Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intercellular adhesion molecule-1 (ICAM-1, CD54), a molecule bound to the cell surface membrane, mediates various cell-cell interactions in inflammation and immunosurveillance. By means of a new specific enzyme-linked immunosorbent assay (ELISA) for soluble ICAM-1, free circulating ICAM-1 was measured in serum from five healthy volunteers, 10 melanoma patients at different stages of their disease, and eight patients receiving high-dose interleukin-2 (IL-2) for metastatic melanoma. No correlation between the concentration of circulating ICAM-1 and the tumor burden could be detected. In melanoma patients receiving high-dose IL-2, we observed an increase of circulating ICAM-1 of up to 200%, compared to the concentration prior to therapy, ranging between 4 and 13 ng/ml. The increase in circulating ICAM-1 was associated with the induction of tumor necrosis factor-alpha and interferon-gamma.
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PMID:Circulating intercellular adhesion molecule-1 in melanoma patients: induction by interleukin-2 therapy. 135 85

The role of cell adhesion molecules (CAM) LFA1, ICAM-1, LFA3, VLA1, VLA4, CD29, CD44, and CD56 in tumor-infiltrating lymphocyte (TIL) and natural killer cell (NK)-mediated killing of target cells was studied. Melanoma cell lines and autologous TIL were derived from seven patients with metastatic melanoma, and cytotoxicity assays were done in the presence and absence of monoclonal antibodies (MoAb) to CAM expressed on melanoma cells or TIL. The melanoma cell lines analyzed were all positive for CD29 and LFA3 expression, negative for LFA1 expression, but showed variable expression of ICAM-1, VLA1, VLA4, CD44, and CD56. The effects of anti-CAM antibodies on TIL-mediated melanoma killing fell into three categories: (1) consistent inhibition of TIL-mediated killing was observed when melanoma cells were pretreated with anti-ICAM1 and anti-LFA-3 MoAb or when TIL were pretreated with anti-LFA1; (2) no effect was observed when melanoma cells were pretreated with anti-CD56; or (3) a discreet, but significant, inhibition was observed when target cells were pretreated with anti-CD29, anti-VLA1, anti-VLA4, and anti-CD44. Cytotoxicity was significantly enhanced by pretreatment of target cells with gamma-interferon (gamma-IFN), although gamma-IFN did not augment surface expression of the CAM studied. The NK-mediated killing of K562 cells was blocked by anti-LFA1, anti-CD18, and anti-ICAM, and partially inhibited by anti-CD44 MoAb. Together, these results suggest that several accessory CAM may play a role in regulating cellular cytotoxicity. Because cytotoxicity generally correlated with the level of expression of CAM in melanoma cells, weak CAM surface expression may provide a means for melanomas to escape immune surveillance.
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PMID:Expression of cell adhesion molecules in human melanoma cell lines and their role in cytotoxicity mediated by tumor-infiltrating lymphocytes. 173 16

Antigen expression was studied by immunohistochemistry in 133 human melanocytic skin lesions to gain insight into the initial steps of tumor development, i.e. in particular the change from melanocytes to benign nevi. We refer to the proposed progression model of Clark and co-workers. The following types of antigens were investigated: (i) intermediate filament antigens (vimentin), (ii) melanoma-associated antigens (HMB-45, NKI/C3, MA-930, LS59), (iii) proliferation-associated antigens (S-100, Ki67, Ro/SSA, calmodulin), (iv) progression-associated antigens (HLA-DR, ICAM-1), and (v) basal membrane antigens (bullous pemphigoid antigen, laminin, fibronectin, collagen type IV). The intensity of expression and the topography of immunoreactive pigment cells were compared with the stage of tumor progression. Special attention was paid to the early steps of this process, i.e. the disturbance of the epidermal melanin unit and the development of melanocytic ("nevocellular")nevi. A dramatic shift of antigen expression (antigen types [i] to [v]) was noted in benign nevi compared with melanocytes. Nevi with cellular atypia disclosed a tendency towards an increased percentage of tumor cells reactive for melanoma- and progression-related antigens (types [ii] and [iv]). However, there was no clear cut level of distinction of antigen expression (types [i] to [v]) between benign and primary malignant melanocytic tumors. So-called dysplastic nevi resembled benign tumors or melanocytes rather than malignant melanoma. Metastatic melanoma of skin showed a relatively high number of Ki67-positive, cycling melanoma cells. The results have a bearing on the concepts of melanocytic nevus ontogenesis and "maturation". It appears that melanocytes lose maturity on their way down to the dermis in contrast to traditional concepts (Abtropfung); this might be of importance for our understanding of melanoma development in association with melanocytic nevi. Our findings are discussed with regard to Clark's model of tumor progression.
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PMID:The initial steps of tumor progression in melanocytic lineage: a histochemical approach. 174 97

Marked heterogeneity for susceptibility to lysis by autologous CTL clones and allogeneic IL-2-activated CD3- and CD3+ lymphocytes was found among 19 clones isolated from a human metastatic melanoma (Me665/2). A subset of 5 clones with the highest susceptibility to lysis had increased ICAM-1 antigen expression. Phenotype analysis for the presence of extracellular matrix receptors in the beta 1- and beta 3-integrin families revealed that the tumor clones with the highest susceptibility to lysis were also characterized by frequent expression or increased expression of multiple receptors in the beta 1 family including VLA-1, -2, -3, -4 and -6. The correlation between phenotypic markers and susceptibility to lysis, seen at the clonal level, was confirmed by selection experiments on the uncloned metastasis Me665/2. In fact, the neoplastic population surviving 3 cycles of immunoselection with IL-2-activated lymphocytes exhibited, in comparison to the unselected metastasis: (1) reduced susceptibility to lysis and (2) reduced expression of ICAM-1 and of VLA antigens. In contrast, enhanced susceptibility to lysis and up-regulation of ICAM-1, VLA-1 and VLA-3 antigens were observed on melanoma cells recovered after invading a reconstituted basement membrane. These data indicate that melanoma cells with enhanced susceptibility to cell-mediated lysis can be identified on the basis of phenotypic characteristics (ICAM-1 and VLA antigen profile) and functional features (invasive ability on reconstituted basement membranes).
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PMID:Human melanoma cells with high susceptibility to cell-mediated lysis can be identified on the basis of ICAM-1 phenotype, VLA profile and invasive ability. 197 67

Metastatic or tumor-draining lymph nodes from six of nine melanoma patients undergoing lymph node dissection for metastatic melanoma generated cytotoxic T cells against autologous melanoma when these lymph node cells were treated by in vitro sensitization and recombinant interleukin-2 (IL-2). During the initial lymphocyte culture (2-6 weeks), cross-reactivity with autologous tumor cells, K562 and Daudi cells was usually noted. Cold-target inhibition assay with K562 and Daudi showed K562/Daudi-associated antigens on melanoma cells. During the later phase of lymphocyte culture with repeated in vitro sensitization (over 6-10 weeks), cytotoxicity was noted against autologous and allogeneic melanoma cells but not against K562. Daudi cells or autologous fibroblasts. Repeated in vitro sensitization resulted in the selection of specific cytotoxic lymphocytes against melanoma. Cold-target inhibition assay with autologous and allogeneic melanoma cells revealed shared and individual antigens. Using blocking monoclonal antibodies, MHC-restricted killing was noted in the autologous system. Further, both the autologous and allogeneic systems could be mediated through adhesion molecules such as ICAM-1 and LFA-3 on melanoma cells and LFA-1 on T cells. This study suggests that a constellation of cytotoxic effector cells and melanoma-associated antigens may be pivotal in tumor killing. Thus, future adoptive immunotherapy should modulate and enhance this complex interaction.
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PMID:Generation of cytotoxic effector cells against human melanoma. 762 96

Immunohistochemical staining with monoclonal antibodies showed a differential distribution of intercellular adhesion molecule 1 (ICAM-1/CD54) and lymphocyte function-associated antigen 3 (LFA-3/CD58) and their respective counterreceptors lymphocyte function-associated antigens 1 (LFA-1/CD11a) and 2 (LFA-2/CD2) on ten melanoma cell lines and in 46 surgically removed metastatic melanoma lesions. CD11a and CD2 were not detected on melanoma cells while CD54 and CD58 were coexpressed on the majority of the melanoma cell populations investigated. CD54 showed a higher degree of intra- and intertumor heterogeneity than CD58. gamma-Interferon and/or tumor necrosis factor alpha upregulated the expression of CD54 by melanoma cells, but neither modulated that of CD58 nor induced that of CD11a and CD2. Anti-CD54 and anti-CD58 monoclonal antibodies partially inhibited the lysis of melanoma cells by allogeneic natural killer cells, lymphokine-activated killer cells and, to a greater extent, by autologous tumor-infiltrating lymphocytes. Soluble CD54 (cCD54) purified from serum of patients with melanoma inhibited the lysis of melanoma cells F0-1 by natural killer cells in a dose-dependent fashion. These results suggest that membrane-bound CD54 and CD58 and cCD54 play a role in host-tumor interactions in patients with malignant melanoma and may account for the relationship between CD54 expression in primary lesions and the clinical course of disease.
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PMID:Differential expression of cell adhesion molecules CD54/CD11a and CD58/CD2 by human melanoma cells and functional role in their interaction with cytotoxic cells. 768 16

In order to investigate the effects of in vivo treatment with interferon-alpha (IFN-alpha) on melanoma antigens, a clinical EORTC trial (No. 18852) was accompanied by an immunohistological study. Twenty patients with melanoma metastases of skin and soft tissues, eventually also of the lung, who were treated with systemic IFN-alpha, were evaluated for a comparison of metastases before (40) and during (42) treatment. Representative cryostat sections were studied immunohistologically with a panel of monoclonal antibodies against differentiation antigens (HMW-MAA, K-1-2, NKI-beteb, M-2-10-15), progression markers (transferrin receptor, ICAM-1, VLA-2), histocompatibility antigens (HLA-A, B, C, HLA-DR) and the proliferation-associated nuclear antigen Ki67. We found an overall reduction of the proliferation-associated antigen Ki-67 (p < 0.01), and an increase in expression of HLA-DR (p < 0.05) and ICAM-1 (trend) during treatment. The intensity of expression of HLA-A, B and C antigens as well as pigmentation (p < 0.01) was found to be increased. Early progression (< or = 8 weeks after onset of treatment) was associated with a lack of phenotypic changes. The data suggest an independent modulation of proliferation, pigmentation, and antigen expression by systemic treatment of metastatic melanoma with IFN-alpha.
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PMID:Effects of systemic interferon-alpha (IFN-alpha) on the antigenic phenotype of melanoma metastases. EORTC melanoma group cooperative study No. 18852. 810 70

Homeobox-containing genes comprise a gene family coding for transcription factors involved in normal development. Class I human homeobox (HOX) genes display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox genes has been associated with both morphological abnormalities and oncogenesis. We have reported that HOX gene expression is (i) specific for normal adult human organs (kidney, colon, lung) and (ii) altered in cancer specimens according to their histological type and stage of tumor progression. Here, we have investigated whether patterns of HOX gene expression are associated with tumor heterogeneity by analyzing the expression of the entire panel of 38 HOX genes in clones isolated from a single human metastatic melanoma call line (Me 665/2). The differential expression of a block of genes located at the 5' end of the HOX C locus allows melanoma clones to be classified into 2 major groups. The 2 patterns of HOX gene expression are inversely associated with 2 distinct surface phenotypes for integrins (VLA-2, VLA-5 and VLA-6) and the adhesion molecule ICAM-1. The genes of the HOX C locus are silent in the clones with high levels of integrins VLA-2, VLA-5 and VLA-6 and of the adhesion molecule ICAM-1 but actively expressed in the clones with low levels of ICAM-1 and lacking VLA-2, VLA-5 and VLA-6. Our results indicate that HOX gene expression reflects the intra-tumor heterogeneity of melanoma clones and suggest that the expression of surface molecules involved in cell-cell and cell-matrix interactions may be related to the patterns of HOX gene expression.
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PMID:Differential patterns of HOX gene expression are associated with specific integrin and ICAM profiles in clonal populations isolated from a single human melanoma metastasis. 864 34

It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer. In malignant melanoma, the intercellular adhesion molecule (ICAM-1) has been described as involved in progression of the disease and is upregulated by TNF alpha. We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-R1 levels were detected only in patients with metastatic melanoma compared with normal controls (P < 0.002), whereas sTNF-R2 levels were increased both in primary and metastatic melanoma (P < 0.001). The ratio of type 2 to type 1 proteins increased in malignant melanoma compared with the controls but remained constant with the progression of the disease. A correlation between sTNF-Rs and sICAM-1 concentrations in patients' sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.
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PMID:Tumour necrosis factor (TNF) soluble receptors in malignant melanoma: correlation with soluble ICAM-1 levels. 881 90

Patients with metastatic melanoma have a very poor prognosis. In many cases, the tumor recurs after surgical excision. Therefore, it might be beneficial for cancer patients to induce an immune attack against the tumor by inserting a cytokine gene into the tumor cells. Here, 14 primary cell cultures could be established from 45 patients with malignant melanoma. Primary cell cultures were transfected via electroporation with the gene encoding for human interleukin-7 (IL-7). Transfection resulted in the production of biologically active IL-7 with an average of 850 pg/mL per 10(6) cells per 24 hours. Irradiation with 10,000 cGy, which inhibited tumor cell growth in vitro, increased the amount of released IL-7 to an average amount of 1050 pg/mL per 10(6) cells per 24 hours. No significant differences in the phenotype were observed in the IL-7-transfected cells compared with nontransfected cells. The expression of HLA class I and II, ICAM-1, and of a melanoma-associated antigen remained unaltered. Transfection with IL-7 had no significant effect on the proliferation of melanoma cells as measured in a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. There was no significant change in the cytokine profile after transfection or irradiation of the cells, but one cell culture expressed a high amount of IL-6 (about 2 ng/mL). IL-6 was expressed in nontransfected cells and was not altered by transfection. Interestingly, transfected cells from primary melanoma cultures possessed a higher sensitivity to immunologic effector cells compared with nontransfected cells. This was true for allogeneic as well as autologous melanoma cells. Our results show the feasibility of a gene transfer into primary human melanoma cells, different from retroviral transduction. IL-7-transfected cells might be of value in vaccination protocols for melanoma patients.
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PMID:Increase of cytotoxic sensitivity of primary human melanoma cells transfected with the interleukin-7 gene to autologous and allogeneic immunologic effector cells. 925 12


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