Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunobiology of tumor-infiltrating dendritic cells (DCs) can be strongly influenced by the cytokine environment present in the malignant tissue. We have previously identified discrete melanoma lines, inducing E-cadherin expression on monocyte-derived DCs in vitro. We demonstrate here that this effect, independent of cell contact, is not inducible in the presence of tumor lysates and requires the constitutive expression of IFN stimulated gene 15 (ISG15) by malignant cells. High-density oligonucleotide arrays were used to investigate the expression pattern of 7000 genes in RNA from two melanoma cell clones competent for E-cadherin induction and two clones devoid of DC-modulating capacity. A total of 13 genes encoding soluble proteins were expressed at higher magnitude in melanomas able to induce E-cadherin expression on DCs. Combining those data with quantitative protein assays, we could narrow our investigation down to three factors: the chemokine CCL5 and the cytokines ISG15 and type I IFNs. Strikingly, >7 ng/ml of ISG15 could be detected in the corresponding melanoma-conditioned medium and induction of E-cadherin on DCs failed in the presence of antibodies neutralizing ISG15 protein. Most importantly, strong cytoplasmic expression of ISG15 was detected by immunohistochemistry in the original tumor specimen from which the melanoma cell lines under investigation were derived. These data describe a novel property of ISG15 targeting induction of E-cadherin on DCs and possibly influencing their migratory behavior.
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PMID:Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells. 1206 88

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein alpha), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-kappaB. The constitutive NF-kappaB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-kappaB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-kappaB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-kappaB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-kappaB and chemokine expression are discussed.
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PMID:Role of CXCL1 in tumorigenesis of melanoma. 1210 Dec 57

The chemokine stromal cell-derived factor 1 (SDF-1) is essential for perinatal viability, B lymphopoiesis, and bone marrow myelopoiesis, and is a potent monocyte and T-lymphocyte chemoattractant. Interactions of SDF-1 with its receptor CXCR4 have been implicated in CD34(+) cell migration and homing. Here it is shown that human SDF-1beta (hSDF-1beta) alone secreted by hSDF-1beta-transduced tumor cells promotes efficacious antitumor responses. The murine C1498 leukemia and B16F1 melanoma models have been studied. For expression of hSDF-1beta by tumor cells (SDF-tumor cells), packaging cell lines secreting retroviruses encoding hSDF-1beta have been used. The results demonstrate that 50% (B16F1) and 90% (C1498) of naive mice injected with SDF-tumor cells reject their tumors. Prophylactic vaccination of naive mice with irradiated SDF-tumor cells leads to systemic immunity, and therapeutic vaccination leads to cure of established tumors. Mice that previously rejected live SDF-tumor cells are immune to the rejected tumor but susceptible to another tumor and have in vitro tumor-specific cytotoxic T lymphocyte (CTL) activity. SDF-tumor cells are not rejected by immunodeficient scid mice. Immunohistochemistry shows significant infiltration of SDF-1 tumors by T cells, and in vivo T-cell depletion studies indicate that CD4(+) T cells are required for SDF-mediated tumor rejection. In conclusion, the present data suggest that SDF-1/CXCR4 interactions have the potential to regulate efficacious antitumor immune responses; exploitation of these interactions may lead to novel therapeutic interventions.
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PMID:Efficacious immunomodulatory activity of the chemokine stromal cell-derived factor 1 (SDF-1): local secretion of SDF-1 at the tumor site serves as T-cell chemoattractant and mediates T-cell-dependent antitumor responses. 1217 69

T-cell-based immunotherapies provide a promising means of cancer treatment although durable antitumor responses are infrequent. A potential reason for these shortcomings may lie in the observed lack of trafficking of specific T cells to tumor. Our increasing knowledge of the process of trafficking involving adhesion molecules and chemokines affords us the opportunity to intervene and correct deficiencies in this process. Chemokines can be expressed by a range of tumors and may serve as suitable targets for directing specific T cells toward tumor. We initially sought to identify which chemokines were produced by a range of human tumor cell lines, and which chemokines and chemokine receptors were expressed by cultured T cells. We identified two chemokines: Growth-Regulated Oncogene-alpha (Gro-alpha; CXCL1) and Regulated on Activation Normal T Cell-Expressed and Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines. Expression was also detected in fine-needle aspirates of melanoma from patients. In addition, we determined the expression of several chemokine receptors on cultured human T cells including CCR1, CCR2, CCR4, CCR5, CXCR3, and CXCR4. Cultured, activated human T cells expressed the chemokines lymphotactin (XCL1), RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha; CCL3) and MIP-1 beta (CCL4), but no appreciable Gro-alpha. In a strategy to direct T cells toward chemokines expressed by tumors we chose Gro-alpha as the target chemokine because it was produced by tumor and not by T cells themselves. However, T cells did not express the receptor for Gro-alpha, CXCR2, and therefore, T cells were transduced with a retroviral vector encoding CXCR2. Calcium ion mobilization, an important first step in chemokine receptor signaling, was subsequently demonstrated in transduced T cells in response to Gro-alpha. In addition, Gro-alpha was chemotactic for T cells expressing CXCR2 in vitro toward both recombinant protein and tumor-derived chemokine. Interestingly we demonstrate, for the first time, that Gro-alpha was able to induce interferon-gamma (IFN-gamma) secretion from transduced T cells, thereby extending our knowledge of other potential functions of CXCR2. This study demonstrates the feasibility of redirecting the migration properties of T cells toward chemokines secreted by tumors.
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PMID:Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. 1242 7

The chemokine receptors CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR) 4 have been implicated in cancer metastasis. To evaluate whether CXCR4 is sufficient to increase tumor metastasis in an organ-specific manner, we transduced murine B16 melanoma cells with CXCR4 (CXCR4-B16) and followed the metastatic fate of the transduced cells in both i.v. and s.c. inoculation models of metastasis. CXCR4-B16 cells demonstrated marked increases (>10-fold) in pulmonary metastasis compared with vector (pLNCX2)-B16 after i.v. and s.c. inoculation of tumor cells. The increase in metastasis could be completely inhibited by T22, a small peptide antagonist of CXCR4. As early as 24 and 48 h after i.v. injection, CXCR4-B16 cells were significantly increased in the lung compared with control B16 cells by 5- and 10-fold (P < 0.05), respectively. CXCR4-B16 cells adhered better to both dermal and pulmonary microvascular endothelial cells relative to control B16 cells. Moreover, CXCL12 promoted the growth of CXCR4-B16 cells in vitro. Whereas expression of CXCR4 in B16 cells dramatically enhanced pulmonary metastasis, metastasis to the lymph nodes, liver, and kidney was rare. Immunohistochemical staining of both primary human cutaneous melanoma and pulmonary metastases revealed CXCR4 expression. Thus, CXCR4 plays a potentially important role in promoting organ-selective metastasis, possibly by stimulating tumor adhesion to microvascular endothelial cells and by enhancing the growth of tumor cells under stress.
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PMID:Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. 1249 76

Currently most attempts at cancer immunotherapy involve the generation of CD8(+) cytotoxic T lymphocytes (CTLs) against tumor-associated antigens. Many tumors, however, have been immunoselected to evade recognition by CTLs and thus alternative approaches to cancer immunotherapy are urgently needed. Here we demonstrate that CD4(+) T cells that recognize a secreted tumor-specific antigen and exhibit a cytokine secretion profile characteristic of Th2 cells, are capable of clearing established lung and visceral metastases of a CTL-resistant melanoma. Clearance of lung metastases by the Th2 cells was found to be totally dependent on the eosinophil chemokine, eotaxin, and partially dependent on the transcription activator signal transducer and activator of transcription 6 (STAT6), with degranulating eosinophils within the tumors inducing tumor regression. In contrast, tumor-specific CD4(+) Th1 cells, that recruited macrophages into the tumors, had no effect on tumor growth. This work provides the basis for a new approach to adoptive T cell immunotherapy of cancer.
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PMID:Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process. 1256 22

Previous work has shown that dendritic cells (DCs) express specific chemokine receptors that allow for coordinated movement in vivo. To test the in vivo relevance of this, we used a murine melanoma system and knockout mice to investigate the function of the chemokine receptor CCR5 and its ligands, CCR ligand (CCL)3 and CCL5. We found that the lack of CCR5 in the host mouse resulted in delayed tumor growth, but this effect was overcome at a higher tumor load. With the administration of tumor charged DCs, CCR5(-/-) mice that had previously been injected with tumor were completely protected from tumor. This effect was dependent on the dose of tumor cells and the expression of CCR5 on the DC and its absence in the host. In contrast, the loss of the CCR5 ligand, CCL3, led to an early delay in tumor growth that did not persist, while the absence of the CCR5 ligand, CCL5, had no effect. Blocking the activity of CCR5 in the host may represent a new strategy for enhancing the activity of a therapeutic melanoma DC vaccine.
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PMID:Host absence of CCR5 potentiates dendritic cell vaccination. 1268 53

The CXC-chemokines Groalpha and interleukin-8 (IL-8) are ligands for two different G protein-coupled receptors, named CXC-chemokine receptor I & II (CXCRI & II). Both cytokines are potent growth factors for human melanoma cells, with only limited proliferative activity towards normal melanocytes. Here we analysed the influence of various cytokines on the expression of CXCRI & II and the CXC-chemokine-induced proliferation in human melanocytes. Flow cytometric studies revealed no protein expression of CXCRI and low protein expression of CXCRII at the cell surface of normal melanocytes. Tumor necrosis factor alpha (TNFalpha) enhanced the mRNA and protein expression of CXCRII, but did not influence expression of CXCRI. A consequence of TNFalpha-pretreatment of human melanocytes was a significant enhancement of the proliferative activity of IL-8 and Groalpha. This study implicates that TNFalpha magnifies the biological activity of CXC-chemokines in melanocytes by induction of CXCRII expression.
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PMID:Tumor necrosis factor alpha induces upregulation of CXC-chemokine receptor type II expression and magnifies the proliferative activity of CXC-chemokines in human melanocytes. 1269 26

The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been recognized for over 200 years, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation. Sentinel lymph node biopsy has rapidly entered the clinical mainstream for melanoma and breast carcinoma, and this technique has provided confirmation of the orderly anatomic progression of tumor cells from primary site to the RLNs through lymphatic capillaries and trunks. Exciting studies involving the pathophysiology of interstitial fluid pressure in tumors and the peritumoral extracellular matrix have focused on lymphatic flow and tumor microenvironment and microcirculation. Molecular techniques have led to the definition of unique markers found on lymphatic endothelial cells. These markers have enabled scientists to identify peritumoral and intratumoral lymphatics and to visualize the ingrowth of tumor cells into the lumena of lymphatic capillaries. Tumor-secreted cytokines, such as vascular endothelial growth factors (VEGF)-C and -D, bind to VEGF receptors on lymphatic endothelial cells and induce proliferation and growth of new lymphatic capillaries; this process is similar to the well-known mechanism of angiogenesis, which results from the proliferation of new blood vessel capillaries. Lymphangiogenesis is associated with an increased incidence of RLN metastasis, and it is possible that this step is essential to the metastatic process. Directional movement toward lymphatics and lymph nodes appears to follow a chemokine gradient, and it is likely that some tumor cells that express certain types of chemokine receptors are more likely to metastasize to the RLNs. In contrast, tumor cells that do not express specific receptors that are responsive to lymphatic chemokines may not metastasize. New knowledge regarding the molecules involved in these processes should enable improvements in prognostic and possibly therapeutic approaches to the management of malignant tumors.
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PMID:Insights into the mechanisms of lymph node metastasis. 1287 64

Platelet endothelial cell adhesion molecule (PECAM-1/CD31), a member of the immunoglobulin superfamily expressed at high levels on endothelial cells, has been recently implicated in angiogenesis. Although antagonism of PECAM-1 inhibited neovascularization in two different animal models of growth factor/chemokine-induced angiogenesis, its participation in tumor angiogenesis has not been established. We therefore investigated its involvement in models of tumor angiogenesis in mice. An antibody against murine PECAM-1 that was shown to block in vitro murine endothelial tube formation inhibited the subcutaneous growth and tumor vascularity of three tumors in mice: A549 human non-small cell lung cancer in SCID mice, B16 murine melanoma in C57BL/6 mice and AB12 murine mesothelioma in Balb/c mice. These studies suggest a possible role for PECAM-1 in the complex process of tumor angiogenesis and provide additional evidence of the importance of endothelial cell adhesion molecules to the formation of new vessels.
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PMID:Antibody against murine PECAM-1 inhibits tumor angiogenesis in mice. 1451 36


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