito, Maria Antonia; Di Marzo, Lucia; Vacca, Angelo; Vanderkerken, Karin

    2014-01-01

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease

  7. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    Energy Technology Data Exchange (ETDEWEB)

    De Veirman, Kim, E-mail: kdeveirm@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Rao, Luigia [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari Medical School, Bari I-70124 (Italy); De Bruyne, Elke; Menu, Eline; Van Valckenborgh, Els [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Van Riet, Ivan [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Stem Cell Laboratory, Division of Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels 1090 (Belgium); Frassanito, Maria Antonia [Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari Medical School, Bari I-70124 (Italy); Di Marzo, Lucia; Vacca, Angelo [Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari Medical School, Bari I-70124 (Italy); Vanderkerken, Karin, E-mail: kdeveirm@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium)

    2014-06-27

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease.

  8. S100 chemokines mediate bookmarking of premetastatic niches

    Science.gov (United States)

    Rafii, Shahin; Lyden, David

    2010-01-01

    Primary tumours release soluble factors, including VEGF-A, TGFβ and TNFα, which induce expression of the chemokines S100A8 and S100A9 in the myeloid and endothelial cells within the lung before tumour metastasis. These chemokine-activated premetastatic niches support adhesion and invasion of disseminating malignant cells, thereby establishing a fertile habitat for metastatic tumours. PMID:17139281

  9. Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma

    International Nuclear Information System (INIS)

    Gockel, Ines; Galle, Peter R; Junginger, Theodor; Moehler, Markus; Schimanski, Carl C; Heinrich, Christian; Wehler, T; Frerichs, K; Drescher, Daniel; Langsdorff, Christian von; Domeyer, Mario; Biesterfeld, Stefan

    2006-01-01

    Prognosis of esophageal cancer is poor despite curative surgery. The chemokine receptor CXCR4 has been proposed to distinctly contribute to tumor growth, dissemination and local immune escape in a limited number of malignancies. The aim of our study was to evaluate the role of CXCR4 in tumor spread of esophageal cancer with a differentiated view of the two predominant histologic types – squamous cell and adenocarcinoma. Esophageal cancer tissue samples were obtained from 102 consecutive patients undergoing esophageal resection for cancer with curative intent. The LSAB+ System was used to detect the protein CXCR4. Tumor samples were classified into two groups based on the homogeneous staining intensity. A cut-off between CXCR4w (= weak expression) and CXCR4s (= strong expression) was set at 1.5 (grouped 0 – 1.5 versus 2.0 – 3). Long-term survival rates were calculated using life tables and the Kaplan-Meier method. Using the Cox's proportional hazards analysis, a model of survival prediction was established. The overall expression rate for CXCR4 in esophageal squamous cell carcinoma was 94.1%. Subdividing these samples, CXCR4w was found in 54.9% and CXCR4s in 45.1%. In adenocarcinoma, an overall expression rate of 89.1% was detected with a weak intensitiy in 71.7% compared to strong staining in 29.3% (p = 0.066 squamous cell versus adenocarcinoma). The Cox's proportional hazards analysis identified the pM-category with a hazard ratio (HR) of 1.860 (95% CI: 1.014–3.414) (p = 0.045), the histologic tumor type (HR: 0.334; 95% CI: 0.180–0.618) (p = 0.0001) and the operative approach (transthoracic > transhiatal esophageal resection) (HR: 0.546; 95% CI: 0.324–0.920) (p = 0.023) as independent factors with a possible influence on the long-term prognosis in patients with esophageal carcinoma, whereas CXCR4 expression was statistically not significant (>0.05). Expression of the chemokine receptor CXCR4 in esophageal cancer is of major relevance in both

  10. Evaluation of promoter methylation status of MLH1 gene in Iranian patients with colorectal tumors and adenoma polyps.

    Science.gov (United States)

    Zarandi, Ashkan; Irani, Shiva; Savabkar, Sanaz; Chaleshi, Vahid; Ghavideldarestani, Maryam; Mirfakhraie, Reza; Khodadoostan, Mahsa; Nazemalhosseini-Mojarad, Ehsan; Asadzadeh Aghdaei, Hamid

    2017-01-01

    The aim of this study was to evaluate the methylation status of the promoter region of MLH1 gene in colorectal cancer (CRC) and its precursor lesions as well as elucidate its association with various clinicopathological characteristics among Iranian population. Epigenetic silencing of mismatch repair genes, such as MLH1 , by methylation of CpG islands of their promoter region has been proved to be an important mechanism in colorectal carcinogenesis. Fifty colorectal cancer and polyp tissue samples including 13 Primary colorectal tumor and 37 Adenoma polyp samples were enrolled in this study. Methylation-specific polymerase chain reaction (MSP) was performed to find the frequency of MLH1 Promoter Methylation. Promoter methylation of MLH1 gene was detected in 5 out of 13 tumor tissues and 4 out of 37 adenoma polyp. The frequency of MLH1 methylation in tumor samples was significantly higher compared to that in polyp tissues (P= 0.026). No significant association was observed between MLH1 promoter methylation and clinicopathological characteristics of the patients. The frequency of  MLH1  promoter methylation in CRC and colon polyp was 18%. Our findings indicated that methylation of MLH1 promoter region alone cannot be considered as a biomarker for early detection of CRC.

  11. The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice

    International Nuclear Information System (INIS)

    Deng, San-Ming; Yan, Xian-Chun; Liang, Liang; Wang, Li; Liu, Yuan; Duan, Juan-Li; Yang, Zi-Yan; Chang, Tian-Fang; Ruan, Bai; Zheng, Qi-Jun; Han, Hua

    2017-01-01

    Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-α. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues. Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro, and enhanced tumor growth when inoculated in vivo in mice. The Dll3-mediated proliferation could be due to increased Akt phosphorylation in LLC cells, because an Akt inhibitor counteracted Dll3-induced proliferation. Moreover, Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling. - Highlights: • The level of Dll3 in Lewis lung carcinoma changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with TNF-α. • The Dll3 was rarely detectable in the para-carcinoma tissues, but positive in 82.1% of NSCLC tissues from 84 patients. • Overexpression of Dll3 in LLC cells promoted tumor growth but did not remarkably alter TME after inoculated in mice. • Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro in an Akt-dependent way. • Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling.

  12. Improvement of Antitumor Therapies Based on Vaccines and Immune-Checkpoint Inhibitors by Counteracting Tumor-Immunostimulation

    Directory of Open Access Journals (Sweden)

    Paula Chiarella

    2018-01-01

    Full Text Available Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors, counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.

  13. Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

    Directory of Open Access Journals (Sweden)

    Susan J. Burke

    2015-05-01

    Full Text Available Enhanced expression of chemotactic cytokines (aka chemokines within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required. In this review, we highlight what is known about the signals and mechanisms that govern the transcription of genes encoding specific chemokine proteins in pancreatic islet β-cells, which include contributions from the NF-κB and STAT1 pathways. We further discuss increased chemokine expression in pancreatic islets during autoimmune-mediated and obesity-related development of diabetes.

  14. Neonatal chemokine levels and risk of autism spectrum disorders

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Grove, Jakob

    2013-01-01

    A potential role of chemokines in the pathophysiology of Autism Spectrum Disorders (ASDs) has been previously suggested. In a recent study we examined levels of three inflammatory chemokines (MCP-1, MIP-1a and RANTES) in samples of amniotic fluid of children diagnosed later in life with ASD...

  15. Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease.

    Science.gov (United States)

    Richmond, Jillian M; Bangari, Dinesh S; Essien, Kingsley I; Currimbhoy, Sharif D; Groom, Joanna R; Pandya, Amit G; Youd, Michele E; Luster, Andrew D; Harris, John E

    2017-02-01

    Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-γ and IFN-γ-induced chemokines to promote T-cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and we found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin showed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients showed that keratinocytes were the major chemokine producers throughout the course of disease, and functional studies using a conditional signal transducer and activator of transcription (STAT)-1 knockout mouse showed that IFN-γ signaling in keratinocytes was critical for disease progression and proper autoreactive T-cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and γδ T cells were not required. These results have important clinical implications, because topical therapies that target IFN-γ signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Lysophosphatidic acid acyltransferase β (LPAATβ promotes the tumor growth of human osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Farbod Rastegar

    2010-12-01

    Full Text Available Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2 in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective

  17. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, T B; Wittenhagen, P

    2007-01-01

    To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta).......To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta)....

  18. Mutations in BALB mitochondrial DNA induce CCL20 up-regulation promoting tumorigenic phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Sligh, James [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Janda, Jaroslav [University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Jandova, Jana, E-mail: jjandova@email.arizona.edu [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States)

    2014-11-15

    Highlights: • Alterations in mitochondrial DNA are commonly found in various human cancers. • Mutations in BALB mitochondrial DNA induce up-regulation of chemokine CCL20. • Increased growth and motility of mtBALB cells is associated with CCL20 levels. • mtDNA changes in BALB induce in vivo tumor growth through CCL20 up-regulation. • Mutations in mitochondrial DNA play important roles in keratinocyte neoplasia. - Abstract: mtDNA mutations are common in human cancers and are thought to contribute to the process of neoplasia. We examined the role of mtDNA mutations in skin cancer by generating fibroblast cybrids harboring a mutation in the gene encoding the mitochondrial tRNA for arginine. This somatic mutation (9821insA) was previously reported in UV-induced hyperkeratotic skin tumors in hairless mice and confers specific tumorigenic phenotypes to mutant cybrids. Microarray analysis revealed and RT-PCR along with Western blot analysis confirmed the up-regulation of CCL20 and its receptor CCR6 in mtBALB haplotype containing the mt-Tr 9821insA allele compared to wild type mtB6 haplotype. Based on reported role of CCL20 in cancer progression we examined whether the hyper-proliferation and enhanced motility of mtBALB haplotype would be associated with CCL20 levels. Treatment of both genotypes with recombinant CCL20 (rmCCL20) resulted in enhanced growth and motility of mtB6 cybrids. Furthermore, the acquired somatic alteration increased the in vivo tumor growth of mtBALB cybrids through the up-regulation of CCL20 since neutralizing antibody significantly decreased in vivo tumor growth of these cells; and tumors from anti-CCL20 treated mice injected with mtBALB cybrids showed significantly decreased CCL20 levels. When rmCCL20 or mtBALB cybrids were used as chemotactic stimuli, mtB6 cybrids showed increased motility while anti-CCL20 antibody decreased the migration and in vivo tumor growth of mtBALB cybrids. Moreover, the inhibitors of MAPK signaling and NF

  19. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, RR; Hundelshausen, P; Nesmelova, IV

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXC...... monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects......) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities...... compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating...

  20. HIF-2α-induced chemokines stimulate motility of fibroblast-like synoviocytes and chondrocytes into the cartilage-pannus interface in experimental rheumatoid arthritis mouse models.

    Science.gov (United States)

    Huh, Yun Hyun; Lee, Gyuseok; Lee, Keun-Bae; Koh, Jeong-Tae; Chun, Jang-Soo; Ryu, Je-Hwang

    2015-10-29

    Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. Here, we focused on the role of hypoxia-inducible factor (HIF)-2α-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion. Collagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-α transgenic mice were used as experimental RA models. Expression patterns of HIF-2α and chemokines were determined via immunostaining, Western blotting and RT-PCR. FLS motility was evaluated using transwell migration and invasion assays. The specific role of HIF-2α was determined via local deletion of HIF-2α in joint tissues or using conditional knockout (KO) mice. Cartilage destruction, synovitis and pannus formation were assessed via histological analysis. HIF-2α and various chemokines were markedly upregulated in degenerating cartilage and pannus of RA joints. HIF-2α induced chemokine expression by chondrocytes in both primary culture and cartilage tissue. HIF-2α -induced chemokines by chondrocytes regulated the migration and invasion of FLS. Local deletion of HIF-2α in joint tissues inhibited pannus formation adjacent to cartilage tissue and cartilage destruction caused by K/BxN serum transfer. Furthermore, conditional knockout of HIF-2α in cartilage blocked pannus formation in adjacent cartilage but not bone tissue, along with inhibition of cartilage erosion caused by K/BxN serum transfer. Our findings suggest that chemokines induced by IL-1β or HIF-2α in chondrocytes regulate pannus expansion by stimulating FLS migration and invasion, leading to cartilage erosion during RA pathogenesis.

  1. Selected CC and CXC chemokines in children with atopic asthma

    Directory of Open Access Journals (Sweden)

    Edyta Machura

    2016-05-01

    Full Text Available Introduction : There are only limited data on CC and CXC chemokines regulation in children with asthma. Aim: We compared the serum profile of selected CC and CXC chemokines in patients with atopic asthma and healthy children. Material and methods : Serum concentration of CC chemokines RANTES, MCP-1, and CXC chemokines IP-10, MIG, IL-8, RANTES was measured using cytometric bead array in 44 children with atopic asthma and 17 healthy subjects. Results: The concentration of RANTES was significantly higher and the MIG level was lower in all children with asthma as compared to their control counterparts. We observed increased RANTES and decreased MIG levels also in patients with stable asthma when compared with children in the control group. The IP-10 concentration was similar between the whole asthma group and healthy controls, while significantly increased levels of this chemokine in acute asthma have been observed when compared to stable asthma. For MCP-1 and IL-8, the serum concentration was similar in all compared groups. The MIG concentration correlated positively with IP-10, IL-8, and CRP levels and negatively with the eosinophil count. A negative correlation between the IP-10 and eosinophil count and a negative correlation between FEV1 and IP-10 were found. Conclusions : An increased serum RANTES level in children with asthma may result in enhancement of Th2 lymphocyte recruitment into the airway. A decreased expression of Th1 chemokine MIG in children with stable asthma may contribute to a diminished antagonizing effect on Th2 cytokine production and hence intensify Th2 predominance. An increased IP-10 level in children during an asthma attack suggest that this chemokine is a serological marker of disease exacerbation.

  2. Macrophages From Irradiated Tumors Express Higher Levels of iNOS, Arginase-I and COX-2, and Promote Tumor Growth

    International Nuclear Information System (INIS)

    Tsai, C.-S.; Chen, F.-H.; Wang, C.-C.; Huang, H.-L.; Jung, Shih-Ming; Wu, C.-J.; Lee, C.-C.; McBride, William H.; Chiang, C.-S.; Hong, J.-H.

    2007-01-01

    Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo

  3. Differential chemokine responses in the murine brain following lyssavirus infection.

    Science.gov (United States)

    Hicks, D J; Núñez, A; Banyard, A C; Williams, A; Ortiz-Pelaez, A; Fooks, A R; Johnson, N

    2013-11-01

    The hallmark of lyssavirus infection is lethal encephalomyelitis. Previous studies have reported distinct lyssavirus isolate-related differences in severity of cellular recruitment into the encephalon in a murine model of infection following peripheral inoculation with rabies virus (RABV) and European bat lyssavirus (EBLV)-1 and -2. In order to understand the role of chemokines in this process, comparative studies of the chemokine pattern, distribution and production in response to infection with these lyssaviruses were undertaken. Expression of CCL2, CCL5 and CXCL10 was observed throughout the murine brain with a distinct caudal bias in distribution, similar to both inflammatory changes and virus antigen distribution. CCL2 immunolabelling was localized to neuronal and astroglial populations. CCL5 immunolabelling was only detected in the astroglia, while CXCL10 labelling, although present in the astroglia, was more prominent in neurons. Isolate-dependent differences in the amount of chemokine immunolabelling in specific brain regions and chemokine production by neurons in vitro were observed, with a greater expression of CCL5 in vivo and CXCL10 production in vitro after EBLV infection. Additionally, strong positive associations between chemokine immunolabelling and perivascular cuffing and, to a lesser extent, virus antigen score were also observed. These differences in chemokine expression may explain the variation in severity of encephalitic changes observed in animals infected with different lyssavirus isolates. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  4. Short-term biomarkers of tumor promotion in mouse skin treated with petroleum middle distillates.

    Science.gov (United States)

    Walborg, E F; DiGiovanni, J; Conti, C J; Slaga, T J; Freeman, J J; Steup, D R; Skisak, C M

    1998-10-01

    Topical application of certain petroleum middle distillates (PMD) to mice produces skin tumors after long latency, and initiation/promotion protocols indicate that this effect is associated with their tumor promoting activity. Since induction of sustained, potentiated epidermal hyperplasia is predictive of promoting activity, five compositionally distinct PMD [hydrodesulfurized kerosene (API 81-07); hydrodesulfurized PMD (API 81-10); odorless light petroleum hydrocarbons; severely hydrotreated light vacuum distillate (LVD); and lightly refined paraffinic oil (LRPO)] were assessed for their effects on epidermal hyperplasia. PMD were administered (2 x/week for 2 weeks) to skin of CD-1 mice. Four quantitative biomarkers of epidermal hyperplasia were evaluated: epidermal thickness, number of nucleated epidermal cells per unit length of basement membrane, labeling (BrdUrd) index of epidermal cells, and induction of epidermal ornithine decarboxylase (ODC) activity. As positive controls, 12-O-tetradecanoylphorbol-13-acetate (TPA) and n-dodecane were utilized. PMD-induced skin irritation was evaluated visually and/or histopathologically. All five PMD produced dose-dependent, skin irritation and epidermal hyperplasia. On a weight basis the magnitude of the maximal PMD-induced effects was similar to that produced by n-dodecane, but > 1000-fold less than that produced by TPA. Epidermal hyperplasia and subacute skin irritancy produced by the five PMD were similar. Of the four short-term markers of tumor promotion assessed, labeling index and epidermal ODC activity were predictive of the relative promoting activities of those PMD for which tumorigenicity bioassay data are available, i.e., API 81-07 > API 81-10 > LRPO. An apparent discrepancy to the predictability of epidermal ODC activity occurred with LRPO:toluene [1:1 (v/v)]. This mixture is nontumorigenic, yet significantly induced epidermal ODC activity. This mixture, however, produced severe epidermal toxicity that

  5. CXCL12 MODULATION OF CXCR4 AND CXCR7 ACTIVITY IN HUMAN GLIOBLASTOMA STEM-LIKE CELLS AND REGULATION OF THE TUMOR MICROENVIRONMENT

    Directory of Open Access Journals (Sweden)

    Roberto eWurth

    2014-05-01

    Full Text Available Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells.Glioblastoma (GBM is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs is believed to be the main responsible for tumor cell dissemination to the brain.GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g. CXCL12 causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4.This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include

  6. Promotion of seminomatous tumors by targeted overexpression of glial cell line-derived neurotrophic factor in mouse testis

    NARCIS (Netherlands)

    Meng, X.; de rooij, D. G.; Westerdahl, K.; Saarma, M.; Sariola, H.

    2001-01-01

    We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) in undifferentiated spermatogonia promotes malignant testicular tumors, which express germ-cell markers. The tumors are invasive and contain aneuploid cells, but no distant metastases have

  7. Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice

    Directory of Open Access Journals (Sweden)

    Mathieu Paul Rodero

    2013-06-01

    Full Text Available Expression of the CC chemokine receptor 1 (CCR1 by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.

  8. Cytokine and chemokine inter-regulation in the inflamed or injured CNS

    DEFF Research Database (Denmark)

    Owens, Trevor; Babcock, Alicia A; Millward, Jason M

    2005-01-01

    the expression of chemokines in the CNS, in the absence of any other inflammatory event, but the profiles differ from those induced by axotomy. Chemokines that bind the CCR2 receptor are implicated in traffic of macrophages and T cells to the denervated hippocampus. Innate responses in the immune system...... are directed by Toll-like receptors (TLR). Our recent studies focus on specific TLR signals as upstream on-switches for glial cytokine and chemokine responses. The biological activity of chemokines is regulated by matrix metalloproteinase enzymes (MMPs) and specific members of this family are expressed...... in response to axonal lesioning. These findings strengthen the case for the sharing of signals between the immune and nervous system....

  9. Enhanced incorporation of radioactive inorganic phosphate into phospholipids of HeLa cells by tumor promoters

    International Nuclear Information System (INIS)

    Nishino, H.; Fujiki, H.; Terada, M.; Sato, S.

    1983-01-01

    Teleocidin, a new tumor promoter, increased incorporation of radioactive inorganic phosphate ( 32 P/sub i/) into phospholipids in HeLa cells. This effect was detected within 1 h on incubation of the cells in medium containing teleocidin. The half-maximum effective dose of teleocidin was approximately 10 ng/ml. The main effect of teleocidin was on the incorporation of 32 P/sub i/ into the phosphatidylcholine fraction, with a lesser effect on 32 P/sub i/ incorporation into other phospholipid fractions. Increased incorporation of 32 P/sub i/ into phospholipids was also observed on incubation of the cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), dihydroteleocidin B, or lyngbyatoxin A, which are all complete tumor promoters, and also with mezerein, which is an incomplete and second stage promoter. On the other hand, at concentrations of up to 1 microgram/ml, 4-O-methyl TPA and C/sub a/ 2 + ionophore A23187, which are incomplete and first stage promoters, and phorbol, which has no promoting activity in skin carcinogenesis, did not cause any increased incorporation of 32 P/sub i/ into phospholipid fractions of HeLa cells

  10. Homogeneous MGMT immunoreactivity correlates with an unmethylated MGMT promoter status in brain metastases of various solid tumors.

    Directory of Open Access Journals (Sweden)

    Barbara Ingold

    Full Text Available The O(6-methylguanine-methyltransferase (MGMT promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical reports on treating brain metastases with temozolomide describe varying effects. This may be due to the fact that MGMT promoter methylation of brain metastases has not yet been explored in depth. Therefore, we assessed MGMT promoter methylation of various brain metastases including those derived from lung (n = 91, breast (n = 72 kidney (n = 49 and from malignant melanomas (n = 113 by methylation-specific polymerase chain reaction (MS-PCR and MGMT immunoreactivity. Fifty-nine of 199 brain metastases (29.6% revealed a methylated MGMT promoter. The methylation rate was the highest in brain metastases derived from lung carcinomas (46.5% followed by those from breast carcinoma (28.8%, malignant melanoma (24.7% and from renal carcinoma (20%. A significant correlation of homogeneous MGMT-immunoreactivity (>95% MGMT positive tumor cells and an unmethylated MGMT promoter was found. Promoter methylation was detected in 26 of 61 (43% tumors lacking MGMT immunoreactivity, in 17 of 63 (27% metastases with heterogeneous MGMT expression, but only in 5 of 54 brain metastases (9% showing a homogeneous MGMT immunoreactivity. Our results demonstrate that a significant number of brain metastases reveal a methylated MGMT-promoter. Based on an obvious correlation between homogeneous MGMT immunoreactivity and unmethylated MGMT promoter, we hypothesize that immunohistochemistry for MGMT may be a helpful diagnostic tool to identify those tumors that probably will not benefit from the use of alkylating agents. The discrepancy between promoter methylation and a lack of MGMT immunoreactivity argues for assessing MGMT promoter methylation both by immunohistochemical as well as by molecular approaches for diagnostic purposes.

  11. The CC chemokine receptor 5 regulates olfactory and social recognition in mice.

    Science.gov (United States)

    Kalkonde, Y V; Shelton, R; Villarreal, M; Sigala, J; Mishra, P K; Ahuja, S S; Barea-Rodriguez, E; Moretti, P; Ahuja, S K

    2011-12-01

    Chemokines are chemotactic cytokines that regulate cell migration and are thought to play an important role in a broad range of inflammatory diseases. The availability of chemokine receptor blockers makes them an important therapeutic target. In vitro, chemokines are shown to modulate neurotransmission. However, it is not very clear if chemokines play a role in behavior and cognition. Here we evaluated the role of CC chemokine receptor 5 (CCR5) in various behavioral tasks in mice using Wt (Ccr5⁺/⁺) and Ccr5-null (Ccr5⁻/⁻)mice. Ccr5⁻/⁻ mice showed enhanced social recognition. Administration of CC chemokine ligand 3 (CCL3), one of the CCR5-ligands, impaired social recognition. Since the social recognition task is dependent on the sense of olfaction, we tested olfactory recognition for social and non-social scents in these mice. Ccr5⁻/⁻ mice had enhanced olfactory recognition for both these scents indicating that enhanced performance in social recognition task could be due to enhanced olfactory recognition in these mice. Spatial memory and aversive memory were comparable in Wt and Ccr5⁻/⁻ mice. Collectively, these results suggest that chemokines/chemokine receptors might play an important role in olfactory recognition tasks in mice and to our knowledge represents the first direct demonstration of an in vivo role of CCR5 in modulating social behavior in mice. These studies are important as CCR5 blockers are undergoing clinical trials and can potentially modulate behavior. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Chemokines in the corpus luteum: Implications of leukocyte chemotaxis

    Directory of Open Access Journals (Sweden)

    Liptak Amy R

    2003-11-01

    Full Text Available Abstract Chemokines are small molecular weight peptides responsible for adhesion, activation, and recruitment of leukocytes into tissues. Leukocytes are thought to influence follicular atresia, ovulation, and luteal function. Many studies in recent years have focused attention on the characterization of leukocyte populations within the ovary, the importance of leukocyte-ovarian cell interactions, and more recently, the mechanisms of ovarian leukocyte recruitment. Information about the role of chemokines and leukocyte trafficking (chemotaxis during ovarian function is important to understanding paracrine-autocrine relationships shared between reproductive and immune systems. Recent advances regarding chemokine expression and leukocyte accumulation within the ovulatory follicle and the corpus luteum are the subject of this mini-review.

  13. Indolo[3,2-b]carbazole inhibits gap junctional intercellular communication in rat primary hepatocytes and acts as a potential tumor promoter

    DEFF Research Database (Denmark)

    Herrmann, Susan; Seidelin, Michel; Bisgaard, Hanne Cathrine

    2002-01-01

    Indole-3-carbinol (I3C) is a naturally occurring substance that shows anti-carcinogenic properties in animal models. Besides its clear anti-carcinogenic effects, some studies indicate that I3C may sometimes act as a tumor promoter. Indolo[3,2-b]carbazole (ICZ), which is formed in the acidic...... environment of the stomach after intake of I3C, has a similar structure to, and shares biological effects with, the well-known tumor promoter 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD). Therefore, we hypothesized that ICZ could be responsible for the potential tumor-promoting activity of I3C. The aim...

  14. Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Ramon eGarcia-Areas

    2014-02-01

    Full Text Available Semaphorins, a large family of molecules involved in the axonal guidance and development of the nervous system, have been recently shown to have both angiogenic and anti-angiogenic properties. Specifically, semaphorin 7A (SEMA7A has been reported to have a chemotactic activity in neurogenesis, and to be an immune modulator via it binding to α1β1integrins. Additionally, SEMA7A has been shown to promote chemotaxis of monocytes, inducing them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in the tumoral context. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4, and that peritoneal macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to peritoneal macrophages derived from normal control mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecules, such as CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2 expression. Mice implanted with SEMA7A silenced tumor cells showed decreased angiogenesis in the tumors compared to the wild type tumors. Furthermore, peritoneal elicited macrophages from mice bearing SEMA7A-silenced tumors produce significantly (p< 0.01 lower levels of angiogenic proteins, such as MIP-2, CXCL1 and MMP-9, compared to macrophages from control DA-3 mammary tumors. We postulate that SEMA7A derived from mammary carcinomas may serve as a monocyte chemoattractant and skew monocytes into a pro-tumorigenic phenotype. A putative relationship between tumor-derived SEMA7A and monocytes could prove valuable in establishing new research avenues towards unraveling important tumor-host immune interactions in breast cancer patients.

  15. Chemokine RANTES in atopic dermatitis.

    Science.gov (United States)

    Glück, J; Rogala, B

    1999-01-01

    Chemokines play a key role in inflammatory diseases. The aim of this study was to estimate chemokine RANTES in the sera of patients with atopic dermatitis (AD) and to analyze the correlation between RANTES serum level and the immunological and clinical parameters of the disease. Serum levels of RANTES (ELISA; R&D Systems), total IgE and specific IgE (FEIA; Pharmacia CAP System) were estimated in 24 patients with AD, 28 patients with pollinosis (PL) and 22 healthy nonatopic subjects (HC). The division of the AD group into a pure AD (pAD) subgroup, without a coexisting respiratory allergy, and a subgroup of patients with AD and a respiratory allergy (AD+AO) was done according to Wütrich. Levels of RANTES were higher in the AD group than in the HC group and the PL group. RANTES levels did not differ among subgroups with various clinical scores and between the pAD and AD+AO subgroups. There were no correlations between levels of RANTES and total IgE. Significant positive correlations between serum levels of RANTES and Dermatophagoides farinae and cat dander-specific IgE were found in the AD group. We conclude that the serum level of chemokine RANTES differs patients with AD from patients with PL. The increase of RANTES concentration in the serum of patients with AD depends neither on a clinical picture nor an IgE system.

  16. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL

    DEFF Research Database (Denmark)

    Staller, Peter; Sulitkova, Jitka; Lisztwan, Joanna

    2003-01-01

    Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source of t...

  17. Development of a flexible and potent hypoxia-inducible promoter for tumor-targeted gene expression in attenuated Salmonella

    NARCIS (Netherlands)

    Mengesha, Asferd; Dubois, Ludwig; Lambin, Philippe; Landuyt, Willy; Chiu, Roland K; Wouters, Bradly G; Theys, Jan

    To increase the potential of attenuated Salmonella as gene delivery vectors for cancer treatment, we developed a hypoxia-inducible promoter system to limit gene expression specifically to the tumor. This approach is envisaged to not only increase tumor specificity, but also to target those cells

  18. Oligodeoxynucleotides Expressing Polyguanosine Motifs Promote Anti-Tumor Activity through the Up-Regulation of IL-2

    Science.gov (United States)

    Kobayashi, Nobuaki; Hong, Choongman; Klinman, Dennis M.; Shirota, Hidekazu

    2012-01-01

    The primary goal of cancer immunotherapy is to elicit an immune response capable of eliminating the tumor. One approach towards accomplishing that goal utilizes general (rather than tumor-specific) immunomodulatory agents to boost the number and activity of pre-existing cytotoxic T lymphocytes. We find that the intra-tumoral injection of poly-G ODN has such an effect, boosting anti-tumor immunity and promoting tumor regression. The anti-tumor activity of polyguanosine (poly-G) oligonucleotides (ODN) was mediated through CD8 T cells in a TLR9 independent manner. Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation. These findings establish poly-G ODN as a novel type of cancer immunotherapy. PMID:23296706

  19. Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-γ-induced expression of the chemokine CXCL9 gene in mouse macrophages

    International Nuclear Information System (INIS)

    Sakaeda, Yoshiichi; Hiroi, Miki; Shimojima, Takahiro; Iguchi, Mayumi; Kanegae, Haruhide; Ohmori, Yoshihiro

    2006-01-01

    Sulindac, a non-steroidal anti-inflammatory drug, has been shown to exert an anti-tumor effect on several types of cancer. To determine the effect of sulindac on intracellular signaling pathways in host immune cells such as macrophages, we investigated the effect of the drug on interferon gamma (IFNγ)-induced expression of signal transducer and activator of transcription 1 (STAT1) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFNγ-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL10 or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFNγ-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFNγ-induced STAT1 activation; however, constitutive nuclear factor κB activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFNγ-inducible gene expression without inhibiting STAT1 activation

  20. TLR5 signaling, commensal microbiota and systemic tumor promoting inflammation: the three parcae of malignant progression.

    Science.gov (United States)

    Rutkowski, Melanie R; Conejo-Garcia, Jose R

    2015-08-01

    We have reported that TLR5-mediated recognition of commensal microbiota modulates systemic tumor-promoting inflammation and malignant progression of tumors at distal locations. Approximately 7-10% of the general population harbors a deleterious single nucleotide polymorphism in TLR5, implicating a novel role for genetic variation during the initiation and progression of cancer.

  1. Tumor-promoting phorbol ester transiently down-modulates the p53 level and blocks the cell cycle

    DEFF Research Database (Denmark)

    Skouv, J.; Jensen, P O; Forchhammer, J

    1994-01-01

    Activation of the protein kinase C signaling pathway by tumor-promoting phorbol esters, such as 4 beta-phorbol 12-myristate 13-acetate (PMA), induced a decrease in the level of p53 mRNA in several serum-starved human cell lines. Also, the tumor-promoting phosphatase inhibitor okadaic acid induced...... a decrease in the p53 mRNA level in the cell lines. Normal diploid as well as various tumor cell lines were tested. Two tumor cell lines, HeLa and A549, both containing the wild-type p53 gene, but very different levels of p53 protein, were studied in detail. In both cell lines, the level of p53 m......RNA was minimal after 9 h of exposure to PMA. After approximately 120 h, the p53 mRNA level was similar to the pretreatment level. PMA induced a similar transient decrease in the level of p53 protein in the A549 cell line. The decrease in the p53 mRNA level could not be explained by changes in the transcriptional...

  2. Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo.

    Science.gov (United States)

    Maussang, David; Mujić-Delić, Azra; Descamps, Francis J; Stortelers, Catelijne; Vanlandschoot, Peter; Stigter-van Walsum, Marijke; Vischer, Henry F; van Roy, Maarten; Vosjan, Maria; Gonzalez-Pajuelo, Maria; van Dongen, Guus A M S; Merchiers, Pascal; van Rompaey, Philippe; Smit, Martine J

    2013-10-11

    The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled receptor superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or small interference (si)RNA has shown promising therapeutic benefits in several tumor models. With the increased interest and effectiveness of biologicals inhibiting membrane-bound receptors we made use of the "Nanobody platform" to target CXCR7. Previously we showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools to efficiently tackle difficult drug targets such as G protein-coupled receptors. In this study we developed and characterized highly selective and potent Nanobodies against CXCR7. Interestingly, the CXCR7-targeting Nanobodies displayed antagonistic properties in contrast with previously reported CXCR7-targeting agents. Several high affinity CXCR7-specific Nanobodies potently inhibited CXCL12-induced β-arrestin2 recruitment in vitro. A wide variety of tumor biopsies was profiled, showing for the first time high expression of CXCR7 in head and neck cancer. Using a patient-derived CXCR7-expressing head and neck cancer xenograft model in nude mice, tumor growth was inhibited by CXCR7-targeting Nanobody therapy. Mechanistically, CXCR7-targeting Nanobodies did not inhibit cell cycle progression but instead reduced secretion of the angiogenic chemokine CXCL1 from head and neck cancer cells in vitro, thus acting here as inverse agonists, and subsequent angiogenesis in vivo. Hence, with this novel class of CXCR7 inhibitors, we further substantiate the therapeutic relevance of targeting CXCR7 in head and neck cancer.

  3. Pulsed high-dose dexamethasone modulates Th1-/Th2-chemokine imbalance in immune thrombocytopenia.

    Science.gov (United States)

    Liu, Zongtang; Wang, Meiying; Zhou, Shufen; Ma, Ji; Shi, Yan; Peng, Jun; Hou, Ming; Guo, Chengshan

    2016-10-24

    Chemokines and chemokine receptors play important roles in autoimmune diseases; however, their role in immune thrombocytopenia (ITP) is unclear. High-dose dexamethasone (HD-DXM) may become a first-line therapy for adult patients with ITP, but the effect of HD-DXM on chemokines in ITP patients is unknown. Our aim was to investigate the mechanism of pulsed HD-DXM for management of ITP, specifically regarding the chemokine pathways. Th1-/Th2-associated chemokine and chemokine receptor profiles in ITP patients before and after pulsed HD-DXM was studied. Plasma levels of CCL5 and CXCL11 (Th1-associated) and of CCL11 (Th2-associated) were determined by ELISA. Gene expression of these three chemokines and their corresponding receptors CCR5, CXCR3, and CCR3, in peripheral blood mononuclear cells (PBMCs) was determined by quantitative RT-PCR. Thirty-three of the thirty-eight ITP patients responded effectively to HD-DXM (oral, 40 mg/day, 4 days). In ITP patients, plasma CXCL11 levels increased, while CCL11 and CCL5 decreased compared to controls (P Th1-/Th2-associated chemokines and chemokine receptors may play important roles in the pathogenesis of ITP. Importantly, regulating Th1 polarization by pulsed HD-DXM may represent a novel approach for immunoregulation in ITP.

  4. Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells.

    Science.gov (United States)

    Powan, Phattrakorn; Luanpitpong, Sudjit; He, Xiaoqing; Rojanasakul, Yon; Chanvorachote, Pithi

    2017-11-01

    The epithelial-to-mesenchymal transition is proposed to be a key mechanism responsible for metastasis-related deaths. Similarly, cancer stem cells (CSCs) have been proposed to be a key driver of tumor metastasis. However, the link between the two events and their control mechanisms is unclear. We used a three-dimensional (3D) tumor spheroid assay and other CSC-indicating assays to investigate the role of E-cadherin in CSC regulation and its association to epithelial-to-mesenchymal transition in lung cancer cells. Ectopic overexpression and knockdown of E-cadherin were found to promote and retard, respectively, the formation of tumor spheroids in vitro but had opposite effects on tumor formation and metastasis in vivo in a xenograft mouse model. We explored the discrepancy between the in vitro and in vivo results and demonstrated, for the first time, that E-cadherin is required as a component of a major survival pathway under detachment conditions. Downregulation of E-cadherin increased the stemness of lung cancer cells but had an adverse effect on their survival, particularly on non-CSCs. Such downregulation also promoted anoikis resistance and invasiveness of lung cancer cells. These results suggest that anoikis assay could be used as an alternative method for in vitro assessment of CSCs that involves dysregulated adhesion proteins. Our data also suggest that agents that restore E-cadherin expression may be used as therapeutic agents for metastatic cancers. Copyright © 2017 the American Physiological Society.

  5. Neuronal chemokines : Versatile messengers in central nervous system cell interaction

    NARCIS (Netherlands)

    de Haas, A. H.; van Weering, H. R. J.; de Jong, E. K.; Boddeke, H. W. G. M.; Biber, K. P. H.

    2007-01-01

    Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS),

  6. Therapeutic implications of chemokine-mediated pathways in atherosclerosis: realistic perspectives and utopias.

    Science.gov (United States)

    Apostolakis, Stavros; Amanatidou, Virginia; Spandidos, Demetrios A

    2010-09-01

    Current perspectives on the pathogenesis of atherosclerosis strongly support the involvement of inflammatory mediators in the establishment and progression of atherosclerostic lesions. Chemokine-mediated mechanisms are potent regulators of such processes by orchestrating the interactions of inflammatory cellular components of the peripheral blood with cellular components of the arterial wall. The increasing evidence supporting the role of chemokine pathways in atherosclerosis renders chemokine ligands and their receptors potential therapeutic targets. In the following review, we aim to highlight the special structural and functional features of chemokines and their receptors in respect to their roles in atherosclerosis, and examine to what extent available data can be applied in disease management practices.

  7. CXC chemokine receptor 2 contributes to host defense in murine urinary tract infection

    NARCIS (Netherlands)

    Olszyna, D. P.; Florquin, S.; Sewnath, M.; Branger, J.; Speelman, P.; van Deventer, S. J.; Strieter, R. M.; van der Poll, T.

    2001-01-01

    CXC chemokines have been implicated in the recruitment of neutrophils to sites of infection. To determine the role of CXC chemokines in the host response to urinary tract infection (UTI), female mice were treated with an antibody against the major CXC chemokine receptor in the mouse, CXCR2, before

  8. Caspase-1 from Human Myeloid-Derived Suppressor Cells Can Promote T Cell-Independent Tumor Proliferation.

    Science.gov (United States)

    Zeng, Qi; Fu, Juan; Korrer, Michael; Gorbounov, Mikhail; Murray, Peter J; Pardoll, Drew; Masica, David L; Kim, Young J

    2018-05-01

    Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell-independent functions within the tumor, sorted monocytic CD14 + CD11b + HLA-DR low/- MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo , growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell-depleted conditions. Adoptive transfer of wild-type Gr-1 + CD11b + MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor-intrinsic MyD88-dependent carcinogenesis. In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell-independent mediator of tumor proliferation. Cancer Immunol Res; 6(5); 566-77. ©2018 AACR . ©2018 American Association for Cancer Research.

  9. The anti-inflammatory effect of low-dose radiation therapy involves a diminished CCL20 chemokine expression and granulocyte/endothelial cell adhesion

    Energy Technology Data Exchange (ETDEWEB)

    Roedel, F. [Dept. of Radiotherapy and Oncology, Univ. of Frankfurt/Main (Germany); Hofmann, D.; Auer, J.; Roellinghoff, M.; Beuscher, H.U. [Inst. of Microbiology and Immunology, Univ. of Erlangen-Nuremberg, Erlangen (Germany); Keilholz, L. [Dept. of Radiotherapy, Clinical Center Bayreuth (Germany); Sauer, R. [Dept. of Radiooncology, Univ. of Erlangen-Nuremberg, Erlangen (Germany)

    2008-01-15

    Background and purpose: low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect, however, the underlying molecular mechanisms are not fully understood. The manipulation of polymorphonuclear neutrophil (PMN) function and/or recruitment may be one mechanism. Chemokines contribute to this process by creating a chemotactic gradient and by activating integrins. This study aimed to characterize the effect of LD-RT on CCL20 chemokine production and PMN/endothelial cell (EC) adhesion. Material and methods: the EC line EA.hy.926 was irradiated with doses ranging from 0 to 3 Gy and was co-cultured with PMNs from healthy donors either by direct cell contact or separated by transwell membrane chambers. CXCL8, CCL18, CCL20 chemokine and tumor necrosis factor-(TNF-){alpha} cytokine levels in supernatants were determined by ELISA and adhesion assays were performed. The functional impact of the cytokines transforming growth factor-(TGF-){beta}{sub 1} and TNF-{alpha} and of the intercellular adhesion molecule-(ICAM-)1 on CCL20 expression was analyzed by using neutralizing antibodies. Results: as compared to CXCL8 and CCL18, CCL20 chemokine secretion was found to be exclusively induced by a direct cell-cell contact between PMNs and EA.hy.926 ECs in a TNF-{alpha}-dependent, but ICAM-1-independent manner. Furthermore, irradiation with doses between 0.5 and 1 Gy resulted in a significant reduction of CCL20 release which was dependent on TGF-{beta}{sub 1} (p < 0.01). The decrease of CCL20 paralleled with a significant reduction in PMN/EA.hy.926 EC adhesion (p < 0.001). Conclusion: the modulation of CCL20 chemokine expression and PMN/EC adhesion adds a further facet to the plethora of mechanisms contributing to the anti-inflammatory efficacy of LD-RT. (orig.)

  10. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    International Nuclear Information System (INIS)

    Yu, Wei; Chai, Hongyan; Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue; Yang, Guifang; Cai, Xiaojun; Falck, John R.; Yang, Jing

    2012-01-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

  11. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2012-10-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

  12. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

    Science.gov (United States)

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-11-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

  13. Preparation and Analysis of N-Terminal Chemokine Receptor Sulfopeptides Using Tyrosylprotein Sulfotransferase Enzymes.

    Science.gov (United States)

    Seibert, Christoph; Sanfiz, Anthony; Sakmar, Thomas P; Veldkamp, Christopher T

    2016-01-01

    In most chemokine receptors, one or multiple tyrosine residues have been identified within the receptor N-terminal domain that are, at least partially, modified by posttranslational tyrosine sulfation. For example, tyrosine sulfation has been demonstrated for Tyr-3, -10, -14, and -15 of CCR5, for Tyr-3, -14, and -15 of CCR8, and for Tyr-7, -12, and -21 of CXCR4. While there is evidence for several chemokine receptors that tyrosine sulfation is required for optimal interaction with the chemokine ligands, the precise role of tyrosine sulfation for chemokine receptor function remains unclear. Furthermore, the function of the chemokine receptor N-terminal domain in chemokine binding and receptor activation is also not well understood. Sulfotyrosine peptides corresponding to the chemokine receptor N-termini are valuable tools to address these important questions both in structural and functional studies. However, due to the lability of the sulfotyrosine modification, these peptides are difficult to obtain using standard peptide chemistry methods. In this chapter, we provide methods to prepare sulfotyrosine peptides by enzymatic in vitro sulfation of peptides using purified recombinant tyrosylprotein sulfotransferase (TPST) enzymes. In addition, we also discuss alternative approaches for the generation of sulfotyrosine peptides and methods for sulfopeptide analysis. © 2016 Elsevier Inc. All rights reserved.

  14. Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes

    NARCIS (Netherlands)

    Nijhara, Ruchika; van Hennik, Paula B.; Gignac, Michelle L.; Kruhlak, Michael J.; Hordijk, Peter L.; Delon, Jerome; Shaw, Stephen

    2004-01-01

    Lymphocytes circulate in the blood and upon chemokine activation rapidly bind, where needed, to microvasculature to mediate immune surveillance. Resorption of microvilli is an early morphological alteration induced by chemokines that facilitates lymphocyte emigration. However, the antecedent

  15. Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain.

    Science.gov (United States)

    Zhang, Zhi-Jun; Jiang, Bao-Chun; Gao, Yong-Jing

    2017-09-01

    Neuropathic pain resulting from damage or dysfunction of the nervous system is a highly debilitating chronic pain state and is often resistant to currently available treatments. It has become clear that neuroinflammation, mainly mediated by proinflammatory cytokines and chemokines, plays an important role in the establishment and maintenance of neuropathic pain. Chemokines were originally identified as regulators of peripheral immune cell trafficking and were also expressed in neurons and glial cells in the central nervous system. In recent years, accumulating studies have revealed the expression, distribution and function of chemokines in the spinal cord under chronic pain conditions. In this review, we provide evidence showing that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron-glia interaction in the spinal cord. First, chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, we recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain.

  16. TLR9 ligation in pancreatic stellate cells promotes tumorigenesis.

    Science.gov (United States)

    Zambirinis, Constantinos P; Levie, Elliot; Nguy, Susanna; Avanzi, Antonina; Barilla, Rocky; Xu, Yijie; Seifert, Lena; Daley, Donnele; Greco, Stephanie H; Deutsch, Michael; Jonnadula, Saikiran; Torres-Hernandez, Alejandro; Tippens, Daniel; Pushalkar, Smruti; Eisenthal, Andrew; Saxena, Deepak; Ahn, Jiyoung; Hajdu, Cristina; Engle, Dannielle D; Tuveson, David; Miller, George

    2015-11-16

    Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis. © 2015 Zambirinis et al.

  17. Liver Tumor Promotion by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Dependent on the Aryl Hydrocarbon Receptor and TNF/IL-1 Receptors

    Science.gov (United States)

    Kennedy, Gregory D.; Nukaya, Manabu; Moran, Susan M.; Glover, Edward; Weinberg, Samuel; Balbo, Silvia; Hecht, Stephen S.; Pitot, Henry C.; Drinkwater, Norman R.; Bradfield, Christopher A.

    2014-01-01

    We set out to better understand the signal transduction pathways that mediate liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxn (“dioxin”). To this end, we first employed congenic mice homozygous for either the Ahrb1 or Ahrd alleles (encoding an aryl hydrocarbon receptor (AHR) with high or low binding affinity for dioxin, respectively) and demonstrated that hepatocellular tumor promotion in response to dioxin segregated with the Ahr locus. Once we had genetic evidence for the importance of AHR signaling, we then asked if tumor promotion by dioxin was influenced by “interleukin-1 (IL-1)-like” inflammatory cytokines. The importance of this question arose from our earlier observation that aspects of the acute hepatocellular toxicity of dioxin are dependent upon IL1-like cytokine signaling. To address this issue, we employed a triple knock-out (TKO) mouse model with null alleles at the loci encoding the three relevant receptors for tumor necrosis factors α and β and IL-1α and IL-1β (i.e., null alleles at the Tnfrsf1a, Tnfrsf1b, and Il-1r1 loci). The observation that TKO mice were resistant to the tumor promoting effects of dioxin in liver suggests that inflammatory cytokines play an important step in dioxin mediated liver tumor promotion in the mouse. Collectively, these data support the idea that the mechanism of dioxin acute hepatotoxicity and its activity as a promoter in a mouse two stage liver cancer model may be similar, i.e., tumor promotion by dioxin, like acute hepatotoxicity, are mediated by the linked action of two receptor systems, the AHR and the receptors for the “IL-1-like” cytokines. PMID:24718703

  18. Comparison of chemokines (CCL-5 and SDF-1), chemokine receptors (CCR-5 and CXCR-4) and IL-6 levels in patients with different severities of depression.

    Science.gov (United States)

    Ogłodek, Ewa A; Szota, Anna; Just, Marek J; Moś, Danuta; Araszkiewicz, Aleksander

    2014-10-01

    Depression can be perceived as a psychoneuroimmunological disorder in which cytokines affecting the body's neurochemical and neuroendocrine functions play an important role. Among cytokines, chemokines participating in activation of the inflammatory response are considered to be crucial. 160 men and women were enrolled in the study. 120 of them were diagnosed with various types of depression. The mean age was 45.2 ± 4.5 years (range: 19-47 years). The control group consisted of 40 healthy individuals. The average age in this group was 42.4 ± 4.1 years. Plasma levels of chemokines and their receptors (CCL-5 - RANTES and CXCR-5, SDF-1 and CXCR-4), as well as of IL-6, were assessed by ELISA. There was an increase in SDF-1 and CCL-5 levels in women and men with different severities of depression, versus the control group. Also, an increase in the IL-6 levels, CXCR4 and CCR-5 receptors was observed in both women and men with all types of depression. Levels of SDF-1 and CCL-5 chemokines, as well as of CCR-5 and CXCR4 chemokine receptors, were higher in women than in men. The results of this study indicate the need for assessment of CCL-5 and SDF-1 chemokines levels, as they are likely markers of developing depression. Early measurement of these chemokines levels may be helpful in choosing the best pharmacotherapy. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma.

    Science.gov (United States)

    Kremer, Veronika; Ligtenberg, Maarten A; Zendehdel, Rosa; Seitz, Christina; Duivenvoorden, Annet; Wennerberg, Erik; Colón, Eugenia; Scherman-Plogell, Ann-Helén; Lundqvist, Andreas

    2017-09-19

    cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells.

  20. Mind the GAP: A Novel Tumor-Promoting Mechanism | Center for Cancer Research

    Science.gov (United States)

    RAS proteins, like light switches, toggle between an “on” conformation where they promote cell growth, survival, and/or the formation of blood vessels (known as angiogenesis) and an “off” conformation in which they are unable to stimulate their target effector proteins. Nearly one-third of human tumors express a mutated RAS gene, which encodes a protein locked permanently in

  1. Solution structure of CXCL5--a novel chemokine and adipokine implicated in inflammation and obesity.

    Directory of Open Access Journals (Sweden)

    Krishna Mohan Sepuru

    Full Text Available The chemokine CXCL5 is selectively expressed in highly specialized cells such as epithelial type II cells in the lung and white adipose tissue macrophages in muscle, where it mediates diverse functions from combating microbial infections by regulating neutrophil trafficking to promoting obesity by inhibiting insulin signaling. Currently very little is known regarding the structural basis of how CXCL5 mediates its novel functions. Towards this missing knowledge, we have solved the solution structure of the CXCL5 dimer by NMR spectroscopy. CXCL5 is a member of a subset of seven CXCR2-activating chemokines (CAC that are characterized by the highly conserved ELR motif in the N-terminal tail. The structure shows that CXCL5 adopts the typical chemokine fold, but also reveals several distinct differences in the 30 s loop and N-terminal residues; not surprisingly, crosstalk between N-terminal and 30 s loop residues have been implicated as a major determinant of receptor activity. CAC function also involves binding to highly sulfated glycosaminoglycans (GAG, and the CXCL5 structure reveals a distinct distribution of positively charged residues, suggesting that differences in GAG interactions also influence function. The availability of the structure should now facilitate the design of experiments to better understand the molecular basis of various CXCL5 functions, and also serve as a template for the design of inhibitors for use in a clinical setting.

  2. Mesenchymal stem cell 1 (MSC1-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ruth S Waterman

    Full Text Available Currently, there are many promising clinical trials using mesenchymal stem cells (MSCs in cell-based therapies of numerous diseases. Increasingly, however, there is a concern over the use of MSCs because they home to tumors and can support tumor growth and metastasis. For instance, we established that MSCs in the ovarian tumor microenvironment promoted tumor growth and favored angiogenesis. In parallel studies, we also developed a new approach to induce the conventional mixed pool of MSCs into two uniform but distinct phenotypes we termed MSC1 and MSC2.Here we tested the in vitro and in vivo stability of MSC1 and MSC2 phenotypes as well as their effects on tumor growth and spread. In vitro co-culture of MSC1 with various cancer cells diminished growth in colony forming units and tumor spheroid assays, while conventional MSCs or MSC2 co-culture had the opposite effect in these assays. Co-culture of MSC1 and cancer cells also distinctly affected their migration and invasion potential when compared to MSCs or MSC2 treated samples. The expression of bioactive molecules also differed dramatically among these samples. MSC1-based treatment of established tumors in an immune competent model attenuated tumor growth and metastasis in contrast to MSCs- and MSC2-treated animals in which tumor growth and spread was increased. Also, in contrast to these groups, MSC1-therapy led to less ascites accumulation, increased CD45+leukocytes, decreased collagen deposition, and mast cell degranulation.These observations indicate that the MSC1 and MSC2 phenotypes may be convenient tools for the discovery of critical components of the tumor stroma. The continued investigation of these cells may help ensure that cell based-therapy is used safely and effectively in human disease.

  3. CONTENTS OF CHEMOKINES AND CYTOKINES IN PERITONEAL FLUID FROM THE PATIENTS WITH ENDOMETRIOSIS OF VARIOUS SEVERITY

    Directory of Open Access Journals (Sweden)

    D. I. Sokolov

    2007-01-01

    Full Text Available Abstract. Endometriosis is a disease accompanied by development of heterotopic endometrial foci at the peritoneum, proliferation of endothelial cells, and inflammatory reaction. Aiming to specify the dynamics of inflammatory process in endometriosis of different severity, as well as significance of chemokines and cytokines in angiogenesis and inflammation, we determined concentrations of RANTES, IL-8, IP-10, MIG, MCP-1 chemokines, as well as IL-4, IL-6 and IL-10 cytokines in peritoneal fluid from patients by endometriosis. Forty women at reproductive age with an endometriosis have been observed. Among them, endometriosis grade I-II was registered in 20 cases, whereas grade III-IV has been confirmed in 20 women. Twenty-two women without evidence of endometriosis referred to diagnostic laparoscopy for pregnancy planning, comprised a control group. Diagnosis of endometriosis was based upon endoscopic findings and results of histological research. Severity grade of endometriosis was estimated according to R-AFS classification. Sampling of peritoneal fluid was carried out when performing surgical laparoscopies. Concentrations of chemokines and cytokines were determined by flow cytometry techniques, using BD Cytometric Bead Array test kits and FACStrack flow cytometer. The amounts of RANTES in peritoneal fluid were higher in grade I-II endometriosis, in comparison with grade III-IV endometriosis and control samples. Concentrations of IP-10, IL-8, МСР-1, MIG, IL-6, and IL-4 were higher than in control group and correlated with severity of the disease. IL-10 was not detectable in peritoneal fluid of the patients with endometriosis. These results suggest a significant role of the mentioned cytokines and chemokines that may promote invasion of endometrial cells, growth of heterotopic endometrioid locuses, development of vascular bed and induction of inflammatory processes, in development and progression of endometriosis.

  4. Chemokines involved in protection from colitis by CD4+CD25+ regulatory T cells

    DEFF Research Database (Denmark)

    Kristensen, Nanna Ny; Brudzewsky, Dan; Gad, Monika

    2006-01-01

    /chemokine receptor-specific gene expression profiling system of 67 genes, the authors have determined the expression profile of chemokine and chemokine receptor genes in the rectum of colitic mice and in mice that have been protected fromcolitis by CD4CD25 regulatory T cells. In mice protected from colitis......, the authors found down regulation of the mRNA expression of the inflammatory chemokine receptors CCR1 and CXCR3 and their ligands CXCL9, CXCL10, CCL5, and CCL7. Also the transcripts for CCR9, CCL25, CCL17, and CXCL1 are found down regulated in protected compared with colitic animals. In addition, the authors......' results suggest that CCL20 is used by CCR6 regulatory T cells in the complex process of controlling colitis because transcripts for this chemokine were expressed to a higher level in protected animals. The chemokine pathways identified in the present study may be of importance for the development of new...

  5. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  6. Promoter methylation of RASSF1A and DAPK and mutations of K-ras, p53, and EGFR in lung tumors from smokers and never-smokers

    International Nuclear Information System (INIS)

    Liu, Yang; Gao, Weimin; Siegfried, Jill M; Weissfeld, Joel L; Luketich, James D; Keohavong, Phouthone

    2007-01-01

    Epidemiological studies indicate that some characteristics of lung cancer among never-smokers significantly differ from those of smokers. Aberrant promoter methylation and mutations in some oncogenes and tumor suppressor genes are frequent in lung tumors from smokers but rare in those from never-smokers. In this study, we analyzed promoter methylation in the ras-association domain isoform A (RASSF1A) and the death-associated protein kinase (DAPK) genes in lung tumors from patients with primarily non-small cell lung cancer (NSCLC) from the Western Pennsylvania region. We compare the results with the smoking status of the patients and the mutation status of the K-ras, p53, and EGFR genes determined previously on these same lung tumors. Promoter methylation of the RASSF1A and DAPK genes was analyzed by using a modified two-stage methylation-specific PCR. Data on mutations of K-ras, p53, and EGFR were obtained from our previous studies. The RASSF1A gene promoter methylation was found in tumors from 46.7% (57/122) of the patients and was not significantly different between smokers and never-smokers, but was associated significantly in multiple variable analysis with tumor histology (p = 0.031) and marginally with tumor stage (p = 0.063). The DAPK gene promoter methylation frequency in these tumors was 32.8% (40/122) and did not differ according to the patients' smoking status, tumor histology, or tumor stage. Multivariate analysis adjusted for age, gender, smoking status, tumor histology and stage showed that the frequency of promoter methylation of the RASSF1A or DAPK genes did not correlate with the frequency of mutations of the K-ras, p53, and EGFR gene. Our results showed that RASSF1A and DAPK genes' promoter methylation occurred frequently in lung tumors, although the prevalence of this alteration in these genes was not associated with the smoking status of the patients or the occurrence of mutations in the K-ras, p53 and EGFR genes, suggesting each of

  7. Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs

    International Nuclear Information System (INIS)

    Kurayoshi, Kenta; Ozono, Eiko; Iwanaga, Ritsuko; Bradford, Andrew P.; Komori, Hideyuki; Ohtani, Kiyoshi

    2014-01-01

    Highlights: • ARF promoter showed higher responsiveness to deregulated E2F activity than the E2F1 promoter. • ARF promoter showed higher cancer cell-specificity than E2F1 promoter to drive gene expression. • HSV-TK driven by ARF promoter showed higher cancer cell-specific cytotoxicity than that driven by E2F1 promoter. - Abstract: In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicide gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter

  8. Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs

    Energy Technology Data Exchange (ETDEWEB)

    Kurayoshi, Kenta [Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan); Ozono, Eiko [Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ (United Kingdom); Iwanaga, Ritsuko; Bradford, Andrew P. [Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045 (United States); Komori, Hideyuki [Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109 (United States); Ohtani, Kiyoshi, E-mail: btm88939@kwansei.ac.jp [Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan)

    2014-07-18

    Highlights: • ARF promoter showed higher responsiveness to deregulated E2F activity than the E2F1 promoter. • ARF promoter showed higher cancer cell-specificity than E2F1 promoter to drive gene expression. • HSV-TK driven by ARF promoter showed higher cancer cell-specific cytotoxicity than that driven by E2F1 promoter. - Abstract: In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicide gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter

  9. E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells

    International Nuclear Information System (INIS)

    Theys, Jan; Jutten, Barry; Habets, Roger; Paesmans, Kim; Groot, Arjan J.; Lambin, Philippe; Wouters, Brad G.; Lammering, Guido; Vooijs, Marc

    2011-01-01

    Background and purpose: Hypoxia is a hallmark of solid cancers and associated with metastases and treatment failure. During tumor progression epithelial cells often acquire mesenchymal features, a phenomenon known as epithelial-to-mesenchymal transition (EMT). Intratumoral hypoxia has been linked to EMT induction. We hypothesized that signals from the tumor microenvironment such as growth factors and tumor oxygenation collaborate to promote EMT and thereby contribute to radioresistance. Materials and methods: Gene expression changes under hypoxia were analyzed using microarray and validated by qRT-PCR. Conversion of epithelial phenotype upon hypoxic exposure, TGFβ addition or oncogene activation was investigated by Western blot and immunofluorescence. Cell survival following ionizing radiation was assayed using clonogenic survival. Results: Upon hypoxia, TGFβ addition or EGFRvIII expression, MCF7, A549 and NMuMG epithelial cells acquired a spindle shape and lost cell-cell contacts. Expression of epithelial markers such as E-cadherin decreased, whereas mesenchymal markers such as vimentin and N-cadherin increased. Combining hypoxia with TGFβ or EGFRvIII expression, lead to more rapid and pronounced EMT-like phenotype. Interestingly, E-cadherin expression and the mesenchymal appearance were reversible upon reoxygenation. Mesenchymal conversion and E-cadherin loss were associated with radioresistance. Conclusions: Our findings describe a mechanism by which the tumor microenvironment may contribute to tumor radioresistance via E-cadherin loss and EMT.

  10. Mouse Mammary Tumor Virus Promoter-Containing Retroviral Promoter Conversion Vectors for Gene-Directed Enzyme Prodrug Therapy are Functional in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Reinhard Klein

    2008-01-01

    Full Text Available Gene directed-enzyme prodrug therapy (GDEPT is an approach for sensitization of tumor cells to an enzymatically activated, otherwise nontoxic, prodrug. Cytochrome P450 2B1 (CYP2B1 metabolizes the prodrugs cyclophosphamide (CPA and ifosfamide (IFA to produce the cytotoxic substances phosphoramide mustard and isophosphoramide mustard as well as the byproduct acrolein. We have constructed a retroviral promoter conversion (ProCon vector for breast cancer GDEPT. The vector allows expression of CYP2B1 from the mouse mammary tumor virus (MMTV promoter known to be active in the mammary glands of transgenic animals. It is anticipated to be used for the generation of encapsulated viral vector producing cells which, when placed inside or close to a tumor, will act as suppliers of the therapeutic CYP2B1 protein as well as of the therapeutic vector itself. The generated vector was effectively packaged by virus producing cells and allowed the production of high levels of enzymatically active CYP2B1 in infected cells which sensitized them to killing upon treatment with both IFA and CPA. Determination of the respective IC50 values demonstrated that the effective IFA dose was reduced by sixteen folds. Infection efficiencies in vivo were determined using a reporter gene-bearing vector in a mammary cancer cell-derived xenograft tumor mouse model.

  11. Cancer-associated adipocytes promotes breast tumor radioresistance

    Energy Technology Data Exchange (ETDEWEB)

    Bochet, Ludivine; Meulle, Aline [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France); Institut National de la Sante et de la Recherche Medicale, INSERM U1048, 1 Avenue du Pr Jean Poulhes, BP 84225, F-31432 Toulouse Cedex (France); Imbert, Sandrine [CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France); Salles, Bernard [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France); Valet, Philippe [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); Institut National de la Sante et de la Recherche Medicale, INSERM U1048, 1 Avenue du Pr Jean Poulhes, BP 84225, F-31432 Toulouse Cedex (France); Muller, Catherine, E-mail: muller@ipbs.fr [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France)

    2011-07-22

    Highlights: {yields} Tumor-surrounding adipocytes contribute to breast cancer progression. {yields} Breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance. {yields} Increased in Chk1 phosphorylation is observed in irradiated co-cultivated tumor cells. {yields} IL-6 is over-expressed in tumor cells co-cultivated with adipocytes. {yields} IL-6 exposure confers increased Chk1 phosphorylation and radioresistance in tumor cells. -- Abstract: Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.

  12. HIV Nef-M1 Effects on Colorectal Cancer Growth in Tumor-induced Spleens and Hepatic Metastasis

    Science.gov (United States)

    Harrington, Willie; Bond, Vincent; Huang, Ming Bo; Powell, Michael; Lillard, James; Manne, Upender; Bumpers, Harvey

    2010-01-01

    CXCR4 receptors have been implicated in tumorigenesis and proliferation, making it a potential target for colorectal cancer therapy. Expression of this chemokine receptor on cellular surfaces appears to promote metastasis by directly stimulating tumor cell migration and invasion. The receptor/ligand, CXCR4/SDF-1α, pair are critically important to angiogenesis and vascular remodeling which supports cancer proliferation. Our work has shown that a novel apoptotic peptide of HIV-1, Nef-M1, can act as a CXCR4 antagonist, inducing apoptosis in CXCR4 containing cells. Four colorectal tumor cell lines (HT-29, LS174t, SW480, WiDr), were evaluated for their response to Nef-M1 peptide via in vivo and in vitro. The presence of CXCR4 receptors on tumor cells was determined using immunohistochemical and RT-PCR analyses. Solid xenografts derived from tumor cell lines grown in SCID mice, were evaluated for the persistence of the receptor. Xenografts propagated in SCID mice from each of the four cell lines demonstrated high levels of receptor expression as well. The effects of Nef-M1 in vivo via splenic injected mice and subsequent hepatic metastasis also demonstrated dramatic reduction of primary tumor growth in the spleen and secondary invasion of the liver. We concluded that Nef-M1 peptide, through physical interaction(s) with CXCR4, drives apoptotic reduction in in vivo primary tumor growth and metastasis. PMID:20383296

  13. Metabolism of indole alkaloid tumor promoter, (-)-indolactam V, which has the fundamental structure of teleocidins, by rat liver microsomes

    Energy Technology Data Exchange (ETDEWEB)

    Hagiwara, N.; Irie, K.; Tokuda, H.; Koshimizu, K.

    1987-07-01

    Metabolic activation and/or deactivation of indole alkaloid tumor promoter, (-)-indolactam V (ILV), was examined using rat liver microsomes. Reaction of ILV with the microsomes supplemented with NADPH and MgCl/sub 2/ gave three major metabolites, which were identified as (-)-N13-desmethylindolactam V and two diastereomers of (-)-2-oxyindolactam V at C-3. The tumor-promoting activities of these metabolites were evaluated by induction of Epstein-Barr virus early antigen and inhibition of specific binding of (/sup 3/H)-12-O-tetradecanoylphorbol-13-acetate to a mouse epidermal particulate fraction, and proved to be conspicuously lower than that of ILV. These results demonstrate that the metabolism of ILV results in detoxification, and that it itself is the tumor-promoting entity. Studies on the enzymes concerned with this metabolism suggested the involvement of cytochrome P-450-containing mixed-function oxidases. Similar deactivation seems to be possible by skin, where the mixed-function oxidases are known to exist.

  14. Impact of genetic variations in C-C chemokine receptors and ligands on infectious diseases.

    Science.gov (United States)

    Qidwai, Tabish; Khan, M Y

    2016-10-01

    Chemokine receptors and ligands are crucial for extensive immune response against infectious diseases such as malaria, leishmaniasis, HIV and tuberculosis and a wide variety of other diseases. Role of chemokines are evidenced in the activation and regulation of immune cell migration which is important for immune response against diseases. Outcome of disease is determined by complex interaction among pathogen, host genetic variability and surrounding milieu. Variation in expression or function of chemokines caused by genetic polymorphisms could be associated with attenuated immune responses. Exploration of chemokine genetic polymorphisms in therapeutic response, gene regulation and disease outcome is important. Infectious agents in human host alter the expression of chemokines via epigenetic alterations and thus contribute to disease pathogenesis. Although some fragmentary data are available on chemokine genetic variations and their contribution in diseases, no unequivocal conclusion has been arrived as yet. We therefore, aim to investigate the association of CCR5-CCL5 and CCR2-CCL2 genetic polymorphisms with different infectious diseases, transcriptional regulation of gene, disease severity and response to therapy. Furthermore, the role of epigenetics in genes related to chemokines and infectious disease are also discussed. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  15. Positive versus negative modulation of different endogenous chemokines for CC-chemokine receptor 1 by small molecule agonists through allosteric versus orthosteric binding

    DEFF Research Database (Denmark)

    Jensen, Pia C; Thiele, Stefanie; Ulven, Trond

    2008-01-01

    7 transmembrane-spanning (7TM) chemokine receptors having multiple endogenous ligands offer special opportunities to understand the molecular basis for allosteric mechanisms. Thus, CC-chemokine receptor 1 (CCR1) binds CC-chemokine 3 and 5 (CCL3 and CCL5) with K(d) values of 7.3 and 0.16 nm......5 and not CCL3 activation is affected by substitutions in the main ligand binding pocket including the conserved GluVII:06 anchor point. A series of metal ion chelator complexes were found to act as full agonists on CCR1 and to be critically affected by the same substitutions in the main ligand...... binding pocket as CCL5 but not by mutations in the extracellular domain. In agreement with the overlapping binding sites, the small non-peptide agonists displaced radiolabeled CCL5 with high affinity. Interestingly, the same compounds acted as allosteric enhancers of the binding of CCL3, with which...

  16. Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2.

    Directory of Open Access Journals (Sweden)

    Satoshi Takagi

    Full Text Available The platelet aggregation-inducing factor Aggrus, also known as podoplanin, is frequently upregulated in several types of tumors and enhances hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2. Thus, Aggrus-CLEC-2 binding could be a therapeutic molecular mechanism for cancer therapy. We generated a new anti-human Aggrus monoclonal antibody, MS-1, that suppressed Aggrus-CLEC-2 binding, Aggrus-induced platelet aggregation, and Aggrus-mediated tumor metastasis. Interestingly, the MS-1 monoclonal antibody attenuated the growth of Aggrus-positive tumors in vivo. Moreover, the humanized chimeric MS-1 antibody, ChMS-1, also exhibited strong antitumor activity against Aggrus-positive lung squamous cell carcinoma xenografted into NOD-SCID mice compromising antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities. Because Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth of the lung squamous cell carcinoma in vivo, Aggrus may be involved in not only tumor metastasis but also tumor growth by promoting platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Our results indicate that molecular target drugs inhibiting specific platelet-tumor interactions can be developed as antitumor drugs that suppress both metastasis and proliferation of tumors such as lung squamous cell carcinoma.

  17. Chemokine receptor expression by inflammatory T cells in EAE

    DEFF Research Database (Denmark)

    Mony, Jyothi Thyagabhavan; Khorooshi, Reza; Owens, Trevor

    2014-01-01

    Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20...... receptor CCR6 has been reported to be selectively expressed by CD4(+) T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed...... whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4(+) T cells produced IFNγ in flow cytometric cytokine assays...

  18. Cytokine and chemokine levels in tears from healthy subjects.

    Science.gov (United States)

    Carreño, Ester; Enríquez-de-Salamanca, Amalia; Tesón, Marisa; García-Vázquez, Carmen; Stern, Michael E; Whitcup, Scott M; Calonge, Margarita

    2010-11-01

    There is growing evidence for the existence of an 'immune tone' in normal tears. The aim of this study was to determine the levels of a large panel of cytokines and chemokines in tears obtained from healthy subjects. These levels can then serve as baseline values for comparison with patients suffering from ocular surface diseases. Nine healthy subjects participated in this study, and normal ocular surface health was documented by the results of a dry eye questionnaire, Schirmer strip wetting, and vital staining of the cornea. Four microliters of tears were collected from each eye and analysed separately with multiplex bead-based assays for the concentration of 30 cytokines and chemokines. Twenty-five cytokines/chemokines were detected. CCL11/Eotaxin1, GM-CSF, G-CSF, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-10, IL-13, IL-12p70, IL-15, CX3CL1/Fractalkine, TNF-α, epidermal growth factor, and CCL4/MIP-1β were present at 5-100 pg/ml. IL-1β, IL-6, IL-7A, CXCL8/IL-8, and CCL2/MCP-1 were present at 100-400 pg/ml. IL-1Ra, CXCL10/IP-10 and vascular endothelial growth factor were present at more than 1000 pg/ml. Multiplex bead-based assays are convenient for cytokine/chemokine detection in tears. Fracktalkine has been detected in human healthy tears for the first time. The knowledge of cytokine/chemokine concentrations in tears from normal subjects is an important reference for further comparison with patients suffering from ocular surface diseases. Variability in their levels can reflect a phenomenon of potential importance for the understanding of the ocular surface cytokine pattern. © 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.

  19. Mesenchymal Stem Cells Promote Pancreatic Tumor Growth by Inducing Alternative Polarization of Macrophages

    Directory of Open Access Journals (Sweden)

    Esha Mathew

    2016-03-01

    Significance: Targeting the stroma is emerging as a new paradigm in pancreatic cancer; however, efforts to that effect are hampered by our limited understanding of the nature and function of stromal components. Here, we uncover previously unappreciated heterogeneity within the stroma and identify interactions among stromal components that promote tumor growth and could be targeted therapeutically.

  20. A novel mechanism of skin tumor promotion involving interferon-gamma (IFNγ)/signal transducer and activator of transcription-1 (Stat1) signaling.

    Science.gov (United States)

    Bozeman, Ronald; Abel, Erika L; Macias, Everardo; Cheng, Tianyi; Beltran, Linda; DiGiovanni, John

    2015-08-01

    The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1(-/-) ) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1(-/-) mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. © 2014 Wiley Periodicals, Inc.

  1. miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.

    Science.gov (United States)

    Sun, Xiaojuan; Charbonneau, Cherie; Wei, Lei; Chen, Qian; Terek, Richard M

    2015-09-01

    Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. ©2015 American Association for Cancer Research.

  2. Viral leads for chemokine-modulatory drugs

    DEFF Research Database (Denmark)

    Lindow, Morten; Lüttichau, Hans Rudolf; Schwartz, Thue W

    2003-01-01

    The chemokine system, which controls leukocyte trafficking, provides several potentially very attractive anti-inflammatory drug targets. However, the complexity and redundancy of this system makes it very difficult to exploit through classical drug discovery. Despite this, viruses have millions...

  3. [Evaluation of chemokines in tears of patients with infectious keratitis].

    Science.gov (United States)

    Hori, Shinsuke; Shoji, Jun; Inada, Noriko; Sawa, Mitsuru

    2013-02-01

    To investigate the chemokine profile in tears of patients with infectious keratitis. Subjects were 32 eyes of 16 patients with infectious keratitis and 5 eyes of 5 healthy volunteers as a control. The patients with infectious keratitis were classified into two groups of eyes: 10 with bacterial keratitis and 6 with Acanthamoeba keratitis. Tear fluid was obtained from both eyes of the patients with infectious keratitis and from the right eyes of the control subjects using filter paper. Chemokine concentration (unit: Odu/mm2) and its profile in tears was analyzed using an antibody-array. In terms of chemokine profile in the bacterial keratitis group, the expression volume of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in the diseased eyes was significantly higher than in the healthy eyes (p tears of the Acanthamoeba keratitis group. Regarding the chemokine ratio, the IL-8/MEC ratio in the diseased eyes of the Pseudomonas keratitis group and the MCP-1/IL-8 in the diseased eyes of the Acanthamoeba keratitis group showed a significantly high level (p tears of infectious keratitis patients is useful as a clinical tear laboratory test to interpret the pathologic condition of infectious keratitis

  4. Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction

    DEFF Research Database (Denmark)

    Idorn, Manja; Olsen, Maria; Halldórsdóttir, Hólmfrídur Rósa

    2018-01-01

    Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune...

  5. Epigenetic Silencing of CXCR4 Promotes Loss of Cell Adhesion in Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Suresh Singh Yadav

    2014-01-01

    Full Text Available In the network of chemokine signaling pathways, recent reports have described the SDF-1α/CXCR4 axis and its role in cancer progression and metastasis. Interestingly, we found downregulation of CXCR4 at both transcript and protein level in cervical cancer cell lines and primary tumors. We also found CXCR4 promoter hypermethylation in cervical cancer cell lines and primary biopsy samples. DNA hypomethylating drug 5-AZA-2′-deoxycytidine and histone deacetylase inhibitor Trichostatin A treatments in cell lines reactivate both CXCR4 transcription and protein expression. Cell adhesion assay demonstrated that autocrine SDF-1α promotes the loss of cell adhesion while paracrine SDF-1α predominantly protects the normal cervical cells from loss of cell adhesion. Cervical cancer cell line C-33A having increased expression of CXCR4 after TSA treatment showed increased cell adhesion by paracrine source of SDF-1α in comparison to untreated C-33A. These findings demonstrate the first evidence that epigenetic silencing of CXCR4 makes the cells inefficient to respond to the paracrine source of SDF-1α leading to loss of cell adhesion, one of the key events in metastases and progression of the disease. Our results provide novel insight of SDF-1α/CXCR4 signaling in tumor microenvironment which may be promising to further delineate molecular mechanism of cervical carcinogenesis.

  6. Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells.

    Science.gov (United States)

    Saijo, Atsuro; Goto, Hisatsugu; Nakano, Mayuri; Mitsuhashi, Atsushi; Aono, Yoshinori; Hanibuchi, Masaki; Ogawa, Hirohisa; Uehara, Hisanori; Kondo, Kazuya; Nishioka, Yasuhiko

    2018-05-01

    Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 + monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches. Copyright © 2018. Published by Elsevier B.V.

  7. MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xia, E-mail: dentistlx@163.com [Department of Stomatology, School of Stomatology and medicine, Foshan Stomatology Hospital, Foshan University, Foshan 528000 (China); Fan, Qinqiao [Department of Hepatobiliary Surgery, Cancer Center, Chenzhou No.1 People' s Hospital, Chenzhou 423000 (China); Li, Jinyun [Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Center South University, Changsha 410013 (China); Song, Jing; Gu, Yangcong [Department of Stomatology, School of Stomatology and medicine, Foshan Stomatology Hospital, Foshan University, Foshan 528000 (China)

    2017-02-01

    Cancer associated fibroblasts (CAFs) are known to be involved in initiation, progression and metastasis of various cancers. However, the molecular mechanism of how CAFs affects the biological function of oral cancer (OC) has not been fully-addressed. In this study, we demonstrated that miR-124 was downregulated in oral CAFs and oral cancer cells (OCCs) when compared with matched normal fibroblasts (NFs). Hypermethylation in the promoter region of miR-124 genes was accounted for its downregulation. Interestingly, CAFs but not NFs exerted promotion effect on OCCs cell proliferation, migration and tumor growth in CAFs/NFs-OCCs co-culture. Furthermore, we identified Chemokine (C-C motif) ligand 2 (CCL2) and Interleukin 8 (IL-8) as two direct targets of miR-124. Over-expression of miR-124 in CAFs-OCCs co-culture abrogated CAFs-promoted OCCs cell growth and migration, and this inhibitory effect can be rescued by addition of CCL2 and IL-8. Finally, we showed that restoration of miR-124 expression by lentiviral infection or formulated miR-124 injection inhibited oral tumor growth in vivo suggesting miR-124 rescue could be a potential rationale for therapeutic applications in oral cancer in the future. - Highlights: • miR-124 was downregulated in oral cancer cells and cancer associated fibroblasts. • Hypermethylation in the promoter region was accounted for miR-124 downregulation. • CCL2 and IL-8 are two direct targets of miR-124. • miR-124 rescue could be a potential rationale for oral cancer therapy.

  8. MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma

    International Nuclear Information System (INIS)

    Li, Xia; Fan, Qinqiao; Li, Jinyun; Song, Jing; Gu, Yangcong

    2017-01-01

    Cancer associated fibroblasts (CAFs) are known to be involved in initiation, progression and metastasis of various cancers. However, the molecular mechanism of how CAFs affects the biological function of oral cancer (OC) has not been fully-addressed. In this study, we demonstrated that miR-124 was downregulated in oral CAFs and oral cancer cells (OCCs) when compared with matched normal fibroblasts (NFs). Hypermethylation in the promoter region of miR-124 genes was accounted for its downregulation. Interestingly, CAFs but not NFs exerted promotion effect on OCCs cell proliferation, migration and tumor growth in CAFs/NFs-OCCs co-culture. Furthermore, we identified Chemokine (C-C motif) ligand 2 (CCL2) and Interleukin 8 (IL-8) as two direct targets of miR-124. Over-expression of miR-124 in CAFs-OCCs co-culture abrogated CAFs-promoted OCCs cell growth and migration, and this inhibitory effect can be rescued by addition of CCL2 and IL-8. Finally, we showed that restoration of miR-124 expression by lentiviral infection or formulated miR-124 injection inhibited oral tumor growth in vivo suggesting miR-124 rescue could be a potential rationale for therapeutic applications in oral cancer in the future. - Highlights: • miR-124 was downregulated in oral cancer cells and cancer associated fibroblasts. • Hypermethylation in the promoter region was accounted for miR-124 downregulation. • CCL2 and IL-8 are two direct targets of miR-124. • miR-124 rescue could be a potential rationale for oral cancer therapy.

  9. Cycling Hypoxia Induces a Specific Amplified Inflammatory Phenotype in Endothelial Cells and Enhances Tumor-Promoting Inflammation In Vivo

    Directory of Open Access Journals (Sweden)

    Céline Tellier

    2015-01-01

    Full Text Available Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor progression. As cycling hypoxia is known to participate in tumor aggressiveness, the purpose of this study was to evaluate its role in tumor-promoting inflammation. Firstly, we assessed the impact of cycling hypoxia in vitro on endothelial inflammatory response induced by tumor necrosis factor α. Results showed that endothelial cells exposed to cycling hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory cytokines, namely, interleukin (IL-6 and IL-8; by an increased expression of adhesion molecules, in particular intercellular adhesion molecule–1 (ICAM-1; and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor–κB overactivation. Secondly, the role of cycling hypoxia was studied on overall tumor inflammation in vivo in tumor-bearing mice. Results showed that cycling hypoxia led to an enhanced inflammation in tumors as prostaglandin-endoperoxide synthase 2 (PTGS2, IL-6, CXCL1 (C-X-C motif ligand 1, and macrophage inflammatory protein 2 (murine IL-8 functional homologs mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling hypoxia–specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5low/PTGS2high/ICAM-1high/IL-6high/IL-8high expression, is associated with a poor prognosis in human colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for colon cancer patients. In conclusion, our findings evidenced for the first time the

  10. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor

    Energy Technology Data Exchange (ETDEWEB)

    Burg, John S.; Ingram, Jessica R.; Venkatakrishnan, A.J.; Jude, Kevin M.; Dukkipati, Abhiram; Feinberg, Evan N.; Angelini, Alessandro; Waghray, Deepa; Dror, Ron O.; Ploegh, Hidde L.; Garcia, K. Christopher (Stanford); (Stanford-MED); (Whitehead); (MIT)

    2015-03-05

    Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor’s inactive state.

  11. Association of CCL11 promoter polymorphisms with schizophrenia in a Korean population.

    Science.gov (United States)

    Kang, Won Sub; Kim, Young Jong; Park, Hae Jeong; Kim, Su Kang; Paik, Jong-Woo; Kim, Jong Woo

    2018-05-20

    Immunological alterations and dysregulation of the inflammatory response have been suggested to play a crucial role in schizophrenia pathophysiology. Growing evidence supports the involvement of chemokines in brain development, thus many chemokines have been studied in relation with schizophrenia. The C-C motif chemokine ligand 11 (CCL11) has been shown to be related with synaptic plasticity and neurogenesis. Moreover, altered levels of CCL11 have been observed in schizophrenia patients. Therefore, we examined whether single nucleotide polymorphisms (SNPs) of the CCL11 in the promoter region contribute to susceptibility to schizophrenia. Four promoter SNPs [rs17809012 (-384T>C), rs16969415 (-426C>T), rs17735961 (-488C>A), and rs4795896 (576G>A)] were genotyped in 254 schizophrenia patients and 405 control subjects using Fluidigm SNPtype assays. The genotype frequency of CCL11 rs4795896 (-576G>A) showed significant association with schizophrenia in a recessive model (AA vs. GG/AG, p schizophrenia (p schizophrenia (p = 0.0044, p schizophrenia in a Korean population. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Immune response CC Chemokines, CCL2 and CCL5 are associated with Pulmonary Sarcoidosis

    LENUS (Irish Health Repository)

    Palchevskiy, Vyacheslav

    2011-04-04

    Abstract Background Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis. Results BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA) and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1), CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. Conclusions These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis.

  13. Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis.

    Science.gov (United States)

    Palchevskiy, Vyacheslav; Hashemi, Nastran; Weigt, Stephen S; Xue, Ying Ying; Derhovanessian, Ariss; Keane, Michael P; Strieter, Robert M; Fishbein, Michael C; Deng, Jane C; Lynch, Joseph P; Elashoff, Robert; Belperio, John A

    2011-04-04

    Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis. BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA) and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1), CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis.

  14. FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells.

    Directory of Open Access Journals (Sweden)

    Sungeun Kim

    Full Text Available Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.

  15. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    Khamis, Z.I.; Sang, Q.A.; Sahab, Z.J.

    2012-01-01

    Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome

  16. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zahraa I. Khamis

    2012-01-01

    Full Text Available Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome.

  17. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yi; Qin, Ling; Ortiz Zacarías, Natalia V.; de Vries, Henk; Han, Gye Won; Gustavsson, Martin; Dabros, Marta; Zhao, Chunxia; Cherney, Robert J.; Carter, Percy; Stamos, Dean; Abagyan, Ruben; Cherezov, Vadim; Stevens, Raymond C.; IJzerman, Adriaan P.; Heitman, Laura H.; Tebben, Andrew; Kufareva, Irina; Handel , Tracy M. (Vertex Pharm); (Leiden-MC); (USC); (BMS); (UCSD)

    2016-12-07

    CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

  18. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

    Science.gov (United States)

    Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M.; Hao, Hongying

    2016-01-01

    The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma. PMID:27063098

  19. Role of CXC chemokine ligand 13 in oral squamous cell carcinoma associated osteolysis in athymic mice.

    Science.gov (United States)

    Pandruvada, Subramanya N M; Yuvaraj, Sambandam; Liu, Xiang; Sundaram, Kumaran; Shanmugarajan, Srinivasan; Ries, William L; Norris, James S; London, Steven D; Reddy, Sakamuri V

    2010-05-15

    Oral squamous cell carcinomas (OSCC) are malignant tumors with a potent activity of local bone invasion; however, the molecular mechanisms of tumor osteolysis are unclear. In this study, we identified high level expression of chemokine ligand, CXCL13 and RANK ligand (RANKL) in OSCC cells (SCC1, SCC12 and SCC14a). OSCC cell-conditioned media (20%) induced osteoclast differentiation which was inhibited by OPG in peripheral blood monocyte cultures indicating that OSCC cells produce soluble RANKL. Recombinant hCXCL13 (10 ng/ml) significantly enhanced RANKL-stimulated osteoclast differentiation in these cultures. Trans-well migration assay identified that CXCL13 induces chemotaxis of peripheral blood monocytes in vitro which was inhibited by addition of anti-CXCR5 receptor antibody. Zymogram analysis of conditioned media from OSCC cells revealed matrix metalloproteinase-9 (MMP-9) activity. Interestingly, CXCL13 treatment to OSCC cells induced CXCR5 and MMP-9 expression suggesting an autocrine regulatory function in OSCC cells. To examine the OSCC tumor cell bone invasion/osteolysis, we established an in vivo model for OSCC by subcutaneous injection of OSCC cells onto the surface of calvaria in NCr-nu/nu athymic mice, which developed tumors in 4-5 weeks. muCT analysis revealed numerous osteolytic lesions in calvaria from OSCC tumor-bearing mice. Histochemical staining of calvarial sections from these mice revealed a significant increase in the numbers of TRAP-positive osteoclasts at the tumor-bone interface. Immunohistochemical analysis confirmed CXCL13 and MMP-9 expression in tumor cells. Thus, our data implicate a functional role for CXCL13 in bone invasion and may be a potential therapeutic target to prevent osteolysis associated with OSCC tumors in vivo.

  20. Tumor hypoxia modulates podoplanin/CCL21 interactions in CCR7+ NK cell recruitment and CCR7+ tumor cell mobilization.

    Science.gov (United States)

    Tejchman, Anna; Lamerant-Fayel, Nathalie; Jacquinet, Jean-Claude; Bielawska-Pohl, Aleksandra; Mleczko-Sanecka, Katarzyna; Grillon, Catherine; Chouaib, Salem; Ugorski, Maciej; Kieda, Claudine

    2017-05-09

    Podoplanin (PDPN), an O-glycosylated, transmembrane, mucin-type glycoprotein, is expressed by cancer associated fibroblasts (CAFs). In malignant transformation, PDPN is subjected to changes and its role is yet to be established. Here we show that it is involved in modulating the activity of the CCL21/CCR7 chemokine/receptor axis in a hypoxia-dependent manner. In the present model, breast cancer MDA-MB-231 cells and NKL3 cells express the surface CCR7 receptor for CCL21 chemokine which is a potent chemoattractant able to bind to PDPN. The impact of the CCL21/CCR7 axis in the molecular mechanism of the adhesion of NKL3 cells and of MDA-MB-231 breast cancer cells was reduced in a hypoxic tumor environment. In addition to its known effect on migration, CCL21/CCR7 interaction was shown to allow NK cell adhesion to endothelial cells (ECs) and its reduction by hypoxia. A PDPN expressing model of CAFs made it possible to demonstrate the same CCL21/CCR7 axis involvement in the tumor cells to CAFs recognition mechanism through PDPN binding of CCL21. PDPN was induced by hypoxia and its overexpression undergoes a reduction of adhesion, making it an anti-adhesion molecule in the absence of CCL21, in the tumor. CCL21/CCR7 modulated NK cells/ECs and MDA-MB-231 cells/CAF PDPN-dependent interactions were further shown to be linked to hypoxia-dependent microRNAs as miRs: miR-210 and specifically miR-21, miR-29b which influence PDPN expression.

  1. Deregulation of a STAT3-IL8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness

    Science.gov (United States)

    de la Iglesia, Núria; Konopka, Genevieve; Lim, Kah Leong; Nutt, Catherine L.; Bromberg, Jacqueline F.; Frank, David A.; Mischel, Paul S.; Louis, David N.; Bonni, Azad

    2009-01-01

    Inactivation of the tumor suppressor PTEN is recognized as a major event in the pathogenesis of the brain tumor glioblastoma. However, the mechanisms by which PTEN loss specifically impacts the malignant behavior of glioblastoma cells including their proliferation and propensity for invasiveness remain poorly understood. Genetic studies suggest that the transcription factor STAT3 harbors a PTEN-regulated tumor suppressive function in mouse astrocytes. Here, we report that STAT3 plays a critical tumor suppressive role in PTEN-deficient human glioblastoma cells. Endogenous STAT3 signaling is specifically inhibited in PTEN-deficient glioblastoma cells. Strikingly, reactivation of STAT3 in PTEN-deficient glioblastoma cells inhibits their proliferation, invasiveness, and ability to spread on myelin. We also identify the chemokine IL8 as a novel target gene of STAT3 in human glioblastoma cells. Activated STAT3 occupies the endogenous IL8 promoter and directly represses IL8 transcription. Consistent with these results, IL8 is upregulated in PTEN-deficient human glioblastoma tumors. Importantly, IL8 repression mediates STAT3-inhibition of glioblastoma cell proliferation, invasiveness, and spreading on myelin. Collectively, our findings uncover a novel link between STAT3 and IL8 whose deregulation plays a key role in the malignant behavior of PTEN-deficient glioblastoma cells. These studies suggest that STAT3 activation or IL8 inhibition may have potential in patient-tailored treatment of PTEN-deficient brain tumors. PMID:18524891

  2. MicroRNA-103 Promotes Colorectal Cancer by Targeting Tumor Suppressor DICER and PTEN

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    Li Geng

    2014-05-01

    Full Text Available MicroRNAs (miRNAs are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms for miRNAs in colorectal cancer remain largely unknown. Here, we found that miR-103 is up-regulated in colorectal cancer and its overexpression is closely associated with tumor proliferation and migration. In addition, repressing the expression of miR-103 apparently inhibits colorectal cancer cell proliferation and migration in vitro and HCT-116 xenograft tumor growth in vivo. Subsequent software analysis and dual-luciferase reporter assay identified two tumor suppressor genes DICER and PTEN as direct targets of miR-103, and up-regulation of DICER and PTEN obtained similar results to that occurred in the silencing of miR-103. In addition, restoration of DICER and PTEN can inhibit miR-103-induced colorectal cancer cell proliferation and migration. Our data collectively demonstrate that miR-103 is an oncogene miRNA that promotes colorectal cancer proliferation and migration through down-regulation of the tumor suppressor genes DICER and PTEN. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for colorectal cancer treatment.

  3. Chemokine Ligand 5 (CCL5 and chemokine receptor (CCR5 genetic variants and prostate cancer risk among men of African Descent: a case-control study

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    Kidd LaCreis R

    2012-11-01

    Full Text Available Abstract Background Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs are associated with various cancers, their impact on prostate cancer (PCA among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Methods Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls using Illumina’s Goldengate genotyping system. Results Inheritance of CCL5 rs2107538 (AA, GA+AA and rs3817655 (AA, AG, AG+AA genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. Conclusions In summary, CCL5 (rs2107538, rs3817655 and CCR5 (rs1799988 sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.

  4. Identification and expression analysis of an atypical chemokine receptor-2 (ACKR2)/CC chemokine binding protein-2 (CCBP2) in rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Qi, Zhitao; Jiang, Yousheng; Holland, Jason W; Nie, Pin; Secombes, Christopher J; Wang, Tiehui

    2015-06-01

    Atypical chemokine receptors (ACKRs) have emerged as key components of the chemokine system, with an essential regulatory function in innate and adaptive immune responses and inflammation. In mammals ACKR2 is a 'scavenging' receptor for inflammatory CC chemokines and plays a central role in the resolution of in vivo inflammatory responses. An ACKR2 like gene has been identified and cloned in rainbow trout (Teleostei) in the present study, enabling the further identification of this molecule in another group of ray-finned teleost fish (Holostei), in a lobe-finned fish (Sarcopterygii-coelacanth), and in reptiles. The identity of these ACKR2 molecules is supported by their conserved structure, and by phylogenetic tree and synteny analysis. Trout ACKR2 is highly expressed in spleen and head kidney, suggesting a homeostatic role of this receptor in limiting the availability of its potential ligands. Trout ACKR2 expression can be modulated in vivo by bacterial and parasitic infections, and in vitro by PAMPs (poly I:C and peptidoglycan) and cytokines (IL-6, TNF-α, IFN-γ and IL-21) in a time dependent manner. These patterns of expression and modulation suggest that trout ACKR2 is regulated in a complex way and has an important role in control of the chemokine network in fish as in mammals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Furin is a chemokine-modifying enzyme

    DEFF Research Database (Denmark)

    Hensbergen, Paul J; Verzijl, Dennis; Balog, Crina I A

    2004-01-01

    Chemokines comprise a class of structurally related proteins that are involved in many aspects of leukocyte migration under basal and inflammatory conditions. In addition to the large number of genes, limited processing of these proteins by a variety of enzymes enhances the complexity of the tota...

  6. Chronic alcohol intake promotes tumor growth in a diethylnitrosamine-induced hepatocarcinogenesis mouse model through increased Wnt/Beta-catenin signaling

    Science.gov (United States)

    Ethanol (EtOH) metabolism is involved in both initiating and promoting mechanisms in hepatocellular carcinoma progression in chronic alcoholics. In this study, we developed a mouse model to test the hypothesis that chronic EtOH consumption promotes tumor growth irrespective of EtOH-related initiati...

  7. Effects of chemokine (C–C motif) ligand 1 on microglial function

    International Nuclear Information System (INIS)

    Akimoto, Nozomi; Ifuku, Masataka; Mori, Yuki; Noda, Mami

    2013-01-01

    Highlights: •CCR8, a specific receptor for CCL-1, was expressed on primary cultured microglia. •Expression of CCR-8 in microglia was upregulated in the presence of CCL-1. •CCL-1 increased motility, proliferation and phagocytosis of cultured microglia. •CCL-1promoted BDNF and IL-6 mRNA, and the release of NO from microglia. •CCL-1 activates microglia and may contribute to the development of neuropathic pain. -- Abstract: Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C–C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain

  8. Effects of chemokine (C–C motif) ligand 1 on microglial function

    Energy Technology Data Exchange (ETDEWEB)

    Akimoto, Nozomi [Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Ifuku, Masataka [Laboratory of Integrative Physiology, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Mori, Yuki [Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Noda, Mami, E-mail: noda@phar.kyushu-u.ac.jp [Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2013-07-05

    Highlights: •CCR8, a specific receptor for CCL-1, was expressed on primary cultured microglia. •Expression of CCR-8 in microglia was upregulated in the presence of CCL-1. •CCL-1 increased motility, proliferation and phagocytosis of cultured microglia. •CCL-1promoted BDNF and IL-6 mRNA, and the release of NO from microglia. •CCL-1 activates microglia and may contribute to the development of neuropathic pain. -- Abstract: Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C–C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain.

  9. Cysteine cathepsins B and X promote epithelial-mesenchymal transition of tumor cells.

    Science.gov (United States)

    Mitrović, Ana; Pečar Fonović, Urša; Kos, Janko

    2017-09-01

    Cathepsins B and X are lysosomal cysteine carboxypeptidases suggested as having a redundant role in cancer. They are involved in a number of processes leading to tumor progression but their role in the epithelial-mesenchymal transition (EMT) remains unknown. We have investigated the contribution of both cathepsins B and X in EMT using tumor cell lines differing in their expression of epithelial and mesenchymal markers and cell morphology. Higher levels of both cathepsins are shown to promote EMT and are associated with the mesenchymal-like cell phenotype. Moreover, simultaneous knockdown of the two peptidases triggers a reverse, mesenchymal to epithelial transition. Of the two cathepsins, cathepsin B appears to be the stronger promotor of EMT. Furthermore, we evaluated the involvement of cathepsin B and X in the transforming growth factor-β1 (TGF-β1) signaling pathway, one of the key signaling mechanisms triggering EMT in cancer. In MCF-7 cells the expression of cathepsin B was shown to depend on their activation with TGF-β1 while, for cathepsin X, a TGF-β1 independent mechanism of induction during EMT is indicated. EMT is thus shown to be another mechanism linking cathepsins B and X with tumor progression. With silencing of their expression or inhibition of enzymatic activity, the tumor cells could be reverted to less aggressive epithelial-like phenotype. Copyright © 2017 Elsevier GmbH. All rights reserved.

  10. Promoter hypermethylation of KLF4 inactivates its tumor suppressor function in cervical carcinogenesis.

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    Wen-Ting Yang

    Full Text Available OBJECTIVE: The KLF4 gene has been shown to be inactivated in cervical carcinogenesis as a tumor suppressor. However, the mechanism of KLF4 silencing in cervical carcinomas has not yet been identified. DNA methylation plays a key role in stable suppression of gene expression. METHODS: The methylation status of the KLF4 promoter CpG islands was analyzed by bisulfite sequencing (BSQ in tissues of normal cervix and cervical cancer. KLF4 gene expression was detected by RT-PCR, immunohistochemistry and western blot. KLF4 promoter methylation in cervical cancer cell line was determined by BSQ and methylation-specific polymerase chain reaction (MS-PCR. Cell proliferation ability was detected by cell growth curve and MTT assay. RESULTS: The methylated allele was found in 41.90% of 24 cervical cancer tissues but only in 11.11% of 11 normal cervix tissues (P<0.005. KLF4 mRNA levels were significantly reduced in cervical cancer tissues compared with normal cervix tissues (P<0.01 and KLF4 mRNA expression showed a significant negative correlation with the promoter hypermethylation (r = -0.486, P = 0.003. Cervical cancer cell lines also showed a significant negative correlation between KLF4 expression and hypermethylation. After treatment with the demethylating agent 5-Azacytidine (5-Aza, the expression of KLF4 in the cervical cancer cell lines at both mRNA and protein levels was drastically increased, the cell proliferation ability was inhibited and the chemosensitivity for cisplatin was significantly increased. CONCLUSION: KLF4 gene is inactivated by methylation-induced silencing mechanisms in a large subset of cervical carcinomas and KLF4 promoter hypermethylation inactivates the gene's function as a tumor suppressor in cervical carcinogenesis.

  11. Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy

    Directory of Open Access Journals (Sweden)

    Carlos Rosas

    2014-01-01

    Full Text Available BACKGROUND: During the last few years it has been shown in several laboratories that Celecoxib (Cx, a non-steroidal anti-inflammatory agent (NSAID normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant to chemotherapeutical drugs used in cancer have not been described. Herein we evaluate the angiogenic and antitumor effects of Cx in the development of a drug-resistant mammary adenocarcinoma tumor (TA3-MTXR. RESULTS: Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM, inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF production and cell proliferation in the tumor. CONCLUSION: The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects.

  12. Urine chemokines indicate pathogenic association of obesity with BPH/LUTS.

    Science.gov (United States)

    Tyagi, Pradeep; Motley, Saundra S; Kashyap, Mahendra; Pore, Subrata; Gingrich, Jeffrey; Wang, Zhou; Yoshimura, Naoki; Fowke, Jay H

    2015-07-01

    High prevalence of lower urinary tract symptoms (LUTS) consistent with benign prostate hyperplasia (BPH) is associated with obesity and prostatic inflammation. Here, we investigated whether chemokines associated with obesity and prostatic inflammation can be measured in normally voided urine of BPH/LUTS patients to demonstrate the mechanistic association between obesity and BPH/LUTS. Frozen urine specimens of BPH/LUTS patients enrolled in the Nashville Men's Health Study were sent for blinded analysis to University of Pittsburgh. Thirty patients were blocked by their AUA-SI (>7 or ≤7) and prostatic enlargement (60 cc). Clinical parameters including age, prostate size, and medications were derived from chart review. CXC chemokines (CXCL-1, CXCL-8, and CXCL-10), CC chemokines (CCL2 and CCL3), and sIL-1ra were measured in thawed urine using Luminex™ xMAP(®) technology and ELISA for NGF. Urinary CCL2 levels were several fold higher compared with the other six proteins, of which CCL3 was detectable in less than one-fourth of patients. Urine levels of sIL-1ra and CXCL-8 were significantly associated with increasing BMI and waist circumference in BPH patients. CXCL-8 showed a marginal association with overall AUA-SI scores, as well as obstructive (p = 0.08) symptom subscores. Prostate volume was inversely and marginally associated with urinary CXCL-10 (p = 0.09). Urine levels of CXCL-8, CXCL-10, and sIL-1ra were associated with varying degrees with LUTS severity, prostate size, and obesity, respectively. These findings in urine are consistent with past studies of chemokine levels from expressed prostatic secretions and demonstrate the potential of noninvasively measured chemokine in urine to objectively classify BPH/LUTS patients.

  13. In vitro and in vivo dependency of chemokine generation on C5a and TNF-alpha

    DEFF Research Database (Denmark)

    Czermak, B J; Sarma, V; Bless, N M

    1999-01-01

    production in vitro and in vivo. Two rat CXC chemokines (macrophage inflammatory protein (MIP)-2 and cytokine-induced neutrophil chemoattractant (CINC)) as well as three rat CC chemokines (MIP-1alpha, MIP-1beta, and monocyte chemoattractant protein (MCP)-1) were investigated. Chemokine generation in vitro...

  14. MicroRNA-219-5p Promotes Tumor Growth and Metastasis of Hepatocellular Carcinoma by Regulating Cadherin 1

    Directory of Open Access Journals (Sweden)

    Jing Yang

    2018-01-01

    Full Text Available MicroRNAs play significant roles in the development of cancer and may serve as promising therapeutic targets. In our previous work, miR-219-5p was identified as one of the important metastasis-related microRNAs in HCC. Here we demonstrated that miR-219-5p expression was elevated in HCC tissues and was associated with vascular invasion and dismal prognosis. In multivariate analysis, miR-219-5p was identified as an independent prognostic indicator for HCC patients. Functional mechanism analyses showed that miR-219-5p promoted HCC cell proliferation and invasion in in vitro, as well as in vivo, tumor growth and metastasis in nude mice models bearing human HCC tumors. In addition, cadherin 1 (CDH1 was revealed to be a downstream target of miR-219-5p in HCC cells. In conclusion, miR-219-5p promotes tumor growth and metastasis of HCC by regulating CDH1 and can serve as a prognostic marker for HCC patients.

  15. ΔNp63α induces the expression of FAT2 and Slug to promote tumor invasion

    Science.gov (United States)

    Dang, Tuyen T.; Westcott, Jill M.; Maine, Erin A.; Kanchwala, Mohammed; Xing, Chao; Pearson, Gray W.

    2016-01-01

    Tumor invasion can be induced by changes in gene expression that alter cell phenotype. The transcription factor ΔNp63α promotes basal-like breast cancer (BLBC) migration by inducing the expression of the mesenchymal genes Slug and Axl, which confers cells with a hybrid epithelial/mesenchymal state. However, the extent of the ΔNp63α regulated genes that support invasive behavior is not known. Here, using gene expression analysis, ChIP-seq, and functional testing, we find that ΔNp63α promotes BLBC motility by inducing the expression of the atypical cadherin FAT2, the vesicular binding protein SNCA, the carbonic anhydrase CA12, the lipid binding protein CPNE8 and the kinase NEK1, along with Slug and Axl. Notably, lung squamous cell carcinoma migration also required ΔNp63α dependent FAT2 and Slug expression, demonstrating that ΔNp63α promotes migration in multiple tumor types by inducing mesenchymal and non-mesenchymal genes. ΔNp63α activation of FAT2 and Slug influenced E-cadherin localization to cell-cell contacts, which can restrict spontaneous cell movement. Moreover, live-imaging of spheroids in organotypic culture demonstrated that ΔNp63α, FAT2 and Slug were essential for the extension of cellular protrusions that initiate collective invasion. Importantly, ΔNp63α is co-expressed with FAT2 and Slug in patient tumors and the elevated expression of ΔNp63α, FAT2 and Slug correlated with poor patient outcome. Together, these results reveal how ΔNp63α promotes cell migration by directly inducing the expression of a cohort of genes with distinct cellular functions and suggest that FAT2 is a new regulator of collective invasion that may influence patient outcome. PMID:27081041

  16. Onbaekwon Suppresses Colon Cancer Cell Invasion by Inhibiting Expression of the CXC Chemokine Receptor 4.

    Science.gov (United States)

    Kim, Buyun; Yoon, Jaewoo; Yoon, Seong Woo; Park, Byoungduck

    2017-06-01

    Cysteine X cysteine (CXC) chemokine receptor 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) were originally identified as chemoattractants between immune cells and sites of inflammation. Since studies have validated an increased level of CXCL12 and its receptor in patients with colorectal cancers, CXCL12/CXCR4 axis has been considered as a valuable marker of cancer metastasis. Therefore, identification of CXCR4 inhibitors has great potential to abrogate tumor metastasis. Onbaekwon (OBW) is a complex herbal formula that is derived from the literature of traditional Korean medicine Dongeuibogam. In this study, we demonstrated that OBW suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasomal and lysosomal inhibitors had no effect to prevent the OBW-induced suppression of CXCR4, suggesting that the inhibitory effect of OBW was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay further confirmed that OBW could block endogenous activation of nuclear factor kappa B, a key transcription factor that regulates the expression of CXCR4 in colon cancer cells. Consistent with the aforementioned molecular basis, OBW abolished cell invasion induced by CXCL12 in colon cancer cells. Together, our results suggest that OBW, as a novel inhibitor of CXCR4, could be a promising therapeutic agent contributing to cancer treatment.

  17. Targeting Spare CC Chemokine Receptor 5 (CCR5) as a Principle to Inhibit HIV-1 Entry*

    OpenAIRE

    Jin, Jun; Colin, Philippe; Staropoli, Isabelle; Lima-Fernandes, Evelyne; Ferret, Cécile; Demir, Arzu; Rogée, Sophie; Hartley, Oliver; Randriamampita, Clotilde; Scott, Mark G. H.; Marullo, Stefano; Sauvonnet, Nathalie; Arenzana-Seisdedos, Fernando; Lagane, Bernard; Brelot, Anne

    2014-01-01

    International audience; : CCR5 binds the chemokines CCL3, CCL4, and CCL5 and is the major coreceptor for HIV-1 entry into target cells. Chemokines are supposed to form a natural barrier against human immunodeficiency virus, type 1 (HIV-1) infection. However, we showed that their antiviral activity is limited by CCR5 adopting low-chemokine affinity conformations at the cell surface. Here, we investigated whether a pool of CCR5 that is not stabilized by chemokines could represent a target for i...

  18. Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna Brink; Grove, Jakob

    2012-01-01

    Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls.......Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls....

  19. Candidate Tumor-Suppressor Gene DLEC1 Is Frequently Downregulated by Promoter Hypermethylation and Histone Hypoacetylation in Human Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Joseph Kwong

    2006-04-01

    Full Text Available Suppression of ovarian tumor growth by chromosome 3p was demonstrated in a previous study. Deleted in Lung and Esophageal Cancer 1 (DLEC1 on 3p22.3 is a candidate tumor suppressor in lung, esophageal, and renal cancers. The potential involvement of DLEC1 in epithelial ovarian cancer remains unknown. In the present study, DLEC1 downregulation was found in ovarian cancer cell lines and primary ovarian tumors. Focus-expressed DLEC1 in two ovarian cancer cell lines resulted in 41% to 52% inhibition of colony formation. No chromosomal loss of chromosome 3p22.3 in any ovarian cancer cell line or tissue was found. Promoter hypermethylation of DLEC1 was detected in ovarian cancer cell lines with reduced DLEC1 transcripts, whereas methylation was not detected in normal ovarian epithelium and DLEC1-expressing ovarian cancer cell lines. Treatment with demethylating agent enhanced DLEC1 expression in 90% (9 of 10 of ovarian cancer cell lines. DLEC1 promoter methylation was examined in 13 high-grade ovarian tumor tissues with DLEC1 downregulation, in which 54% of the tumors showed DLEC1 methylation. In addition, 80% of ovarian cancer cell lines significantly upregulated DLEC1 transcripts after histone deacetylase inhibitor treatment. Therefore, our results suggested that DLEC1 suppressed the growth of ovarian cancer cells and that its downregulation was closely associated with promoter hypermethylation and histone hypoacetylation.

  20. Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Carmen J. Marsit

    2008-01-01

    Full Text Available Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC, but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  1. The prognostic value of CXC-chemokine receptor 2 (CXCR2) in gastric cancer patients

    International Nuclear Information System (INIS)

    Wang, Zhenglin; Liu, Hao; Shen, Zhenbin; Wang, Xuefei; Zhang, Heng; Qin, Jing; Xu, Jiejie; Sun, Yihong; Qin, Xinyu

    2015-01-01

    CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells. The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection. Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center. CXCR2 expression levels were correlated to clinicopathological variables and OS. CXCR2 expression was mainly located in the cytoplasm of gastric carcinoma cells. High CXCR2 expression was associated with poor tumor differentiation (p = 0.021), increased tumor depth (p < 0.001), lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001) and short OS (p = 0.001). CXCR2 expression was an independent prognostic factor for OS (p = 0.001) in multivariate analysis, and could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with gastric cancer. Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients. CXCR2 might be a promising therapeutic target of postoperative adjuvant treatment. The online version of this article (doi:10.1186/s12885-015-1793-9) contains supplementary material, which is available to authorized users

  2. [Multi-channel promotion of lung cancer progress by bone marrow derived mesenchymal stem cells in tumor microenvironment].

    Science.gov (United States)

    Luo, D; Hu, S Y; Liu, G X

    2018-02-23

    Objective: To observe the growth and metastasis of lung cancer promoted by bone marrow derived mesenchymal stem cells (BMSCs) in tumor microenvironment and investigate the underlined mechanisms. Methods: Specific chemotaxis of BMSCs towards lung cancer was observed, and the tumor growth and metastasis were assessed in vivo . Furthermore, CD34 expression determined by immunohistochemistry was used to assess the microvessel density (MVD), and the expressions of GFP and α-SMA determined by immunofluorescence were used to detect the BMSCs derived mesenchymal cells. We investigated the effect of BMSCs on migration, invasion of lung cancer cells including A549 and H446 cells by using scratch assays and Transwell Assay in vitro. We also explored the effect of BMSCs on epithelial mesenchymal transition of A549 and H446 cells by observing the phenotype transition and E-Cadherin protein expression detected by Western blot. At last, we screened the potentially key soluble factors by enzyme linked immunosorbent assay (ELISA). Results: In NOD mice, labeled BMSCs injected via tail vein were special chemotaxis to tumor cells, and promoted the tumor growth [the time of tumor formation in A549+ BMSCs and A549 alone was (5.0±1.5) days and (10.0±3.6) days, respectively, P cell carcinoma and promoted the migration and invasion of lung cancer cells (the A of cells in the migrated lower chambers of A549+ BMSCs and A549 alone was 1.9±0.2 and 1.1±0.1, respectively, P cells in the migrated lower chambers of H446+ BMSCs and H446 alone was 1.9±0.3 and 0.9±0.2, respectively, P cell shape was longer and sharper, the intercellular junctions were reduced and the relative expression level of E-Cadherin protein in A549 co-cultured with BMDCs was 0.36, significantly down-regulated when compared to 0.55 of A549 alone ( P cells alone ( P <0.05). The concentration of IL-6 in the conditional medium of BMSCs, A549 co-cultured with BMSCs and H446 co-cultured with BMSCs was 910.5, 957.2, and 963

  3. Internal radiotherapy of liver cancer with rat hepato-carcinoma-intestine-pancreas gene as a liver tumor-specific promoter

    Energy Technology Data Exchange (ETDEWEB)

    Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J. [Hop Paul Brousse, INSERM, Hepatobiliary Ctr, U785, F-94800 Villejuif (France); Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J. [Univ Paris Sud, Fac Med, F-94800 Villejuif (France); Boisgard, R.; Tavitian, B. [INSERM, U803, F-91400 Orsay (France); Boisgard, R.; Tavitian, B. [CEA, Serv Hosp Frederic Joliot, Lab Imagerie Mol Expt, F-91400 Orsay (France); Roux, J.; Cales, P. [Univ Angers, UPRES EA 3859, Lab Hemodynam Interact Fibrose et Invas Tumorale H, Angers (France); Clerc, J. [Hop Cochin, AP HP, Dept Nucl Med, F-75014 Paris (France)

    2008-07-01

    The hepato-carcinoma-intestine-pancreas (HIP) gene, also called pancreatitis-associated protein-1 (PAP1) or Reg III {alpha}, is activated in most human hepatocellular carcinomas (HCCs) but not in normal liver, which suggests that HIP regulatory sequence could be used as efficient liver tumor-specific promoters to express a therapeutic polynucleotide in liver cancer. The sodium iodide sym-porter (NIS), which has recognized therapeutic and reporter gene properties, is appropriate to evaluate the transcriptional strength and specificity of the HIP promoter in HCC. For this purpose, we constructed a recombinant rat HIP-NIS adeno-viral vector (AdrHIP-NIS), and evaluated its performance as a mediator of selective radio-iodide uptake in tumor hepatocytes. Western blot, immunofluorescence, and iodide uptake assays were performed in AdrHIP-NIS-infected primary hepatocytes and transformed hepatic and non-hepatic cells. Nuclear imaging, tissue counting and immuno-histo-chemistry were performed in normal and HCC-bearing Wistar rats infected with AdrHIP-NIS intra-tumorally or via the hepatic artery. In AdrHIP-NIS-infected transformed hepatic cells, functional NIS was strongly expressed, as in cells infected with a cytomegalovirus-NIS vector. No NIS expression was found in AdrHIP-NIS-infected normal hepatocytes or transformed non-hepatic cells. In rats bearing multi-nodular HCC, AdrHIP-NIS triggered functional NIS expression that was preferential in tumor hepatocytes. Administration of 18 mCi of {sup 131}I resulted in the destruction of AdrHIP-NIS-injected nodules. This study has identified the rHIP regulatory sequence as a potent liver tumor-specific promoter for the transfer of therapeutic genes, and AdrHIP-NIS-mediated. {sup 131}I therapy as a valuable option for the treatment of multi-nodular HCC. (authors)

  4. Internal radiotherapy of liver cancer with rat hepato-carcinoma-intestine-pancreas gene as a liver tumor-specific promoter

    International Nuclear Information System (INIS)

    Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J.; Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J.; Boisgard, R.; Tavitian, B.; Boisgard, R.; Tavitian, B.; Roux, J.; Cales, P.; Clerc, J.

    2008-01-01

    The hepato-carcinoma-intestine-pancreas (HIP) gene, also called pancreatitis-associated protein-1 (PAP1) or Reg III α, is activated in most human hepatocellular carcinomas (HCCs) but not in normal liver, which suggests that HIP regulatory sequence could be used as efficient liver tumor-specific promoters to express a therapeutic polynucleotide in liver cancer. The sodium iodide sym-porter (NIS), which has recognized therapeutic and reporter gene properties, is appropriate to evaluate the transcriptional strength and specificity of the HIP promoter in HCC. For this purpose, we constructed a recombinant rat HIP-NIS adeno-viral vector (AdrHIP-NIS), and evaluated its performance as a mediator of selective radio-iodide uptake in tumor hepatocytes. Western blot, immunofluorescence, and iodide uptake assays were performed in AdrHIP-NIS-infected primary hepatocytes and transformed hepatic and non-hepatic cells. Nuclear imaging, tissue counting and immuno-histo-chemistry were performed in normal and HCC-bearing Wistar rats infected with AdrHIP-NIS intra-tumorally or via the hepatic artery. In AdrHIP-NIS-infected transformed hepatic cells, functional NIS was strongly expressed, as in cells infected with a cytomegalovirus-NIS vector. No NIS expression was found in AdrHIP-NIS-infected normal hepatocytes or transformed non-hepatic cells. In rats bearing multi-nodular HCC, AdrHIP-NIS triggered functional NIS expression that was preferential in tumor hepatocytes. Administration of 18 mCi of 131 I resulted in the destruction of AdrHIP-NIS-injected nodules. This study has identified the rHIP regulatory sequence as a potent liver tumor-specific promoter for the transfer of therapeutic genes, and AdrHIP-NIS-mediated. 131 I therapy as a valuable option for the treatment of multi-nodular HCC. (authors)

  5. Transfection of tumor-infiltrating T cells with mRNA encoding CXCR2

    DEFF Research Database (Denmark)

    Idorn, Manja; thor Straten, Eivind Per; Svane, Inge Marie

    2016-01-01

    Adoptive T-cell therapy based on the infusion of patient’s own immune cells after ex vivo culturing is among the most potent forms of personalized treatment among recent clinical developments for the treatment of cancer. However, despite high rates of successful initial clinical responses, only...... infused T cells migrating to the tumor and the clinical response, but also that only a small fraction of adoptively transferred Tcells reach the tumor site. In this chapter, we describe a protocol for transfection of TILs with mRNA encoding the chemokine receptor CXCR2 transiently redirecting...

  6. Preparation of C-terminally modified chemokines by expressed protein ligation.

    Science.gov (United States)

    Baumann, Lars; Steinhagen, Max; Beck-Sickinger, Annette G

    2013-01-01

    In order to link structural features on a molecular level to the function of chemokines, site-specific modification strategies are strongly required. These can be used to incorporate fluorescent dyes and/or physical probes to allow investigations in a wide range of biological and physical techniques, e.g., nuclear magnetic resonance (NMR) spectroscopy, fluorescence microscopy, fluorescence resonance energy transfer (FRET), or fluorescence correlation spectroscopy (FCS). Only a limited number of functional groups within the 20 canonical amino acids allow ligation strategies that can be helpful to introduce novel functionalities, which in turn expand the scope of chemoselective and orthogonal reactivity of (semi)synthetic chemokines. In the present chapter we mainly focus on the fabulous history of native chemical ligation (NCL) and provide a general protocol for the preparation of C-terminally modified SDF-1α including tips and tricks for practical work. We believe that this protocol can be easily adapted to other chemokines and many proteins in general.

  7. Role of atypical chemokine receptor ACKR2 in experimental oral squamous cell carcinogenesis.

    Science.gov (United States)

    da Silva, Janine Mayra; Dos Santos, Tálita Pollyanna Moreira; Saraiva, Adriana Machado; Fernandes de Oliveira, Ana Laura; Garlet, Gustavo Pompermaier; Batista, Aline Carvalho; de Mesquita, Ricardo Alves; Russo, Remo Castro; da Silva, Tarcília Aparecida

    2018-03-14

    Chemokines and chemokine receptors are critical in oral tumourigenesis. The atypical chemokine receptor ACKR2 is a scavenger of CC chemokines controlling the availability of these molecules at tumour sites, but the role of ACKR2 in the context of oral carcinogenesis is unexplored. In this study, wild-type (WT) and ACKR2 deficient mice (ACKR2 -/- ) were treated with chemical carcinogen 4-nitroquinoline-1-oxide (4NQO) for induction of oral carcinogenesis. Tongues were collected for macro and microscopic analysis and to evaluate the expression of ACKRs, CC chemokines and its receptors, inflammatory cytokines, angiogenic factors, adhesion molecules and extracellular matrix components. An increased expression of ACKR2 in squamous cell carcinoma (SCC) lesions of 4NQO-treated WT mice was observed. No significant differences were seen in the ACKR1, ACKR3 and ACKR4 mRNA expression comparing SCC lesions from WT and ACKR2 -/- treated mice. Significantly higher expression of CCL2, IL-6 and IL-17 was detected in ACKR2 -/- treated mice. In contrast, the expression of other CC-chemokines, and receptors, angiogenic factors, adhesion molecules and extracellular matrix components were similarly increased in SCC lesions of both groups. Clinical and histopathological analysis revealed no differences in inflammatory cell recruitment and in the SCC incidence comparing WT and ACKR2 -/- treated mice. The results suggest that ACKR2 expression regulates inflammation in tumour-microenvironment but the absence of ACKR2 does not impact chemically-induced oral carcinogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Molecular mechanisms of drug resistance and tumor promotion involving mammalian ribonucleotide reductase

    Energy Technology Data Exchange (ETDEWEB)

    Choy, B.B.K.

    1991-01-01

    Mammalian ribonucleotide reductase is a highly regulated, rate-limiting activity responsible for converting ribonucleoside diphosphates to the deoxyribonucleotide precursors of DNA. The enzyme consists of two nonidentical proteins called M1 and M2, both of which are required for activity. Hydroxyurea is an antitumor agent which inhibits ribonucleotide reductase by interacting with the M2 component specifically at a unique tyrosyl free radical. Studies were conducted on a series of drug resistant mouse cell lines, selected by a step-wise procedure for increasing levels of resistance to the cytotoxic effects of hydroxyurea. Each successive drug selection step leading to the isolation of highly resistant cells was accompanied by stable elevations in cellular resistance and ribonucleotide reductase activity. The drug resistant cell lines exhibited gene amplification of the M2 gene, elevated M2 mRNA, and M2 protein. In addition to M2 gene amplification, posttranscriptional modulation also occurred during the drug selection. Studies of the biosynthesis rates with exogenously added iron suggest a role for iron in regulating the level of M2 protein when cells are cultured in the presence of hydroxyurea. The hydroxyurea-inactivated ribonucleotide reductase protein M2 has a destabilized iron centre, which readily releases iron. Altered expression of ferritin appears to be required for the development of hydroxyurea resistance in nammalian cells. The results show an interesting relationship between the expressions of ribonucleotide reductase and ferritin. The phorbol ester tumor promoter, TPA, is also able to alter the expression of M2. TPA was able to induce M2 mRNA levels transiently up to 18-fold within 1/2 hour. This rapid and large elevation of ribonucleotide reductase suggests that the enzyme may play a role in tumor promotion. Studies of the M2 promoter region were undertaken to better understand the mechanism of TPA induction of M2.

  9. Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors.

    Science.gov (United States)

    Levine, A Joan; Phipps, Amanda I; Baron, John A; Buchanan, Daniel D; Ahnen, Dennis J; Cohen, Stacey A; Lindor, Noralane M; Newcomb, Polly A; Rosty, Christophe; Haile, Robert W; Laird, Peter W; Weisenberger, Daniel J

    2016-01-01

    The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31-0.82). These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. MLH1 DNA methylation status should be taken into account in etiologic studies. ©2015 American Association for Cancer Research.

  10. Clinicopathological risk factor distributions for MLH1 promoter region methylation in CIMP positive tumors

    Science.gov (United States)

    Levine, A. Joan; Phipps, Amanda I.; Baron, John A.; Buchanan, Daniel D.; Ahnen, Dennis J.; Cohen, Stacey A.; Lindor, Noralane M.; Newcomb, Polly A.; Rosty, Christophe; Haile, Robert W.; Laird, Peter W.; Weisenberger, Daniel J.

    2015-01-01

    Background The CpG Island Methylator Phenotype (CIMP) is a major molecular pathway in colorectal cancer (CRC). Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. Methods We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations and family CRC history with MLH1 methylation status in a large population-based sample of CIMP-positive CRCs defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Results Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR=0.50; 95% Confidence Interval (0.31, 0.82)). Conclusions These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. Impact MLH1 DNA methylation status should be taken into account in etiologic studies. PMID:26512054

  11. Processing of natural and recombinant CXCR3-targeting chemokines and implications for biological activity.

    Science.gov (United States)

    Hensbergen, P J; van der Raaij-Helmer, E M; Dijkman, R; van der Schors, R C; Werner-Felmayer, G; Boorsma, D M; Scheper, R J; Willemze, R; Tensen, C P

    2001-09-01

    Chemokines comprise a class of peptides with chemotactic activity towards leukocytes. The potency of different chemokines for the same receptor often varies as a result of differences in primary structure. In addition, post-translational modifications have been shown to affect the effectiveness of chemokines. Although in several studies, natural CXCR3-targeting chemokines have been isolated, detailed information about the proteins and their possible modifications is lacking. Using a combination of liquid chromatography and mass spectrometry we studied the protein profile of CXCR3-targeting chemokines expressed by interferon-gamma-stimulated human keratinocytes. The biological implications of one of the identified modifications was studied in more detail using calcium mobilization and chemotaxis assays. We found that the primary structure of human CXCL10 is different from the generally accepted sequence. In addition we identified a C-terminally truncated CXCL10, lacking the last four amino acids. Native CXCL11 was primarily found in its intact mature form but we also found a mass corresponding to an N-terminally truncated human CXCL11, lacking the first two amino acids FP, indicating that this chemokine is a substrate for dipeptidylpeptidase IV. Interestingly, this same truncation was found when we expressed human CXCL11 in Drosophila S2 cells. The biological activity of this truncated form of CXCL11 was greatly reduced, both in calcium mobilization (using CXCR3 expressing CHO cells) as well as its chemotactic activity for CXCR3-expressing T-cells. It is concluded that detailed information on chemokines at the protein level is important to characterize the exact profile of these chemotactic peptides as modifications can severely alter their biological activity.

  12. Serum concentrations of chemokines (CCL-5 and CXCL-12), chemokine receptors (CCR-5 and CXCR-4), and IL-6 in patients with posttraumatic stress disorder and avoidant personality disorder.

    Science.gov (United States)

    Ogłodek, Ewa A; Szota, Anna M; Moś, Danuta M; Araszkiewicz, Aleksander; Szromek, Adam R

    2015-12-01

    Posttraumatic stress disorder (PTSD) can be perceived as a psychoneuroimmunological disorder in which cytokines affecting the neurochemical and neuroendocrine functions of the body play an important role. Among cytokines, chemokines participating in activation of the inflammatory response are considered to be crucial. 220 men and women were enrolled in the study. 180 of them constituted the study group. The studied groups consisted of: 60 patients with a diagnosed avoidant personality disorders (APD), 60 patients with a diagnosed APD and with PTSD and of 60 patients with PTSD but without a APD. There were 30 women and 30 men in each group of 60 subjects. The control group consisted of 40 healthy individuals. The plasma levels of chemokines and their receptors (CCL-5, CXCR-5, CXCL-12 and CXCR-4), as well as IL-6, were assessed by ELISA. There was an increase in the CXCL-12 and CCL-5 levels in women and men with the PTSD versus the control group. Also, increased levels of IL-6 and the receptors CXCR-4, CCR-5 were observed in women and men with PTSD. The levels of CXCL-12 and CCL-5 chemokines, as well as CCR-5 and CXCR4 receptors were higher in women than in men. The results of this study indicate a need for assessment of the CCL-5 and CXCL-12 chemokine levels, as they are likely markers of PTSD. Measurement of the concentrations of chemokines, chemokine receptors and IL-6 in women and men with PTSD along with concomittant APD may be useful for early detection of mental disorders. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  13. Chemokines: a new dendritic cell signal for T cell activation

    Directory of Open Access Journals (Sweden)

    Christoph A Thaiss

    2011-08-01

    Full Text Available Dendritic cells (DCs are the main inducers and regulators of cytotoxic T lymphocyte (CTL responses against viruses and tumors. One checkpoint to avoid misguided CTL activation, which might damage healthy cells of the body, is the necessity for multiple activation signals, involving both antigenic as well as additional signals that reflect the presence of pathogens. DCs provide both signals when activated by ligands of pattern recognition receptors and licensed by helper lymphocytes. Recently, it has been established that such T cell licensing can be facilitated by CD4+ T helper cells (classical licensing or by NKT cells (alternative licensing. Licensing regulates the DC/CTL cross-talk at multiple layers. Direct recruitment of CTLs through chemokines released by licensed DCs has recently emerged as a common theme and has a crucial impact on the efficiency of CTL responses. Here, we discuss recent advances in our understanding of DC licensing for cross-priming and implications for the temporal and spatial regulation underlying this process. Future vaccination strategies will benefit from a deeper insight into the mechanisms that govern CTL activation.

  14. Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization

    Directory of Open Access Journals (Sweden)

    Giulia Ottaviani

    2016-09-01

    Full Text Available Laser therapy, recently renamed as photobiomodulation, stands as a promising supportive treatment for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. Here we explored the anti-cancer effect of 3 laser protocols, set at the most commonly used wavelengths, in B16F10 melanoma and oral carcinogenesis mouse models. While laser light increased cell metabolism in cultured cells, the in vivo outcome was reduced tumor progression. This striking, unexpected result, was paralleled by the recruitment of immune cells, in particular T lymphocytes and dendritic cells, which secreted type I interferons. Laser light also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, an emerging strategy to control tumor progression. Collectively, these results set photobiomodulation as a safety procedure in oncological patients and open the way to its innovative use for cancer therapy.

  15. Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization.

    Science.gov (United States)

    Tsunoda, Satoshi; Nakamura, Toshiyuki; Sakurai, Hiroaki; Saiki, Ikuo

    2007-04-01

    Fibroblast growth factor (FGF)-2 has been considered to play a critical role in neovascularization in several tumors; however, its precise role in tumor progression is not fully understood. In the present study, we have characterized the role of FGF-2 in B16-BL6 mouse melanoma cells, focusing on effects during the initial phase of tumor growth. FGF-2 was injected at the tumor inoculation site of dorsal skin during the initial phase. FGF-2 induced marked tumor growth and lymph node metastasis. This was well correlated with an increase in neovascularization in the host stroma. FGF-2 also recruited inflammatory and mesenchymal cells in host stroma. Marked tumor growth, pulmonary metastasis and intensive neovascularization in tumor parenchyma were also observed after a single injection of FGF-2 into the footpad inoculation site. In contrast, repeated injections of FGF-2 at a site remote from the footpad tumor were ineffective in promoting tumor growth and metastasis. These promoting activities of FGF-2 were blocked by local injections of a glucocorticoid hormone, suggesting that host inflammatory responses induced by FGF-2 are associated with FGF-2-induced tumor progression. In addition, although FGF-2 did not promote cellular proliferation and vascular endothelial growth factor A (VEGFA) mRNA expression in B16-BL6 cells in vitro, FGF-2 induced VEGFA expression in host stroma rather than tumor tissue, and local injections of a neutralizing antibody against VEGFA inhibited these activities of FGF-2 in vivo. These results indicate that abundant FGF-2 during the initial phase of tumor growth induces VEGFA-dependent intensive neovascularization in host stroma, and supports marked tumor growth and metastasis.

  16. Anti-tumor effect of adenovirus-mediated suicide gene therapy under control of tumor-specific and radio-inducible chimeric promoter in combination with γ-ray irradiation in vivo

    International Nuclear Information System (INIS)

    Sun Wenjie; Yu Haijun; Xiongjie; Xu Yu; Liao Zhengkai; Zhou Fuxiang; Xie Conghua; Zhou Yunfeng

    2011-01-01

    Objective: To detect the selective inhibitory effects of irradiation plus adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic acid (IAA) suicide gene system using tumor-specific and radio-inducible chimeric promoter on human hepatocellular carcinoma subcutaneously xenografted in nude mouse. Methods: Recombinant replicated-deficient adenovirus vector containing HRP gene and chimeric human telomerase reverse transcriptase (hTERT) promoter carrying 6 radio-inducible CArG elements was constructed. A human subcutaneous transplanting hepatocellular carcinoma (MHCC97 cell line) model was treated with γ-ray irradiation plus intra-tumor injections of adenoviral vector and intra-peritoneal injections of prodrug IAA. The change of tumor volume and tumor growth inhibiting rate, the survival time of nude mice, as well as histopathology of xenograft tumor and normal tissues were evaluated. Results: Thirty one days after the treatment, the relative tumor volumes in the negative, adenovirus therapy, irradiation, and combination groups were 49.23±4.55, 27.71±7.74, 28.53±10.48 and 11.58±3.23, respectively.There was a significantly statistical difference among them (F=16.288, P<0.01).The inhibition effect in the combination group was strongest as compared with that in other groups, and its inhibition ratio was 76.5%. The survival period extended to 43 d in the combination group, which showed a significantly difference with that in the control group (χ 2 =18.307, P<0.01). The area of tumors necrosis in the combination group was larger than that in the other groups, and the normal tissues showed no treatment-related toxic effect in all groups. However, multiple hepatocellular carcinoma metastases were observed in the liver in the control group, there were a few metastases in the monotherapy groups and no metastasis in the combination group. Conclusions: Adenovirus-mediated suicide gene therapy plus radiotherapy dramatically could inhibit tumor growth and prolong

  17. Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.

    Science.gov (United States)

    Marchan, Rosemarie; Büttner, Bettina; Lambert, Jörg; Edlund, Karolina; Glaeser, Iris; Blaszkewicz, Meinolf; Leonhardt, Gregor; Marienhoff, Lisa; Kaszta, Darius; Anft, Moritz; Watzl, Carsten; Madjar, Katrin; Grinberg, Marianna; Rempel, Eugen; Hergenröder, Roland; Selinski, Silvia; Rahnenführer, Jörg; Lesjak, Michaela S; Stewart, Joanna D; Cadenas, Cristina; Hengstler, Jan G

    2017-09-01

    Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589-601. ©2017 AACR . ©2017 American Association for Cancer Research.

  18. Repeated measurement of nasal lavage fluid chemokines in school-age children with asthma.

    Science.gov (United States)

    Noah, Terry L; Tudor, Gail E; Ivins, Sally S; Murphy, Paula C; Peden, David B; Henderson, Frederick W

    2006-02-01

    Inflammatory processes at the mucosal surface may play a role in maintenance of asthma pathophysiology. Cross-sectional studies in asthmatic patients suggest that chemokines such as interleukin 8 (IL-8) are overproduced by respiratory epithelium. To test the hypothesis that chemokine levels are persistently elevated in the respiratory secretions of asthmatic children at a stable baseline. We measured nasal lavage fluid (NLF) levels of chemokines and other mediators at 3- to 4-month intervals in a longitudinal study of asthmatic children, with nonasthmatic siblings as controls. In a linear mixed-model analysis, both family and day of visit had significant effects on nasal mediators. Thus, data for 12 asthmatic-nonasthmatic sibling pairs who had 3 or more same-day visits were analyzed separately. For sibling pairs, median eosinophil cationic protein levels derived from serial measurements in NLF were elevated in asthmatic patients compared with nonasthmatic patients, with a near-significant tendency for elevation of total protein and eotaxin levels as well. However, no significant differences were found for IL-8 or several other chemokines. Ratios of IL-13 or IL-5 to interferon-gamma released by house dust mite antigen-stimulated peripheral blood mononuclear cells, tested on a single occasion, were significantly increased for asthmatic patients. Substantial temporal and family-related variability exists in nasal inflammation in asthmatic children. Although higher levels of eosinophil cationic protein are usually present in NLF of patients with stable asthma compared with patients without asthma, chemokines other than eotaxin are not consistently increased. Eosinophil activation at the mucosal surface is a more consistent predictor of asthmatic symptoms than nonspecific elevation of epithelium-derived inflammatory chemokine levels.

  19. Furin is a chemokine-modifying enzyme: in vitro and in vivo processing of CXCL10 generates a C-terminally truncated chemokine retaining full activity.

    Science.gov (United States)

    Hensbergen, Paul J; Verzijl, Dennis; Balog, Crina I A; Dijkman, Remco; van der Schors, Roel C; van der Raaij-Helmer, Elizabeth M H; van der Plas, Mariena J A; Leurs, Rob; Deelder, André M; Smit, Martine J; Tensen, Cornelis P

    2004-04-02

    Chemokines comprise a class of structurally related proteins that are involved in many aspects of leukocyte migration under basal and inflammatory conditions. In addition to the large number of genes, limited processing of these proteins by a variety of enzymes enhances the complexity of the total spectrum of chemokine variants. We have recently shown that the native chemokine CXCL10 is processed at the C terminus, thereby shedding the last four amino acids. The present study was performed to elucidate the mechanism in vivo and in vitro and to study the biological activity of this novel isoform of CXCL10. Using a combination of protein purification and mass spectrometric techniques, we show that the production of C-terminally truncated CXCL10 by primary keratinocytes is inhibited in vivo by a specific inhibitor of pro-protein convertases (e.g. furin) but not by inhibition of matrix metalloproteinases. Moreover, CXCL10 is processed by furin in vitro, which is abrogated by a mutation in the furin recognition site. Using GTPgammaS binding, Ca(2+) mobilization, and chemotaxis assays, we demonstrate that the C-terminally truncated CXCL10 variant is a potent ligand for CXCR3. Moreover, the inverse agonist activity on the virally encoded receptor ORF74 and the direct antibacterial activity of CXCL10 are fully retained. Hence, we have identified furin as a novel chemokine-modifying enzyme in vitro and most probably also in vivo, generating a C-terminally truncated CXCL10, which fully retains its (inverse) agonistic properties.

  20. The murine gammaherpesvirus-68 chemokine-binding protein M3 inhibits experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Millward, Jason M; Holst, Peter J; Høgh-Petersen, Mette

    2010-01-01

    M3 (AdM3) directly to the CNS to evaluate the capacity of this protein to inhibit neuroinflammation using the experimental autoimmune encephalomyelitis (EAE) model. Treatment with the AdM3 vector significantly reduced the clinical severity of EAE, attenuated CNS histopathology, and reduced numbers......Chemokines are critical mediators of immune cell entry into the central nervous system (CNS), as occurs in neuroinflammatory disease such as multiple sclerosis. Chemokines are also implicated in the immune response to viral infections. Many viruses encode proteins that mimic or block chemokine...... of immune cells infiltrating the CNS. These results suggest that M3 may represent a novel therapeutic approach to neuroinflammatory disease....

  1. Tumor attributes predicting cutaneous metastatic destiny: a report of two interesting cases.

    Science.gov (United States)

    Gurumurthi, Ravichandran; Thirumalai, Raja; Easow, Jose M; Mohan, Subhashini

    2014-07-01

    Cutaneous metastases are the result of complex interaction between the tumor cells ("seed") and the host environment ("soil"). Metastases to the skin can be an early sign of internal malignancy or represent recurrence of the primary tumor and portends a poorer prognosis. Invasion and metastasis are the hallmarks of on cogenesis. Skin is the largest organ in the body, but the incidence of metastases is low. With advances in molecular biology, factors responsible for the initiation and perpetuation of metastatic tumor cells at distant sites are being elucidated. The concept of "pre-metastatic niche" and interaction between various chemokines has given a new outlook in understanding the organ specificity of metastatic tumor cells. We present two cases of cutaneous metastases with interesting clinical findings correlating with its biologic subtypes.

  2. Chemokine Receptors and Integrin Function in Prostate Cancer

    National Research Council Canada - National Science Library

    McCarthy, James

    2000-01-01

    Preliminary data demonstrated that the addition of specific alpha-chemokines, IL-8 and Gro-alpha, to prostate carcinoma cell cultures, leads to an increase in the motility and invasion of these cells in vitro...

  3. Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer

    NARCIS (Netherlands)

    Guerrero-Preston, Rafael; Michailidi, Christina; Marchionni, Luigi; Pickering, Curtis R.; Frederick, Mitchell J.; Myers, Jeffrey N.; Yegnasubramanian, Srinivasan; Hadar, Tal; Noordhuis, Maartje G.; Zizkova, Veronika; Fertig, Elana; Agrawal, Nishant; Westra, William; Koch, Wayne; Califano, Joseph; Velculescu, Victor E.; Sidransky, David

    Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing

  4. Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice.

    Science.gov (United States)

    Jiang, Shu-Heng; Li, Jun; Dong, Fang-Yuan; Yang, Jian-Yu; Liu, De-Jun; Yang, Xiao-Mei; Wang, Ya-Hui; Yang, Min-Wei; Fu, Xue-Liang; Zhang, Xiao-Xin; Li, Qing; Pang, Xiu-Feng; Huo, Yan-Miao; Li, Jiao; Zhang, Jun-Feng; Lee, Ho-Young; Lee, Su-Jae; Qin, Wen-Xin; Gu, Jian-Ren; Sun, Yong-Wei; Zhang, Zhi-Gang

    2017-07-01

    of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B-LYN-p85 complex, which increased PI3K-Akt-mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  5. Impact of Cytokines and Chemokines on Alzheimer's Disease Neuropathological Hallmarks.

    Science.gov (United States)

    Domingues, Catarina; da Cruz E Silva, Odete A B; Henriques, Ana Gabriela

    2017-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by aggregates of β-amyloid peptides, which deposit as senile plaques, and of TAU protein, which forms neurofibrillary tangles. It is now widely accepted that neuroinflammation is implicated in AD pathogenesis. Indeed, inflammatory mediators, such as cytokines and chemokines (chemotactic cytokines) can impact on the Alzheimer´s amyloid precursor protein by affecting its expression levels and amyloidogenic processing and/or β -amyloid aggregation. Additionally, cytokines and chemokines can influence kinases' activities, leading to abnormal TAU phosphorylation. To date there is no cure for AD, but several therapeutic strategies have been directed to prevent neuroinflammation. Anti-inflammatory, but also anti-amyloidogenic compounds, such as flavonoids were shown to favourably modulate some pathological events associated with neurodegeneration. This review focuses on the role of cytokines and chemokines in AD-associated pathologies, and summarizes the potential anti-inflammatory therapeutic approaches aimed at preventing or slowing down disease progression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    Directory of Open Access Journals (Sweden)

    Kerstin Stemmer

    2012-09-01

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

  7. [Peptide fragments of chemokine domain of fractalkine: effect on human monocyte migration].

    Science.gov (United States)

    Kukhtina, N B; Aref'eva, T I; Ruleva, N Iu; Sidorova, M V; Az'muko, A A; Bespalova, Zh D; Krasnikova, T L

    2012-01-01

    Leukocyte chemotaxis to the area of tissue damage is mediated by chemokines. According to the primary structure, chemokines are divided into four families, fractalkine (CX3CL1) is the only one member of CX3C family and the only membrane-bound chemokine. Fractalkine molecule includes the extracellular N-terminal chemokine domain, mucin-like rod, the transmembrane and the intracellular domains. In membrane-bound state fractalkine has the properties of an adhesion molecule. Chemokine domain of fractalkine (CDF) is released from cell membrane by proteolysis, and this soluble form acts as a chemoattractant for leukocytes expressing fractalkine receptor CX3CR1. Fractalkine is involved in development of a number of pathological processes caused by inflammation, and therefore a search for fractalkine inhibitors is very important. For this purpose we identified several antigenic determinants--the fragments of CDF, and the following peptides were synthesized--P41-52 H-Leu-Glu-Thr-Arg-Gln-His-Arg-Leu-Phe-Cys-Ala-Asp-NH2, P53-60 H-Pro-Lys-Glu-Gln-Trp-Val-Lys-Asp-NH2 and P60-71 H-Asp-Ala-Met-Gln-His-Leu-Asp-Arg-Gln-Ala-Ala-Ala-NH2. The peptide effects on adhesion and migration of human peripheral blood monocytes expressing fractalkine receptors were investigated. In the presence of CDF and P41-52 we observed the increased adhesion and migration of monocytes compared with spontaneous values. Peptides P53-60 and P60-71 significantly inhibited monocyte adhesion and migration stimulated by CDF. Since the chemotactic activity of chemokines was shown to be dependent on their binding to glycosaminoglycans of the cell surface and extracellular matrix, the effect ofpeptides on the interaction of CDF with heparin was analyzed by ELISA. Peptide P41-52 competed with CDF for heparin binding, while peptides P53-60 and P60-71 had no significant activity.

  8. Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy.

    Science.gov (United States)

    Abelius, Martina S; Lempinen, Esma; Lindblad, Karin; Ernerudh, Jan; Berg, Göran; Matthiesen, Leif; Nilsson, Lennart J; Jenmalm, Maria C

    2014-06-01

    The influence of the intra-uterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) whether the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) whether the maternal chemokine levels during pregnancy influenced the offspring's chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children. The Th1-associated chemokines CXCL9, CXCL10, CXCL11, and the Th2-associated chemokines CCL17, CCL18 and CCL22 were quantified by Luminex and ELISA in 20 women with and 36 women without allergic symptoms at gestational week (gw) 10-12, 15-16, 25, 35, 39 and 2 and 12 months post-partum and in their children at birth, 6, 12, 24 months and 6 years of age. Total IgE levels were measured using ImmunoCAP Technology. The levels of the Th2-like chemokines were not magnified by pregnancy. Instead decreased levels were shown during pregnancy (irrespectively of maternal allergy status) as compared to post-partum. In the whole group, the Th1-like chemokine levels were higher at gw 39 than during the first and second trimester and post-partum. Maternal CXCL11, CCL18 and CCL22 levels during and after pregnancy correlated with the corresponding chemokines in the offspring during childhood. Increased CCL22 and decreased CXCL10 levels in the children were associated with sensitisation and increased CCL17 levels with allergic symptoms during childhood. Maternal chemokine levels were not associated with maternal allergic disease. Allergic symptoms and sensitisation were associated with decreased Th1- and increased Th2-associated chemokine levels during childhood, indicating a Th2 shift in the allergic children, possibly influenced by the maternal immunity during pregnancy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. CD147 Promotes CXCL1 Expression and Modulates Liver Fibrogenesis

    Directory of Open Access Journals (Sweden)

    Wen-Pu Shi

    2018-04-01

    Full Text Available Activated hepatic stellate cells (HSCs release pro-inflammatory and pro-fibrogenic factors. CXC chemokine-ligand-1 (CXCL1 is expressed on HSCs. We previously found that the CD147 is overexpressed in activated HSCs. In this study, we showed an important role of CD147 in promoting liver fibrosis by activating HSCs and upregulating expression of chemokines. Specifically, we found that CD147 specific deletion in HSCs mice alleviated CCl4-induced liver fibrosis and inhibited HSCs activation. Overexpression of CD147 upregulated the secretion of CXCL1. Meanwhile, CXCL1 promoted HSCs activation through autocrine. Treating with PI3K/AKT inhibitor could effectively suppress CD147-induced CXCL1 expression. Taken together, these findings suggest that CD147 regulates CXCL1 release in HSCs by PI3K/AKT signaling. Inhibition of CD147 attenuates CCl4-induced liver fibrosis and inflammation. Therefore, administration of targeting CD147 could be a promising therapeutic strategy in liver fibrosis.

  10. Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma

    Science.gov (United States)

    Torok, Kathryn S.; Kurzinski, Katherine; Kelsey, Christina; Yabes, Jonathan; Magee, Kelsey; Vallejo, Abbe N.; Medsger, Thomas; Feghali-Bostwick, Carol A.

    2015-01-01

    Objective To evaluate peripheral blood T-helper (TH) cell associated cytokine and chemokine profiles in localized scleroderma (LS), and correlate them with clinical disease features, including disease activity parameters. Methods A 29-plex Luminex platform was used to analyze the humoral profile of plasma samples from 69 pediatric LS patients and 71 healthy pediatric controls. Cytokine/chemokine levels were compared between these two groups and within LS patients, focusing on validated clinical outcome measures of disease activity and damage in LS. Results Plasma levels of IP-10, MCP-1, IL-17a, IL-12p70, GM-CSF, PDGF-bb, IFN-α2, and IFN-γ were significantly higher in LS compared to healthy controls. Analysis within the LS group demonstrated IP-10, TNF-α and GM-CSF correlated with clinical measures of disease activity. Several cytokines/chemokines correlated with anti-histone antibody, while only a few correlated with positive ANA and single-stranded DNA antibody. Conclusion This is the first time that multiple cytokines and chemokines have been examined simultaneously LS. In general, a TH-1 (IFN-γ) and TH-17 (IL-17a) predominance was demonstrated in LS compared to healthy controls. There is also an IFN–γ signature with elevated IP-10, MCP-1 and IFN-γ, which has been previously demonstrated in systemic sclerosis, suggesting a shared pathophysiology. Within the LS patients, those with active disease demonstrated IP-10, TNF-α and GM-CSF, which may potentially serve as biomarkers of disease activity in the clinical setting. PMID:26254121

  11. Elevated Plasma Chemokines for Eosinophils in Neuromyelitis Optica Spectrum Disorders during Remission

    Directory of Open Access Journals (Sweden)

    Yanping Tong

    2018-02-01

    Full Text Available BackgroundA prominent pathological feature of neuromyelitis optica spectrum disorders (NMOSD is markedly greater eosinophilic infiltration than that seen in other demyelinating diseases, like multiple sclerosis (MS. Eosinophils express the chemokine receptor CCR3, which is activated by eotaxins (CCL11/eotaxin-1, CCL24/eotaxin-2, CCL26/eotaxin-3 and CCL13 [monocyte chemoattractant protein (MCP-4]. Moreover, CCL13 is part of the chemokine set that activates CCR2. The present study aimed to evaluate plasma levels of eotaxins (CCL11, CCL24, and CCL26 and MCPs (CCL13, CCL2, CCL8, and CCL7 in patients with NMOSD during remission.MethodsHealthy controls (HC; n = 30 and patients with MS (n = 47 and NMOSD (n = 58 in remission were consecutively enrolled in this study between January 2016 and August 2017. Plasma CCL11, CCL24, CCL26, CCL2, CCL8, CCL7, CCL13, tumor necrosis factor (TNF-α, and interleukin (IL-1β levels were detected using the human cytokine multiplex assay.ResultsPlasma CCL13, CCL11, and CCL26 levels were all significantly higher in patients with NMOSD than in HC and patients with MS. No significant differences were found in the CCL13, CCL11, or CCL26 levels between patients with NMOSD receiving and not receiving immunosuppressive therapy. The plasma levels of TNF-α and IL-1β, which stimulate the above chemokines, were higher in patients with NMOSD than in HC. There was no difference in CCL24 levels among the three groups. In most cases, the CCL7 levels were below the threshold value of the human cytokine multiplex assay, which is in line with other studies. Adjusted multiple regression analyses showed a positive association of CCL13 levels with the number of relapses after controlling gender, age, body mass index, and disease duration in patients with NMOSD.ConclusionThe study indicates that in NMOSD, the overproduction of cytokines such as IL-1β and TNF-α during remission stimulates eosinophilic chemoattractants such as

  12. Identification of chemokines associated with the recruitment of decidual leukocytes in human labour: potential novel targets for preterm labour.

    Directory of Open Access Journals (Sweden)

    Sarah A Hamilton

    Full Text Available Current therapies for preterm labour (PTL focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface. Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL and term labour (TL, thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL, idiopathic PTL and PTL with infection (PTLI. Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid

  13. TFPI-2 is a putative tumor suppressor gene frequently inactivated by promoter hypermethylation in nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Wang, Shumin; Ma, Ning; Murata, Mariko; Huang, Guangwu; Zhang, Zhe; Xiao, Xue; Zhou, Xiaoying; Huang, Tingting; Du, Chunping; Yu, Nana; Mo, Yingxi; Lin, Longde; Zhang, Jinyan

    2010-01-01

    Epigenetic silencing of tumor suppressor genes play important roles in NPC tumorgenesis. Tissue factor pathway inhibitor-2 (TFPI-2), is a protease inhibitor. Recently, TFPI-2 was suggested to be a tumor suppressor gene involved in tumorigenesis and metastasis in some cancers. In this study, we investigated whether TFPI-2 was inactivated epigenetically in nasopharyngeal carcinoma (NPC). Transcriptional expression levels of TFPI-2 was evaluated by RT-PCR. Methylation status were investigated by methylation specific PCR and bisulfate genomic sequencing. The role of TFPI-2 as a tumor suppressor gene in NPC was addressed by re-introducing TFPI-2 expression into the NPC cell line CNE2. TFPI-2 mRNA transcription was inactivated in NPC cell lines. TFPI-2 was aberrantly methylated in 66.7% (4/6) NPC cell lines and 88.6% (62/70) of NPC primary tumors, but not in normal nasopharyngeal epithelia. TFPI-2 expression could be restored in NPC cells after demethylation treatment. Ectopic expression of TFPI-2 in NPC cells induced apoptosis and inhibited cell proliferation, colony formation and cell migration. Epigenetic inactivation of TFPI-2 by promoter hypermethylation is a frequent and tumor specific event in NPC. TFPI-2 might be considering as a putative tumor suppressor gene in NPC

  14. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice.

    Science.gov (United States)

    Gu, Jian-Wei; Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-05-15

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer

  15. CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR.

    Science.gov (United States)

    Circelli, Luisa; Sciammarella, Concetta; Guadagno, Elia; Tafuto, Salvatore; del Basso de Caro, Marialaura; Botti, Giovanni; Pezzullo, Luciano; Aria, Massimo; Ramundo, Valeria; Tatangelo, Fabiana; Losito, Nunzia Simona; Ieranò, Caterina; D'Alterio, Crescenzo; Izzo, Francesco; Ciliberto, Gennaro; Colao, Annamaria; Faggiano, Antongiulio; Scala, Stefania

    2016-04-05

    To evaluate the possible crosstalk between C-X-C chemokine receptor 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12)/C-X-C chemokine receptor 7 (CXCR7) axis with the mammalian target of rapamycin (mTOR) pathway in neuroendocrine tumors (NETs). Sixty-one human NETs were included into the study. CXCR4/CXCL12/CXCR7 axis and mTOR pathway were assessed by qRT-PCR and immunohistochemistry (IHC). The effect of mTOR inhibitor, RAD001, was evaluated on CXCR4 pathway through proliferation and p-Erk and p-AKT induction. CXCR4/CXCL12/CXCR7 axis and p-mTOR were found to be active and correlated with grading, Ki67 index and tumor stage. mTOR pathway activation significantly correlated with poor prognosis. In human NET cells, CXCL12 induced mTOR signalling while AMD3100 (CXCR4-antagonist) impaired it. The mTOR-antagonist, RAD001, impaired the CXCL12-dependent induction of CXCR4 downstream effectors. Combination of AMD3100 and RAD001 potentiate cell growth inhibition. CXCR4/CXCL12/CXCR7 axis is active in NETs and signals on mTOR. CXCR4 might be considered a prognostic factor in NETs. Combined treatment with AMD3100 and RAD001 may provide clinical benefits in NET patients with drug-resistant.

  16. Quantitative analysis of the secretion of the MCP family of chemokines by muscle cells

    DEFF Research Database (Denmark)

    Henningsen, Jeanette; Pedersen, Bente Klarlund; Kratchmarova, Irina

    2011-01-01

    by Amino acids in Cell culture (SILAC) method for quantitative analysis resulted in the identification and generation of quantitative profiles of 59 growth factors and cytokines, including 9 classical chemokines. The members of the CC chemokine family of proteins such as monocyte chemotactic proteins 1, 2...

  17. CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration.

    Directory of Open Access Journals (Sweden)

    Gregory C Wilson

    Full Text Available Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy.Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration.We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2 and keratinocyte-derived chemokine (KC, was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.

  18. Canonical and Non-Canonical NF-κB Signaling Promotes Breast Cancer Tumor-Initiating Cells

    Science.gov (United States)

    Kendellen, Megan F.; Bradford, Jennifer W.; Lawrence, Cortney L.; Clark, Kelly S.; Baldwin, Albert S.

    2014-01-01

    Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors, and the development of metastases. TICs have been identified in various tumors, including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the NF-κB family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition (EMT) and by upregulating the expression of the inflammatory cytokines IL-1β and IL-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. PMID:23474754

  19. submitter Emerging importance of chemokine receptor CXCR3 and its ligands in cardiovascular diseases

    CERN Document Server

    Altara, R; Brandao, R D; Zeidan, A; Booz, G W; Zouein, F A

    2016-01-01

    The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the deve...

  20. Chemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation.

    Science.gov (United States)

    Alejo, Alí; Ruiz-Argüello, M Begoña; Pontejo, Sergio M; Fernández de Marco, María Del Mar; Saraiva, Margarida; Hernáez, Bruno; Alcamí, Antonio

    2018-05-03

    The role of cytokines and chemokines in anti-viral defense has been demonstrated, but their relative contribution to protective anti-viral responses in vivo is not fully understood. Cytokine response modifier D (CrmD) is a secreted receptor for TNF and lymphotoxin containing the smallpox virus-encoded chemokine receptor (SECRET) domain and is expressed by ectromelia virus, the causative agent of the smallpox-like disease mousepox. Here we show that CrmD is an essential virulence factor that controls natural killer cell activation and allows progression of fatal mousepox, and demonstrate that both SECRET and TNF binding domains are required for full CrmD activity. Vaccination with recombinant CrmD protects animals from lethal mousepox. These results indicate that a specific set of chemokines enhance the inflammatory and protective anti-viral responses mediated by TNF and lymphotoxin, and illustrate how viruses optimize anti-TNF strategies with the addition of a chemokine binding domain as soluble decoy receptors.

  1. TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.

    Science.gov (United States)

    Chavali, P L; Saini, R K R; Zhai, Q; Vizlin-Hodzic, D; Venkatabalasubramanian, S; Hayashi, A; Johansson, E; Zeng, Z-j; Mohlin, S; Påhlman, S; Hansford, L; Kaplan, D R; Funa, K

    2014-10-30

    Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.

  2. Migration and chemokine receptor pattern of colitis-preventing DX5+NKT cells.

    Science.gov (United States)

    Hornung, Matthias; Werner, Jens M; Farkas, Stefan; Schlitt, Hans J; Geissler, Edward K

    2011-11-01

    DX5(+)NKT cells are a subpopulation of NKT cells expressing both T cell receptor and NK cell markers that show an immune-regulating function. Transferred DX5(+)NKT cells from immune competent Balb/c mice can prevent or reduce induced colitis in severe combined immunodeficient (SCID) mice. Here, we investigated the in vivo migration of DX5(+)NKT cells and their corresponding chemokine receptor patterns. DX5(+)NKT cells were isolated from spleens of Balb/c mice and transferred into Balb/c SCID mice. After 2 and 8 days, in vivo migration was examined using in vivo microscopy. In addition, the chemokine receptor pattern was analyzed with fluorescence-activated cell sorting (FACS) and the migration assay was performed. Our results show that labeled DX5(+)NKT cells were primarily detectable in mesenteric lymph nodes and spleen after transfer. After 8 days, DX5(+)NKT cells were observed in the colonic tissues, especially the appendix. FACS analysis of chemokine receptors in DX5(+)NKT cells revealed expression of CCR3, CCR6, CCR9, CXCR3, CXCR4, and CXCR6, but no CCR5, CXCR5, or the lymphoid homing receptor CCR7. Stimulation upregulated especially CCR7 expression, and chemokine receptor patterns were different between splenic and liver DX5(+)NKT cells. These data indicate that colitis-preventing DX5(+)NKT cells need to traffic through lymphoid organs to execute their immunological function at the site of inflammation. Furthermore, DX5(+)NKT cells express a specific chemokine receptor pattern with an upregulation of the lymphoid homing receptor CCR7 after activation.

  3. Genetic and Epigenetic Tumor Suppressor Gene Silencing are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Non small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Marsit, C. J.; Kelsey, K. T.; Houseman, E. A.; Kelsey, K. T.; Houseman, E. A.; Nelson, H. H.

    2008-01-01

    Both genetic and epigenetic alterations characterize human non small cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hyper methylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hyper methylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hyper methylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hyper methylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  4. Comparative study of CXC chemokines modulation in brown trout (Salmo trutta) following infection with a bacterial or viral pathogen.

    Science.gov (United States)

    Gorgoglione, Bartolomeo; Zahran, Eman; Taylor, Nick G H; Feist, Stephen W; Zou, Jun; Secombes, Christopher J

    2016-03-01

    Chemokine modulation in response to pathogens still needs to be fully characterised in fish, in view of the recently described novel chemokines present. This paper reports the first comparative study of CXC chemokine genes transcription in salmonids (brown trout), with a particular focus on the fish specific CXC chemokines (CXCL_F). Adopting new primer sets, optimised to specifically target mRNA, a RT-qPCR gene screening was carried out. Constitutive gene expression was assessed first in six tissues from SPF brown trout. Transcription modulation was next investigated in kidney and spleen during septicaemic infection induced by a RNA virus (Viral Haemorrhagic Septicaemia virus, genotype Ia) or by a Gram negative bacterium (Yersinia ruckeri, ser. O1/biot. 2). From each target organ specific pathogen burden, measured detecting VHSV-glycoprotein or Y. ruckeri 16S rRNA, and IFN-γ gene expression were analysed for their correlation to chemokine transcription. Both pathogens modulated CXC chemokine gene transcript levels, with marked up-regulation seen in some cases, and with both temporal and tissue specific effects apparent. For example, Y. ruckeri strongly induced chemokine transcription in spleen within 24h, whilst VHS generally induced the largest increases at 3d.p.i. in both tissues. This study gives clues to the role of the novel CXC chemokines, in comparison to the other known CXC chemokines in salmonids. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. The frequency of CCR5 promoter polymorphisms and CCR5 32 mutation in Iranian populations

    Directory of Open Access Journals (Sweden)

    Mohammad Zare-Bidaki

    2015-04-01

    Full Text Available Evidence showed that chemokines serve as pro-migratory factors for immune cells. CCL3, CCL4 and CCL5, as the main CC  chemokines subfamily members, activate immune cells through binding to CC chemokine receptor 5 or CCR5. Macrophages, NK cells and T lymphocytes express CCR5 and thus, affected CCR5 expression or functions could be associated with altered immune responses. Deletion of 32 base pairs (D 32 in the exon 1 of the CCR5 gene, which is known as CCR5 D 32 mutation causes down regulation and malfunction of the molecule. Furthermore, it has been evidenced that three polymorphisms in the promoter region of CCR5 modulate its expression. Altered CCR5 expression in microbial infection and immune related diseases have been reported by several researchers but the role of CCR5 promoter polymorphisms and CCR5 D 32 mutation in Iranian patients suffering from these diseases are controversial. Due to the fact that Iranian people have different genetic backgrounds compared to other ethnics, hence, CCR5 promoter polymorphisms and CCR5 D 32 mutation association with the diseases may be different in Iranian patients. Therefore, this review addresses the most recent information regarding the prevalence as well as association of the mutation and polymorphisms in Iranian patients with microbial infection and immune related diseases as along with normal population.

  6. Effects of a tumor promoter and an anti-promoter on spontaneous and UV-induced 6-thioguanine-resistant mutations and sister-chromatid exchanges in V79 Chinese hamster cells

    International Nuclear Information System (INIS)

    Fujiwara, Y.; Kano, Y.; Tatsumi, M.; Paul, P.

    1980-01-01

    The effects of a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and/or an anti-promoter antipain (protease inhibitor) on spontaneous and ultraviolet-induced sister-chromatid exchanges (SCEs) and 6-thioguanine-resistant (6TGsup(r)) recessive mutations were examined in V79 Chinese hamster cells in culture. TPA and/or antipain neither significantly altered base-line and UV-induced immediate SCE frequencies, nor decreased the level of delayed SCEs which persisted 6-7 days after irradiation. TPA and/or antipain appeared to enhance the recovery of UV-induced 6TGsup(r) colonies at the plateau expression phase despite non-mutagenicity by themselves and unaltered metabolic cooperation. Thus, the results conceivably imply that the 6TGsup(r)-recessive mutation expression, but not fixation, can be modulated at the cell level by TPA and/or antipain. Our results, together with the recent results of Loveday and Latt, may argue against the notion that TPA enhances the antipain-suppressible SCEs as an index of mitotic recombination in relevance with a tumor-promotion mechanism. (orig.)

  7. Consequences of ChemR23 heteromerization with the chemokine receptors CXCR4 and CCR7.

    Science.gov (United States)

    de Poorter, Cédric; Baertsoen, Kevin; Lannoy, Vincent; Parmentier, Marc; Springael, Jean-Yves

    2013-01-01

    Recent studies have shown that heteromerization of the chemokine receptors CCR2, CCR5 and CXCR4 is associated to negative binding cooperativity. In the present study, we build on these previous results, and investigate the consequences of chemokine receptor heteromerization with ChemR23, the receptor of chemerin, a leukocyte chemoattractant protein structurally unrelated to chemokines. We show, using BRET and HTRF assays, that ChemR23 forms homomers, and provide data suggesting that ChemR23 also forms heteromers with the chemokine receptors CCR7 and CXCR4. As previously described for other chemokine receptor heteromers, negative binding cooperativity was detected between ChemR23 and chemokine receptors, i.e. the ligands of one receptor competed for the binding of a specific tracer of the other. We also showed, using mouse bone marrow-derived dendritic cells prepared from wild-type and ChemR23 knockout mice, that ChemR23-specific ligands cross-inhibited CXCL12 binding on CXCR4 in a ChemR23-dependent manner, supporting the relevance of the ChemR23/CXCR4 interaction in native leukocytes. Finally, and in contrast to the situation encountered for other previously characterized CXCR4 heteromers, we showed that the CXCR4-specific antagonist AMD3100 did not cross-inhibit chemerin binding in cells co-expressing ChemR23 and CXCR4, demonstrating that cross-regulation by AMD3100 depends on the nature of receptor partners with which CXCR4 is co-expressed.

  8. Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems

    Science.gov (United States)

    Dusi, Veronica; Ghidoni, Alice; Ravera, Alice; De Ferrari, Gaetano M.; Calvillo, Laura

    2016-01-01

    Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a “working-network” in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described. PMID:27242392

  9. Tumor-promoting phorbol ester amplifies the inductions of tyrosine aminotransferase and ornithine decarboxylase by glucocorticoid

    International Nuclear Information System (INIS)

    Kido, H.; Fukusen, N.; Katunuma, N.

    1987-01-01

    In adrenalectomized rats, the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) markedly enhanced the inductions of tyrosine aminotransferase (TAT) and ornithine decarboxylase by glucocorticoids, even with sufficient concentration of glucocorticoids to have a maximal effect, whereas it had no effect on TAT activity and increased ornithine decarboxylase activity only slightly in the absence of glucocorticoids. Phorbol derivatives and components of TPA such as 4β-phorbol, phorbol 12-tetradecanoate, phorbol 13-acetate, and 4-O-methylphorbol 12-tetradecanoate 13-acetate, which have no tumor-promoting activity or ability to activate protein kinase C, did not have any effect on TAT induction by glucocorticoid. TPA enhanced the induction of TAT by various glucocorticoids but had no effect on induction of TAT by glucagon or insulin and did not enhance the induction of glucose-6-phosphate dehydrogenase by 17β-estradiol. These results suggest that TPA specifically enhances the induction of TAT and ornithine decarboxylase by glucocorticoids. Similar effects of TPA on TAT induction by glucocorticoid were observed in primary cultures of adult rat hepatocytes. Another activator of protein kinase C, rac-1,2-dioctanoylglycerol, was also found to have similar effects on the cells

  10. Elevated CXC chemokines in urine noninvasively discriminate OAB from UTI.

    Science.gov (United States)

    Tyagi, Pradeep; Tyagi, Vikas; Qu, Xianggui; Chuang, Yao Chi; Kuo, Hann-Chorng; Chancellor, Michael

    2016-09-01

    Overlapping symptoms of overactive bladder (OAB) and urinary tract infection (UTI) often complicate the diagnosis and contribute to overprescription of antibiotics. Inflammatory response is a shared characteristic of both UTI and OAB and here we hypothesized that molecular differences in inflammatory response seen in urine can help discriminate OAB from UTI. Subjects in the age range of (20-88 yr) of either sex were recruited for this urine analysis study. Urine specimens were available from 62 UTI patients with positive dipstick test before antibiotic treatment. Six of these patients also provided urine after completion of antibiotic treatment. Subjects in cohorts of OAB (n = 59) and asymptomatic controls (n = 26) were negative for dipstick test. Urinary chemokines were measured by MILLIPLEX MAP Human Cytokine/Chemokine Immunoassay and their association with UTI and OAB was determined by univariate and multivariate statistics. Significant elevation of CXCL-1, CXCL-8 (IL-8), and CXCL-10 together with reduced levels for a receptor antagonist of IL-1A (sIL-1RA) were seen in UTI relative to OAB and asymptomatic controls. Elevated CXCL-1 urine levels predicted UTI with odds ratio of 1.018 and showed a specificity of 80.77% and sensitivity of 59.68%. Postantibiotic treatment, reduction was seen in all CXC chemokines with a significant reduction for CXCL-10. Strong association of CXCL-1 and CXCL-10 for UTI over OAB indicates mechanistic differences in signaling pathways driving inflammation secondary of infection in UTI compared with a lack of infection in OAB. Urinary chemokines highlight molecular differences in the paracrine signaling driving the overlapping symptoms of UTI and OAB. Copyright © 2016 the American Physiological Society.

  11. IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines

    DEFF Research Database (Denmark)

    Tran, E H; Prince, E N; Owens, T

    2000-01-01

    Dynamic interplay between cytokines and chemokines directs trafficking of leukocyte subpopulations to tissues in autoimmune inflammation. We have examined the role of IFN-gamma in directing chemokine production and leukocyte infiltration to the CNS in experimental autoimmune encephalomyelitis (EA......-gamma in EAE, acting on T cell proliferation and directing chemokine production, with profound implications for the onset and progression of disease.......). BALB/c and C57BL/6 mice are resistant to induction of EAE by immunization with myelin basic protein. However, IFN-gamma-deficient (BALB/c) and IFN-gammaR-deficient (C57BL/6) mice developed rapidly progressing lethal disease. Widespread demyelination and disseminated leukocytic infiltration of spinal...

  12. Orphan chemokine receptors in neuroimmunology : functional and pharmacological analysis of L-CCR and HCR

    NARCIS (Netherlands)

    Zuurman, Michael Wilhelmer

    2003-01-01

    In this thesis we have investigated the expression and biological activity of the orphan chemokine receptors L-CCR/HCR in astrocytes and microglia. Several lines of evidence indicate that the chemokines CCL2, CCL5, CCL7 and CCL8 are agonists for these receptors. Although a variety of biological

  13. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities.

    Directory of Open Access Journals (Sweden)

    Janice B B Lam

    Full Text Available Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive.In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1 and thioredoxin reductase (TrxR1 were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1.Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/Akt signalling pathway through a mechanism involving Trx1/TrxR1

  14. Cytokines and chemokines involved in acute retinal necrosis

    NARCIS (Netherlands)

    L. De Visser (Lenneke); J.H. de Boer (Joke); G.T. Rijkers; Wiertz, K. (Karin); H.J. van den Ham; de Boer, R. (Rob); van Loon, A.M. (Anton M.); A. Rothová (Aniki); J.D.F. de Groot-Mijnes (Jolanda )

    2017-01-01

    textabstractPURPOSE. To investigate which cytokines and chemokines are involved in the immunopatho-genesis of acute retinal necrosis (ARN), and whether cytokine profiles are associated with clinical manifestations, such as visual outcome. METHODS. Serum and aqueous humor (AH) samples of 19 patients

  15. Cytokines and Chemokines Involved in Acute Retinal Necrosis

    NARCIS (Netherlands)

    de Visser, Lenneke; H de Boer, Joke; T Rijkers, Ger; Wiertz, Karin; van den Ham, Henk-Jan; de Boer, Rob; M van Loon, Anton; Rothova, Aniki; de Groot-Mijnes, Jolanda D F

    2017-01-01

    Purpose: To investigate which cytokines and chemokines are involved in the immunopathogenesis of acute retinal necrosis (ARN), and whether cytokine profiles are associated with clinical manifestations, such as visual outcome. Methods: Serum and aqueous humor (AH) samples of 19 patients with ARN were

  16. Differential subnetwork of chemokines/cytokines in human, mouse, and rat brain cells after oxygen-glucose deprivation.

    Science.gov (United States)

    Du, Yang; Deng, Wenjun; Wang, Zixing; Ning, MingMing; Zhang, Wei; Zhou, Yiming; Lo, Eng H; Xing, Changhong

    2017-04-01

    Mice and rats are the most commonly used animals for preclinical stroke studies, but it is unclear whether targets and mechanisms are always the same across different species. Here, we mapped the baseline expression of a chemokine/cytokine subnetwork and compared responses after oxygen-glucose deprivation in primary neurons, astrocytes, and microglia from mouse, rat, and human. Baseline profiles of chemokines (CX3CL1, CXCL12, CCL2, CCL3, and CXCL10) and cytokines (IL-1α, IL-1β, IL-6, IL-10, and TNFα) showed significant differences between human and rodents. The response of chemokines/cytokines to oxygen-glucose deprivation was also significantly different between species. After 4 h oxygen-glucose deprivation and 4 h reoxygenation, human and rat neurons showed similar changes with a downregulation in many chemokines, whereas mouse neurons showed a mixed response with up- and down-regulated genes. For astrocytes, subnetwork response patterns were more similar in rats and mice compared to humans. For microglia, rat cells showed an upregulation in all chemokines/cytokines, mouse cells had many down-regulated genes, and human cells showed a mixed response with up- and down-regulated genes. This study provides proof-of-concept that species differences exist in chemokine/cytokine subnetworks in brain cells that may be relevant to stroke pathophysiology. Further investigation of differential gene pathways across species is warranted.

  17. The virus-encoded chemokine vMIP-II inhibits virus-induced Tc1-driven inflammation

    DEFF Research Database (Denmark)

    Lindow, Morten; Nansen, Anneline; Bartholdy, Christina

    2003-01-01

    The human herpesvirus 8-encoded protein vMIP-II is a potent in vitro antagonist of many chemokine receptors believed to be associated with attraction of T cells with a type 1 cytokine profile. For the present report we have studied the in vivo potential of this viral chemokine antagonist to inhib...

  18. Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jae-Hyun Park

    2015-05-01

    Full Text Available The stroma of breast cancer can promote the disease’s progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV–Neu] and a triple-negative/basal-like [C3(1–Simian virus 40 large T antigen (Tag] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9, an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1, an MMP9 substrate, were increased in C3(1-Tag;Mmp9−/− compared to C3(1-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1-Tag;Mmp9−/− mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed.

  19. Consequences of ChemR23 heteromerization with the chemokine receptors CXCR4 and CCR7.

    Directory of Open Access Journals (Sweden)

    Cédric de Poorter

    Full Text Available Recent studies have shown that heteromerization of the chemokine receptors CCR2, CCR5 and CXCR4 is associated to negative binding cooperativity. In the present study, we build on these previous results, and investigate the consequences of chemokine receptor heteromerization with ChemR23, the receptor of chemerin, a leukocyte chemoattractant protein structurally unrelated to chemokines. We show, using BRET and HTRF assays, that ChemR23 forms homomers, and provide data suggesting that ChemR23 also forms heteromers with the chemokine receptors CCR7 and CXCR4. As previously described for other chemokine receptor heteromers, negative binding cooperativity was detected between ChemR23 and chemokine receptors, i.e. the ligands of one receptor competed for the binding of a specific tracer of the other. We also showed, using mouse bone marrow-derived dendritic cells prepared from wild-type and ChemR23 knockout mice, that ChemR23-specific ligands cross-inhibited CXCL12 binding on CXCR4 in a ChemR23-dependent manner, supporting the relevance of the ChemR23/CXCR4 interaction in native leukocytes. Finally, and in contrast to the situation encountered for other previously characterized CXCR4 heteromers, we showed that the CXCR4-specific antagonist AMD3100 did not cross-inhibit chemerin binding in cells co-expressing ChemR23 and CXCR4, demonstrating that cross-regulation by AMD3100 depends on the nature of receptor partners with which CXCR4 is co-expressed.

  20. Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms

    Science.gov (United States)

    Specht, Elisa; Wirtz, Ralph M.; Sayeg, Manal; Baum, Richard P.; Schulz, Stefan; Lupp, Amelie

    2015-01-01

    Introduction For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. Methods CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. Results CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. Conclusions With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy. PMID:25671300

  1. Prostaglandin F2α–F-Prostanoid Receptor Signalling Promotes Neutrophil Chemotaxis via Chemokine (CXC motif) Ligand-1 in Endometrial Adenocarcinoma

    Science.gov (United States)

    Wallace, Alison E; Sales, Kurt J; Catalano, Roberto D; Anderson, Richard A; Williams, Alistair RW; Wilson, Martin R; Schwarze, Jurgen; Wang, Hongwei; Rossi, Adriano G; Jabbour, Henry N

    2009-01-01

    The prostaglandin F2α (PGF2α) receptor (FP) is elevated in endometrial adenocarcinoma. This study found that PGF2α signalling via FP regulates expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in endometrial adenocarcinoma cells. Expression of CXCL1 and its receptor, CXCR2, are elevated in cancer tissue as compared to normal endometrium and localised to glandular epithelium, endothelium and stroma. Treatment of Ishikawa cells stably transfected with the FP receptor (FPS cells) with 100nM PGF2α increased CXCL1 promoter activity, mRNA and protein expression, and these effects were abolished by co-treatment of cells with FP antagonist or chemical inhibitors of Gq, EGFR and ERK. Similarly, CXCL1 was elevated in response to 100 nM PGF2α in endometrial adenocarcinoma explant tissue. CXCL1 is a potent neutrophil chemoattractant. The expression of CXCR2 colocalised to neutrophils in endometrial adenocarcinoma and increased neutrophils were present in endometrial adenocarcinoma compared with normal endometrium. Conditioned media from PGF2α-treated FPS cells stimulated neutrophil chemotaxis which could be abolished by CXCL1 protein immunoneutralisation of the conditioned media or antagonism of CXCR2. Finally, xenograft tumours in nude mice arising from inoculation with FPS cells showed increased neutrophil infiltration compared to tumours arising from wild-type cells or following treatment of mice bearing FPS tumours with CXCL1-neutralising antibody. In conclusion, our results demonstrate a novel PGF2α-FP pathway that may regulate the inflammatory microenvironment in endometrial adenocarcinoma via neutrophil chemotaxis. PMID:19549892

  2. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS

    DEFF Research Database (Denmark)

    Babcock, Alicia A; Kuziel, William A; Rivest, Serge

    2003-01-01

    Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused by e...

  3. Different Cytokine and Chemokine Expression Patterns in Malignant Compared to Those in Nonmalignant Renal Cells

    Directory of Open Access Journals (Sweden)

    Nadine Gelbrich

    2017-01-01

    Full Text Available Objective. Cytokines and chemokines are widely involved in cancer cell progression and thus represent promising candidate factors for new biomarkers. Methods. Four renal cell cancer (RCC cell lines (Caki-1, 786-O, RCC4, and A498 and a nonmalignant renal cell line (RC-124 were examined with respect to their proliferation. The cytokine and chemokine expression pattern was examined by a DNA array (Human Cytokines & Chemokines RT2 Profiler PCR Array; Qiagen, Hilden, Germany, and expression profiles were compared. Results. Caki-1 and 786-O cells exhibited significantly increased proliferation rates, whereas RCC4 and A498 cells demonstrated attenuated proliferation, compared to nonmalignant RC-124 cells. Expression analysis revealed 52 cytokines and chemokines primarily involved in proliferation and inflammation and differentially expressed not only in malignant and nonmalignant renal cells but also in the four RCC cell lines. Conclusion. This is the first study examining the expression of 84 cytokines and chemokines in four RCC cell lines compared to that in a nonmalignant renal cell line. VEGFA, NODAL, and BMP6 correlated with RCC cell line proliferation and, thus, may represent putative clinical biomarkers for RCC progression as well as for RCC diagnosis and prognosis.

  4. Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma.

    Science.gov (United States)

    Sekar, Divya; Govene, Luisa; Del Río, María-Luisa; Sirait-Fischer, Evelyn; Fink, Annika F; Brüne, Bernhard; Rodriguez-Barbosa, José I; Weigert, Andreas

    2018-03-07

    Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA) on type I NKT cells in polyoma middle T oncogene-driven (PyMT) murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1) were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity.

  5. Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma

    Directory of Open Access Journals (Sweden)

    Divya Sekar

    2018-03-01

    Full Text Available Natural Killer T cells (NKT cells are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA on type I NKT cells in polyoma middle T oncogene-driven (PyMT murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1 were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity.

  6. The chemokines CCL11, CCL20, CCL21, and CCL24 are preferentially expressed in polarized human secondary lymphoid follicles.

    Science.gov (United States)

    Buri, Caroline; Gutersohn, Andreas; Hauser, Chantal; Kappeler, Andreas; Mueller, Christoph

    2004-10-01

    Chemokines regulate cellular trafficking to and from lymphoid follicles. Here, the distribution pattern of four CCL chemokines is defined by in situ hybridization in human lymphoid follicles from tonsils and lymph nodes (LNs) of newborns and adults. Cells expressing CCL11 (eotaxin) and CCL20 (Exodus) were preferentially located within follicles, while cells expressing CCL21 (secondary lymphoid-tissue chemokine) and CCL24 (eotaxin-2) mRNA were almost exclusively found in the perifollicular areas. Hence, the two CCR3-binding chemokines, CCL11 and CCL24, showed a mutually exclusive expression pattern in the intra- and extra-follicular areas, respectively. Chemokine gene expression paralleled follicular maturation: in tonsils, where approximately 80% of follicles are polarized, CCL11 and CCL20 mRNA-positive cells were detected more frequently than in lymph nodes from adults, where about half of follicles are non-polarized. No intrafollicular chemokine expression was detectable in the primary follicles from newborns. Extrafollicular cells expressing CCL21 and CCL24 were again more frequent in tonsils than in LNs from adults. The observed preferential presence of cells expressing CC chemokines in polarized human lymphoid follicles indicates that chemokines are not only instrumental in the induction of follicle formation, but may also be involved in their further differentiation.

  7. The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior

    Directory of Open Access Journals (Sweden)

    Florian Weinberg

    2017-06-01

    Full Text Available Despite being overexpressed in different tumor entities, RIO kinases are hardly characterized in mammalian cells. We investigated the role of these atypical kinases in different cancer cells. Using isogenic colon-, breast- and lung cancer cell lines, we demonstrate that knockdown of RIOK1, but not of RIOK2 or RIOK3, strongly impairs proliferation and invasiveness in conventional and 3D culture systems. Interestingly, these effects were mainly observed in RAS mutant cancer cells. In contrast, growth of RAS wildtype Caco-2 and Bcr-Abl-driven K562 cells is not affected by RIOK1 knockdown, suggesting a specific requirement for RIOK1 in the context of oncogenic RAS signaling. Furthermore, we show that RIOK1 activates NF-κB signaling and promotes cell cycle progression. Using proteomics, we identified the pro-invasive proteins Metadherin and Stathmin1 to be regulated by RIOK1. Additionally, we demonstrate that RIOK1 promotes lung colonization in vivo and that RIOK1 is overexpressed in different subtypes of human lung- and breast cancer. Altogether, our data suggest RIOK1 as a potential therapeutic target, especially in RAS-driven cancers.

  8. A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

    Directory of Open Access Journals (Sweden)

    Sergio Arancibia

    Full Text Available Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH. This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH and the Concholepas hemocyanin (CCH. FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4(+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer

  9. A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

    Science.gov (United States)

    Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C; Manubens, Augusto; De Ioannes, Alfredo E; Becker, María Inés

    2014-01-01

    Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4(+) lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy.

  10. Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

    Science.gov (United States)

    Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

    2006-02-01

    To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

  11. Cell motility in chronic lymphocytic leukemia: defective Rap1 and alphaLbeta2 activation by chemokine.

    Science.gov (United States)

    Till, Kathleen J; Harris, Robert J; Linford, Andrea; Spiller, David G; Zuzel, Mirko; Cawley, John C

    2008-10-15

    Chemokine-induced activation of alpha4beta1 and alphaLbeta2 integrins (by conformational change and clustering) is required for lymphocyte transendothelial migration (TEM) and entry into lymph nodes. We have previously reported that chemokine-induced TEM is defective in chronic lymphocytic leukemia (CLL) and that this defect is a result of failure of the chemokine to induce polar clustering of alphaLbeta2; engagement of alpha4beta1 and autocrine vascular endothelial growth factor (VEGF) restore clustering and TEM. The aim of the present study was to characterize the nature of this defect in alphaLbeta2 activation and determine how it is corrected. We show here that the alphaLbeta2 of CLL cells is already in variably activated conformations, which are not further altered by chemokine treatment. Importantly, such treatment usually does not cause an increase in the GTP-loading of Rap1, a GTPase central to chemokine-induced activation of integrins. Furthermore, we show that this defect in Rap1 GTP-loading is at the level of the GTPase and is corrected in CLL cells cultured in the absence of exogenous stimuli, suggesting that the defect is the result of in vivo stimulation. Finally, we show that, because Rap1-induced activation of both alpha4beta1 and alphaLbeta2 is defective, autocrine VEGF and chemokine are necessary to activate alpha4beta1 for ligand binding. Subsequently, this binding and both VEGF and chemokine stimulation are all needed for alphaLbeta2 activation for motility and TEM. The present study not only clarifies the nature of the alphaLbeta2 defect of CLL cells but is the first to implicate activation of Rap1 in the pathophysiology of CLL.

  12. Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression.

    Science.gov (United States)

    Ma, Ruihua; Ji, Tiantian; Chen, Degao; Dong, Wenqian; Zhang, Huafeng; Yin, Xiaonan; Ma, Jingwei; Liang, Xiaoyu; Zhang, Yi; Shen, Guanxin; Qin, Xiaofeng; Huang, Bo

    2016-04-01

    Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

  13. Extracellular Disulfide Bridges Serve Different Purposes in Two Homologous Chemokine Receptors, CCR1 and CCR5

    DEFF Research Database (Denmark)

    Rummel, Pia Cwarzko; Thiele, Stefanie; Hansen, Laerke Smidt

    2013-01-01

    interact with residues in the main binding crevice, we show that the 7TM-conserved bridge is essential for all types of ligand-mediated activation, whereas the chemokine-conserved bridge is dispensable for small-molecule activation in CCR1. However, in striking contrast to previous studies in other...... chemokine receptors, high affinity CCL3 chemokine binding was maintained in the absence of either bridge. In CCR5, the closest homolog to CCR1, a completely different dependency was observed as neither chemokine activation nor binding was retained in the absence of either bridge. In contrast, both bridges...... where dispensable for small-molecule activation. This indicates that CCR5 activity is independent of extracellular regions, whereas in CCR1, preserved folding of ECL2 is necessary for activation. These results indicate that conserved structural features in a receptor subgroup, does not necessarily...

  14. [Initiation, promotion, initiation experiments with radon and cigarette smoke: Lung tumors in rats]. Progress report

    International Nuclear Information System (INIS)

    Moolgavkar, S.H.

    1994-01-01

    During the past several years, the authors have made considerable progress in modeling carcinogenesis in general, and in modeling radiation carcinogenesis, in particular. They present an overview of their progress in developing stochastic carcinogenesis models and applying them to experimental and epidemiologic data sets. Traditionally, cancer models have been used for the analysis of incidence (or prevalence) data in epidemiology and time to tumor data in experimental studies. The relevant quantities for the analysis of these data are the hazard function and the probability of tumor. The derivation of these quantities is briefly described here. More recently, the authors began to use these models for the analysis of data on intermediate lesions on the pathway to cancer. Such data are available in experimental carcinogenesis studies, in particular in initiation and promotion studies on the mouse skin and the rat liver. If however, quantitative information on intermediate lesions on the pathway to lung cancer were to be come available at some future date, the methods that they have developed for the analysis of initiation-promotion experiments could easily be applied to the analysis of these lesions. The mathematical derivations here are couched in terms of a particular two-mutation model of carcinogenesis. Extension to models postulating more than two mutations is not always straightforward

  15. Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

    Science.gov (United States)

    Liu, Bigang; Gong, Shuai; Li, Qiuhui; Chen, Xin; Moore, John; Suraneni, Mahipal V; Badeaux, Mark D; Jeter, Collene R; Shen, Jianjun; Mehmood, Rashid; Fan, Qingxia; Tang, Dean G

    2017-08-08

    This project was undertaken to address a critical cancer biology question: Is overexpression of the pluripotency molecule Nanog sufficient to initiate tumor development in a somatic tissue? Nanog1 is critical for the self-renewal and pluripotency of ES cells, and its retrotransposed homolog, NanogP8 is preferentially expressed in somatic cancer cells. Our work has shown that shRNA-mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 promotes cancer stem cell phenotypes and properties. To address the key unanswered question whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo , we generated a NanogP8 transgenic mouse model, in which the ARR 2 PB promoter was used to drive NanogP8 cDNA. Surprisingly, the ARR 2 PB-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors in >2 years. Also, both wild type and ARR 2 PB-NanogP8 transgenic mice responded similarly to castration and regeneration and castrated ARR 2 PB-NanogP8 transgenic mice also did not develop tumors. By crossing the ARR 2 PB-NanogP8 transgenic mice with ARR 2 PB-Myc (i.e., Hi-Myc) mice, we found that the double transgenic (i.e., ARR 2 PB-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Interestingly, however, we observed white dots in the ventral lobes of the double transgenic prostates, which were characterized as overgrown ductules/buds featured by crowded atypical Nanog-expressing luminal cells. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

  16. Promoting Effects of Milk on the Development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced Mammary Tumors in Rats

    International Nuclear Information System (INIS)

    Ma, De-Fu; Katoh, Ryohei; Zhou, Hong; Wang, Pei-Yu

    2007-01-01

    To assess the effect of milk on the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, 48 female Sprague-Dawley rats treated with DMBA were divided into 3 groups and given 1 of 3 test solutions for 20 weeks as their drinking liquid: milk, estrone sulfate solution or tap water. The milk group showed a significantly great incidence (75%) in tumor development compared with the water group (38%) and was comparable to the estrone sulfate group (69%). Mean tumor number per rat in the milk group was significantly higher than that in the water group (p=0.009). We classified the mammary tumors into three histological types: intraductal papilloma, fibroadenoma, and adenocarcinoma. Although the percent of intraductal papilloma and fibroadenoma was almost same among the three groups, malignant tumor was found only in the milk and estrone sulfate groups. In conclusion, our results indicate that milk as well as estrone sulfate promotes the development of DMBA-induced mammary tumors in rat and could be associated with the occurrence of adenocarcinoma

  17. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression.

    Science.gov (United States)

    Scarlatti, G; Tresoldi, E; Björndal, A; Fredriksson, R; Colognesi, C; Deng, H K; Malnati, M S; Plebani, A; Siccardi, A G; Littman, D R; Fenyö, E M; Lusso, P

    1997-11-01

    Following the identification of the C-C chemokines RANTES, MIP-1alpha and MIP-1beta as major human immunodeficiency virus (HIV)-suppressive factors produced by CD8+ T cells, several chemokine receptors were found to serve as membrane co-receptors for primate immunodeficiency lentiretroviruses. The two most widely used co-receptors thus far recognized, CCR5 and CXCR4, are expressed by both activated T lymphocytes and mononuclear phagocytes. CCR5, a specific RANTES, MIP-1alpha and MIP-1 receptor, is used preferentially by non-MT2-tropic HIV-1 and HIV-2 strains and by simian immunodeficiency virus (SIV), whereas CXCR4, a receptor for the C-X-C chemokine SDF-1, is used by MT2-tropic HIV-1 and HIV-2, but not by SIV. Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co-receptors for selected viral isolates. The third variable region (V3) of the gp120 envelope glycoprotein of HIV-1 has been fingered as a critical determinant of the co-receptor choice. Here, we document a consistent pattern of evolution of viral co-receptor usage and sensitivity to chemokine-mediated suppression in a longitudinal follow-up of children with progressive HIV-1 infection. Viral isolates obtained during the asymptomatic stages generally used only CCR5 as a co-receptor and were inhibited by RANTES, MIP-1alpha and MIP-1beta, but not by SDF-1. By contrast, the majority of the isolates derived after the progression of the disease were resistant to C-C chemokines, having acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage. Surprisingly, most of these isolates were also insensitive to SDF-1, even when used in combination with RANTES. An early acquisition of CXCR4 usage predicted a poor prognosis. In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines. Discrete changes in the V3 domain

  18. Backbone dynamics of the human CC-chemokine eotaxin

    Energy Technology Data Exchange (ETDEWEB)

    Ye Jiqing; Mayer, Kristen L.; Stone, Martin J. [Indiana University, Department of Chemistry (United States)

    1999-10-15

    Eotaxin is a CC chemokine with potent chemoattractant activity towards eosinophils. {sup 15}N NMR relaxation data have been used to characterize the backbone dynamics of recombinant human eotaxin. {sup 15}N longitudinal (R{sub 1}) and transverse (R{sub 2}) auto relaxation rates, heteronuclear {sup 1}H-{sup 15}N steady-state NOEs, and transverse cross-relaxation rates ({eta}{sub xy}) were obtained at 30 deg. C for all resolved backbone secondary amide groups using {sup 1} H-detected two-dimensional NMR experiments. Ratios of transverse auto and cross relaxation rates were used to identify NH groups influenced by slow conformational rearrangement. Relaxation data were fit to the extended model free dynamics formalism, yielding parameters describing axially symmetric molecular rotational diffusion and the internal dynamics of each NH group. The molecular rotational correlation time ({tau}{sub m}) is 5.09{+-}0.02 ns, indicating that eotaxin exists predominantly as a monomer under the conditions of the NMR study. The ratio of diffusion rates about unique and perpendicular axes (D{sub parallel}/D{sub perpendicular}) is 0.81{+-}0.02. Residues with large amplitudes of subnanosecond motion are clustered in the N-terminal region (residues 1-19), the C-terminus (residues 68-73) and the loop connecting the first two {beta}-strands (residues 30-37). N-terminal flexibility appears to be conserved throughout the chemokine family and may have implications for the mechanism of chemokine receptor activation. Residues exhibiting significant dynamics on the microsecond-millisecond time scale are located close to the two conserved disulfide bonds, suggesting that these motions may be coupled to disulfide bond isomerization.

  19. The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain ChemokineChemokine Receptor Network: A Molecular Study in an Animal Model of Depression

    Directory of Open Access Journals (Sweden)

    Ewa Trojan

    2017-11-01

    Full Text Available An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokinechemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α, CX3CL1 (fractalkine and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1, was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine

  20. Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

    DEFF Research Database (Denmark)

    Nijnik, Anastasia; Madera, Laurence; Ma, Shuhua

    2010-01-01

    and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host...... defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity....

  1. Interferon-regulated chemokine score associated with improvement in disease activity in refractory myositis patients treated with rituximab.

    Science.gov (United States)

    López De Padilla, Consuelo M; Crowson, Cynthia S; Hein, Molly S; Strausbauch, Michael A; Aggarwal, Rohit; Levesque, Marc C; Ascherman, Dana P; Oddis, Chester V; Reed, Ann M

    2015-01-01

    The purpose of this study was to investigate whether serum interferon (IFN)-regulated chemokine and distinct cytokine response profiles are associated with clinical improvement in patients with refractory inflammatory myopathy treated with rituximab. In a randomised, placebo-phase trial Rituximab in Myositis Trial (RIM), 200 refractory adult and paediatric myositis subjects received rituximab. Following rituximab, clinical response and disease activity were assessed. Serum samples and clinical data were collected at baseline and several time-points after rituximab treatment. Multiplexed sandwich immunoassays quantified serum levels of IFN-regulated chemokines and other pro-inflammatory cytokines. Composite IFN-regulated chemokine and Th1, Th2, Th17 and regulatory cytokine scores were computed. Baseline IFN-regulated chemokine, Th1, Th2, Th17 and regulatory cytokine scores correlated with baseline physician global VAS, whereas the baseline Th1, Th2 and Th17 cytokine scores correlated with baseline muscle VAS. We also found baseline IFN-regulated chemokine scores correlated with specific non-muscular targets such as baseline cutaneous (r=0.29; p=0.002) and pulmonary (r=0.18; p=0.02) VAS scores. Among all cytokine/chemokines examined, the baseline score of IFN-regulated chemokines demonstrated the best correlation with changes in muscle VAS at 8 (r=-0.19; p=0.01) and 16 weeks (r=-0.17; p=0.03) following rituximab and physician global VAS at 16 weeks (r=-0.16; p=0.04). In vitro experiments showed increased levels of IL-8 (p=0.04), MCP-1 (p=0.04), IL-6 (p=0.03), IL-1β (p=0.04), IL-13 (p=0.04), IL-10 (p=0.02), IL-2 (p=0.04) and IFN-γ (p=0.02) in supernatants of TLR-3 stimulated PBMCs from non-responder compared to patients responders to rituximab. IFN-regulated chemokines before treatment is associated with improvement in disease activity measures in refractory myositis patients treated with rituximab.

  2. B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.

    Directory of Open Access Journals (Sweden)

    Kavitha Kothur

    Full Text Available Myelin oligodendrocyte glycoprotein antibody (MOG Ab associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS and -negative (NEG groups.We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8, transverse myelitis (TM = 2 n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9 demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19 as well as some of Th17 related cytokines (IL-6 AND G-CSF compared to MOG Ab NEG group (all p<0.01. In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

  3. Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Ransohoff, R M; Strieter, R M

    2004-01-01

    The chemokine monocyte chemoattractant protein (MCP)-1/CCL2 and its receptor CCR2 have been strongly implicated in disease pathogenesis in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), whereas data on the CCL2-CCR2 axis are scarce in MS. We studied...... the expression of CCR2 on leukocytes in blood and cerebrospinal fluid (CSF) from patients with monosymptomatic optic neuritis and MS, and the concentration of CCL2 in the CSF from these patients. Results were compared with the results in non-inflammatory neurological controls and were correlated with other...... parameters (magnetic resonance imaging and CSF data). Our findings suggest a limited role for CCL2/CCR2 in early active MS....

  4. Structure, function and physiological consequences of virally encoded chemokine seven transmembrane receptors

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Smit, M J; Waldhoer, M

    2008-01-01

    A number of human and animal herpes viruses encode G-protein coupled receptors with seven transmembrane (7TM) segments-most of which are clearly related to human chemokine receptors. It appears, that these receptors are used by the virus for immune evasion, cellular transformation, tissue targeting...... pathogenesis is still poorly understood. Here we focus on the current knowledge of structure, function and trafficking patterns of virally encoded chemokine receptors and further address the putative roles of these receptors in virus survival and host -cell and/or -immune system modulation. Finally, we...

  5. CXCL5 Promotes Prostate Cancer Progression

    Directory of Open Access Journals (Sweden)

    Lesa A Begley

    2008-03-01

    Full Text Available CXCL5 is a proangiogenic CXC-type chemokine that is an inflammatory mediator and a powerful attractant for granulocytic immune cells. Unlike many other chemokines, CXCL5 is secreted by both immune (neutrophil, monocyte, and macrophage and nonimmune (epithelial, endothelial, and fibroblastic cell types. The current study was intended to determine which of these cell types express CXCL5 in normal and malignant human prostatic tissues, whether expression levels correlated with malignancy and whether CXCL5 stimulated biologic effects consistent with a benign or malignant prostate epithelial phenotype. The results of these studies show that CXCL5 protein expression levels are concordant with prostate tumor progression, are highly associated with inflammatory infiltrate, and are frequently detected in the lumens of both benign and malignant prostate glands. Exogenous administration of CXCL5 stimulates cellular proliferation and gene transcription in both nontransformed and transformed prostate epithelial cells and induces highly aggressive prostate cancer cells to invade through synthetic basement membrane in vitro. These findings suggest that the inflammatory mediator, CXCL5, may play multiple roles in the etiology of both benign and malignant proliferative diseases in the prostate.

  6. Transcriptional profiling provides insights into metronomic cyclophosphamide-activated, innate immune-dependent regression of brain tumor xenografts

    International Nuclear Information System (INIS)

    Doloff, Joshua C; Waxman, David J

    2015-01-01

    Cyclophosphamide treatment on a six-day repeating metronomic schedule induces a dramatic, innate immune cell-dependent regression of implanted gliomas. However, little is known about the underlying mechanisms whereby metronomic cyclophosphamide induces innate immune cell mobilization and recruitment, or about the role of DNA damage and cell stress response pathways in eliciting the immune responses linked to tumor regression. Untreated and metronomic cyclophosphamide-treated human U251 glioblastoma xenografts were analyzed on human microarrays at two treatment time points to identify responsive tumor cell-specific factors and their upstream regulators. Mouse microarray analysis across two glioma models (human U251, rat 9L) was used to identify host factors and gene networks that contribute to the observed immune and tumor regression responses. Metronomic cyclophosphamide increased expression of tumor cell-derived DNA damage, cell stress, and cell death genes, which may facilitate innate immune activation. Increased expression of many host (mouse) immune networks was also seen in both tumor models, including complement components, toll-like receptors, interferons, and cytolysis pathways. Key upstream regulators activated by metronomic cyclophosphamide include members of the interferon, toll-like receptor, inflammatory response, and PPAR signaling pathways, whose activation may contribute to anti-tumor immunity. Many upstream regulators inhibited by metronomic cyclophosphamide, including hypoxia-inducible factors and MAP kinases, have glioma-promoting activity; their inhibition may contribute to the therapeutic effectiveness of the six-day repeating metronomic cyclophosphamide schedule. Large numbers of responsive cytokines, chemokines and immune regulatory genes linked to innate immune cell recruitment and tumor regression were identified, as were several immunosuppressive factors that may contribute to the observed escape of some tumors from metronomic CPA

  7. Stromal-dependent tumor promotion by MIF family members.

    Science.gov (United States)

    Mitchell, Robert A; Yaddanapudi, Kavitha

    2014-12-01

    Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Astrocyte production of the chemokine macrophage inflammatory protein-2 is inhibited by the spice principle curcumin at the level of gene transcription

    Directory of Open Access Journals (Sweden)

    Santoro Thomas J

    2005-02-01

    Full Text Available Abstract Background In neuropathological processes associated with neutrophilic infiltrates, such as experimental allergic encephalitis and traumatic injury of the brain, the CXC chemokine, macrophage inflammatory protein-2 (MIP-2 is thought to play a pivotal role in the induction and perpetuation of inflammation in the central nervous system (CNS. The origin of MIP-2 in inflammatory disorders of the brain has not been fully defined but astrocytes appear to be a dominant source of this chemokine. Curcumin is a spice principle in, and constitutes approximately 4 percent of, turmeric. Curcumin's immunomodulating and antioxidant activities suggest that it might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation. Relatively unexplored, but relevant to its potential therapeutic efficacy in neuroinflammatory syndromes is the effect of curcumin on chemokine production. To examine the possibility that curcumin may influence CNS inflammation by mechanisms distinct from its known anti-oxidant activities, we studied the effect of this spice principle on the synthesis of MIP-2 by astrocytes. Methods Primary astrocytes were prepared from neonatal brains of CBA/CaJ mice. The cells were stimulated with lipopolysaccharide in the presence or absence of various amount of curcumin or epigallocatechin gallate. MIP-2 mRNA was analyzed using semi-quantitative PCR and MIP-2 protein production in the culture supernatants was quantified by ELISA. Astrocytes were transfected with a MIP-2 promoter construct, pGL3-MIP-2, and stimulated with lipopolysaccharide in the presence or absence of curcumin. Results The induction of MIP-2 gene expression and the production of MIP-2 protein were inhibited by curcumin. Curcumin also inhibited lipopolysaccharide-induced transcription of the MIP-2 promoter reporter gene construct in primary astrocytes. However MIP-2 gene induction by lipopolysaccharide was not inhibited by another anti

  9. Astrocyte production of the chemokine macrophage inflammatory protein-2 is inhibited by the spice principle curcumin at the level of gene transcription.

    Science.gov (United States)

    Tomita, Michiyo; Holman, Brita J; Santoro, Christopher P; Santoro, Thomas J

    2005-02-25

    BACKGROUND: In neuropathological processes associated with neutrophilic infiltrates, such as experimental allergic encephalitis and traumatic injury of the brain, the CXC chemokine, macrophage inflammatory protein-2 (MIP-2) is thought to play a pivotal role in the induction and perpetuation of inflammation in the central nervous system (CNS). The origin of MIP-2 in inflammatory disorders of the brain has not been fully defined but astrocytes appear to be a dominant source of this chemokine.Curcumin is a spice principle in, and constitutes approximately 4 percent of, turmeric. Curcumin's immunomodulating and antioxidant activities suggest that it might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation. Relatively unexplored, but relevant to its potential therapeutic efficacy in neuroinflammatory syndromes is the effect of curcumin on chemokine production. To examine the possibility that curcumin may influence CNS inflammation by mechanisms distinct from its known anti-oxidant activities, we studied the effect of this spice principle on the synthesis of MIP-2 by astrocytes. METHODS: Primary astrocytes were prepared from neonatal brains of CBA/CaJ mice. The cells were stimulated with lipopolysaccharide in the presence or absence of various amount of curcumin or epigallocatechin gallate. MIP-2 mRNA was analyzed using semi-quantitative PCR and MIP-2 protein production in the culture supernatants was quantified by ELISA. Astrocytes were transfected with a MIP-2 promoter construct, pGL3-MIP-2, and stimulated with lipopolysaccharide in the presence or absence of curcumin. RESULTS: The induction of MIP-2 gene expression and the production of MIP-2 protein were inhibited by curcumin. Curcumin also inhibited lipopolysaccharide-induced transcription of the MIP-2 promoter reporter gene construct in primary astrocytes. However MIP-2 gene induction by lipopolysaccharide was not inhibited by another anti-oxidant, epigallocatechin

  10. Crystallization and preliminary X-ray analysis of the chemokine-binding protein from orf virus (Poxviridae)

    International Nuclear Information System (INIS)

    Couñago, Rafael Miguez; Fleming, Stephen B.; Mercer, Andrew A.; Krause, Kurt L.

    2010-01-01

    The chemokine-binding protein from orf virus was purified and crystallized. The morphology and diffraction behaviour of these crystals was significantly improved through the use of additives known as Silver Bullets. The parapoxvirus orf virus (ORFV) encodes a chemokine-binding protein (CBP) that functions to downregulate the host’s immune response at the site of infection by blocking the chemokine-induced recruitment of immune cells. In order to shed light on the structural determinants of CBP–chemokine binding, ORFV CBP was crystallized as part of an ongoing structure–function study on this protein. ORFV CBP crystals were obtained by the sitting-drop vapour-diffusion technique using ammonium citrate as a precipitant. The crystal quality was greatly improved through the addition of small-molecule additives to the crystallization mother liquor. ORFV CBP crystals diffracted X-rays to 2.50 Å resolution and belonged to the hexagonal space group P6 1 22 or its enantiomorph P6 5 22, with unit-cell parameters a = b = 75.62, c = 282.49 Å, α = 90, β = 90, γ = 120°

  11. Targeting the chemokine receptor CXCR3 and its ligand CXCL10 in the central nervous system

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke

    2004-01-01

    focuses on the present data regarding CXCL10 (previously known as IP-10) and CXRC3 in multiple sclerosis, since consistent data has suggested that this chemokine/chemokine receptor pair has a pivotal role in leukocyte recruitment into the central nervous system (CNS) in multiple sclerosis....

  12. Abnormal peritoneal regulation of chemokine activation-The role of IL-8 in pathogenesis of endometriosis.

    Science.gov (United States)

    Sikora, Justyna; Smycz-Kubańska, Marta; Mielczarek-Palacz, Aleksandra; Kondera-Anasz, Zdzisława

    2017-04-01

    Endometriosis is a chronic inflammatory disease associated with an impairment in immune response. Disorders in the peritoneal fluid and ectopic endometrium macrophage populations and their secretory products create a specific microenvironment inducing the development of the disease. The important factors involved in inflammation associated with endometriosis are chemokines, especially interleukin (IL)-8. For this reason, the current study briefly reviews the role of IL-8 in the pathogenesis of endometriosis. A systematic review was done on all published studies that compared IL-8 expression and concentration in patients with and without endometriosis to evaluate their potential as biomarkers for the disease. IL-8 induces chemotaxis of neutrophils and other immune cells; also, it is a potent angiogenic agent. Most researchers pointed to the increased peritoneal and serum IL-8 levels and showed correlation with the severity of the disease, size and number of the active lesions. IL-8 takes part in all processes during the development of the disease: adhesion, invasion, and implantation of ectopic tissue. Additionally, the chemokine plays a role in growth and maintenance of ectopic endometrial tissue directly affecting endometrial cell proliferation. IL-8 might also protect ectopic cells against death by apoptosis. It may act as an autocrine growth factor in the endometrium and promotes the vicious circle of endometrial cell attachment and, in consequence, may lead to a transformation from acute to chronic inflammation stage. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Mast cells: potential positive and negative roles in tumor biology.

    Science.gov (United States)

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. ©2013 AACR.

  14. Clinical Utility of promoter methylation of the tumor suppressor genes DKK3, and RASSF1A in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Marwa H. Saied

    2018-04-01

    Full Text Available Background: DNA methylation is the commonest known epigenetic change that results in silencing of tumor suppressor genes. Promoter methylation of tumor suppressor genes has the potential for early detection of breast cancer. Aim: Aim is to examine the potential usefulness of blood based methylation specific polymerase chain reaction (MSP of methylated DKK3 and RASSF1A genes in early detection of breast cancer. Method: Methylation status of DKK3 and RASSF1 was investigated in forty breast cancer patients, twenty fibroadenoma patients and twenty healthy ladies as control group using MSP. Results: Methylation of DKK3 promoter was found in 22.5% of breast cancer patients, while DKK3 methylation was absent in both fibroadenoma patients and control group. Similarly, methylation of RASSF1 promoter was found in 17.5% of breast cancer patients and in none of fibroadenoma and control group. Conclusion: Promoter methylation of DKK3 and RASSF1 was found in breast cancer patients while absent in control group suggesting that tumorspecific methylation of the two genes (DKK3 and RASSF1A might be a valuable biomarker for the early detection of breast cancer. Keywords: DNA methylation, Breast cancer, DKK3, RASSF1

  15. Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

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    Jin Qi

    2017-08-01

    Full Text Available Background/Aims: Mesenchymal stem/stromal cells (MSCs are known to home to sites of tumor microenvironments where they participate in the formation of the tumor microenvironment and to interplay with tumor cells. However, the potential functional effects of MSCs on tumor cell growth are controversial. Here, we, from the view of bone marrow MSC-derived exosomes, study the molecular mechanism of MSCs on the growth of human osteosarcoma and human gastric cancer cells. Methods: MSCs derived from human bone marrow (hBMSCs were isolated and cultured in complete DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin, cell culture supernatants containing exosomes were harvested and exosome purification was performed by ultracentrifugation. Osteosarcoma (MG63 and gastric cancer (SGC7901 cells, respectively, were treated with hBMSC-derived exosomes in the presence or absence of a small molecule inhibitor of Hedgehog pathway. Cell viability was measured by transwell invasion assay, scratch migration assay and CCK-8 test. The expression of the signaling molecules Smoothened, Patched-1, Gli1 and the ligand Shh were tested by western blot and RT-PCR. Results: In this study, we found that hBMSC-derived exosomes promoted MG63 and SGC7901 cell growth through the activation of Hedgehog signaling pathway. Inhibition of Hedgehog signaling pathway significantly suppressed the process of hBMSC-derived exosomes on tumor growth. Conclusion: Our findings demonstrated the new roles of hedgehog signaling pathway in the hBMSCs-derived exosomes induced tumor progression.

  16. Tropoelastin regulates chemokine expression in fibroblasts in Costello syndrome

    International Nuclear Information System (INIS)

    Tatano, Yutaka; Fujinawa, Reiko; Kozutsumi, Yasunori; Takahashi, Tsutomu; Tsuji, Daisuke; Takeuchi, Naohiro; Tsuta, Kohji; Takada, Goro; Sakuraba, Hitoshi; Itoh, Kohji

    2008-01-01

    Costello syndrome is a multiple congenital anomaly associated with growth and mental retardation, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Comprehensive expression analysis revealed remarkable up-regulation of several cytokines and chemokines including Gro family proteins, interleukin-1β (IL-1β), IL-8 and MCP-1 but down-regulation of extracellular matrix components including collagens and proteoglycans of skin fibroblasts derived from a Japanese Costello syndrome patient characterized by significantly reduced tropoelastin mRNA, impaired elastogenesis and enhanced cell proliferation. In contrast, decreases in these chemokines and IL-1β expression were observed in Costello fibroblastic cell lines stably expressing the bovine tropoelastin (btEln) gene and in restored elastic fibers. These results strongly suggest that the human TE gene (ELN) transfer could be applicable for the gene therapy of a group of Costello syndrome patients with reduced ELN gene expression

  17. Low intensity shear stress increases endothelial ELR+ CXC chemokine production via a focal adhesion kinase-p38{beta} MAPK-NF-{kappa}B pathway.

    Science.gov (United States)

    Shaik, Sadiq S; Soltau, Thomas D; Chaturvedi, Gaurav; Totapally, Balagangadhar; Hagood, James S; Andrews, William W; Athar, Mohammad; Voitenok, Nikolai N; Killingsworth, Cheryl R; Patel, Rakesh P; Fallon, Michael B; Maheshwari, Akhil

    2009-02-27

    CXC chemokines with a glutamate-leucine-arginine (ELR) tripeptide motif (ELR(+) CXC chemokines) play an important role in leukocyte trafficking into the tissues. For reasons that are not well elucidated, circulating leukocytes are recruited into the tissues mainly in small vessels such as capillaries and venules. Because ELR(+) CXC chemokines are important mediators of endothelial-leukocyte interaction, we compared chemokine expression by microvascular and aortic endothelium to investigate whether differences in chemokine expression by various endothelial types could, at least partially, explain the microvascular localization of endothelial-leukocyte interaction. Both in vitro and in vivo models indicate that ELR(+) CXC chemokine expression is higher in microvascular endothelium than in aortic endothelial cells. These differences can be explained on the basis of the preferential activation of endothelial chemokine production by low intensity shear stress. Low shear activated endothelial ELR(+) CXC chemokine production via cell surface heparan sulfates, beta(3)-integrins, focal adhesion kinase, the mitogen-activated protein kinase p38beta, mitogen- and stress-associated protein kinase-1, and the transcription factor.

  18. PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth.

    Directory of Open Access Journals (Sweden)

    Michael C Schmid

    Full Text Available Tumor inflammation, the recruitment of myeloid lineage cells into the tumor microenvironment, promotes angiogenesis, immunosuppression and metastasis. CD11b+Gr1lo monocytic lineage cells and CD11b+Gr1hi granulocytic lineage cells are recruited from the circulation by tumor-derived chemoattractants, which stimulate PI3-kinase γ (PI3Kγ-mediated integrin α4 activation and extravasation. We show here that PI3Kγ activates PLCγ, leading to RasGrp/CalDAG-GEF-I&II mediated, Rap1a-dependent activation of integrin α4β1, extravasation of monocytes and granulocytes, and inflammation-associated tumor progression. Genetic depletion of PLCγ, CalDAG-GEFI or II, Rap1a, or the Rap1 effector RIAM was sufficient to prevent integrin α4 activation by chemoattractants or activated PI3Kγ (p110γCAAX, while activated Rap (RapV12 promoted constitutive integrin activation and cell adhesion that could only be blocked by inhibition of RIAM or integrin α4β1. Similar to blockade of PI3Kγ or integrin α4β1, blockade of Rap1a suppressed both the recruitment of monocytes and granulocytes to tumors and tumor progression. These results demonstrate critical roles for a PI3Kγ-Rap1a-dependent pathway in integrin activation during tumor inflammation and suggest novel avenues for cancer therapy.

  19. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth

    Science.gov (United States)

    Yin, Yuan; Cai, Xing; Chen, Xi; Liang, Hongwei; Zhang, Yujing; Li, Jing; Wang, Zuoyun; Chen, Xiulan; Zhang, Wen; Yokoyama, Seiji; Wang, Cheng; Li, Liang; Li, Limin; Hou, Dongxia; Dong, Lei; Xu, Tao; Hiroi, Takachika; Yang, Fuquan; Ji, Hongbin; Zhang, Junfeng; Zen, Ke; Zhang, Chen-Yu

    2014-01-01

    An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion. PMID:25223704

  20. Tumor suppressor maspin as a modulator of host immune response to cancer

    Directory of Open Access Journals (Sweden)

    Sijana H. Dzinic

    2015-10-01

    Full Text Available Despite the promising clinical outcome, the primary challenge of the curative cancer immunotherapy is to overcome the dichotomy of the immune response: tumor-evoked immunostimulatory versus tumor-induced immunosuppressive. The goal needs to be two-fold, to re-establish sustainable antitumor-cancer immunity and to eliminate immunosuppression. The successful elimination of cancer cells by immunosurveillance requires the antigenic presentation of the tumor cells or tumor-associated antigens and the expression of immunostimulatory cytokines and chemokines by cancer and immune cells. Tumors are heterogeneous and as such, some of the tumor cells are thought to have stem cell characteristics that enable them to suppress or desensitize the host immunity due to acquired epigenetic changes. A central mechanism underlying tumor epigenetic instability is the increased histone deacetylase (HDAC-mediated repression of HDAC-target genes regulating homeostasis and differentiation. It was noted that pharmacological HDAC inhibitors are not effective in eliminating tumor cells partly because they may induce immunosuppression. We have shown that epithelial-specific tumor suppressor maspin, an ovalbumin-like non-inhibitory serine protease inhibitor, reprograms tumor cells toward better differentiated phenotypes by inhibiting HDAC1. Recently, we uncovered a novel function of maspin in directing host immunity towards tumor elimination. In this review, we discuss the maspin and maspin/HDAC1 interplay in tumor biology and immunology. We propose that maspin based therapies may eradicate cancer.

  1. Inhibition of gap-junctional intercellular communication and activation of mitogen-activated protein kinases by cyanobacterial extracts--indications of novel tumor-promoting cyanotoxins?

    Science.gov (United States)

    Bláha, Ludĕk; Babica, Pavel; Hilscherová, Klára; Upham, Brad L

    2010-01-01

    Toxicity and liver tumor promotion of cyanotoxins microcystins have been extensively studied. However, recent studies document that other metabolites present in the complex cyanobacterial water blooms may also have adverse health effects. In this study we used rat liver epithelial stem-like cells (WB-F344) to examine the effects of cyanobacterial extracts on two established markers of tumor promotion, inhibition of gap-junctional intercellular communication (GJIC) and activation of mitogen-activated protein kinases (MAPKs) - ERK1/2. Extracts of cyanobacteria (laboratory cultures of Microcystis aeruginosa and Aphanizomenon flos-aquae and water blooms dominated by these species) inhibited GJIC and activated MAPKs in a dose-dependent manner (effective concentrations ranging 0.5-5mgd.w./mL). Effects were independent of the microcystin content and the strongest responses were elicited by the extracts of Aphanizomenon sp. Neither pure microcystin-LR nor cylindrospermopsin inhibited GJIC or activated MAPKs. Modulations of GJIC and MAPKs appeared to be specific to cyanobacterial extracts since extracts from green alga Chlamydomonas reinhardtii, heterotrophic bacterium Klebsiella terrigena, and isolated bacterial lipopolysaccharides had no comparable effects. Our study provides the first evidence on the existence of unknown cyanobacterial toxic metabolites that affect in vitro biomarkers of tumor promotion, i.e. inhibition of GJIC and activation of MAPKs.

  2. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    DEFF Research Database (Denmark)

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel

    2017-01-01

    of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin...... A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher...... selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate...

  3. The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Ron L H Har

    Full Text Available Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR(cystatin. Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors.Urine and serum cytokines/chemokines (Luminex platform and GFR(cystatin were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m(2 and hyperfiltering (n = 31, T1D-H, GFR ≥ 135 ml/min/1.73 m(2 adolescents with T1D (ages 10-16, and in age and sex matched healthy control subjects (HC, n = 59.We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076.Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.

  4. A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6

    DEFF Research Database (Denmark)

    Lüttichau, Hans R; Clark-Lewis, Ian; Jensen, Peter Østrup

    2003-01-01

    The chemokine-like, secreted protein product of the U83 gene from human herpesvirus 6, here named vCCL4, was chemically synthesized to be characterized in a complete library of the 18 known human chemokine receptors expressed individually in stably transfected cell lines. vCCL4 was found to cause...... being equally or more efficacious in causing cell migration than CCL2 and CCL7 and considerably more efficacious than CCL8 and CCL13. It is concluded that human herpesvirus 6 encodes a highly selective and efficacious CCR2 agonist, which will attract CCR2 expressing cells, for