Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of normal human melanocyte and nevus cultures with an adenovirus 12-Simian Virus 40 hybrid virus (Ad12-SV40) produced transformed cells that expressed SV40-T antigen. The Ad12-SV40 cells exhibited rapid cell proliferation to high cell densities and efficient growth in soft agar, but none of 15 transformed melanocyte and nevus cultures formed tumors when injected s.c. or under the renal capsule into athymic nude mice. While the Ad12-SV40-transformed cells lost certain properties associated with the melanocytic phenotype, i.e., pigmentation, tyrosinase activity and melanosome content, the expression of melanoma-associated antigens, including nerve growth factor receptor, p97 melano-transferrin, and chondroitin sulfate proteoglycan, remained stable. The transformed melanocytes acquired the ability to express HLA-DR antigen, which is found on nevus and melanoma cells. Total ganglioside patterns in Ad12-SV40-transformed cells changed to reflect more advanced stages of tumor progression. Transformed melanocytes, like nevus and melanoma cells, showed increased GD3 content and transformed nevus cells increased GD2 which is a feature of malignant melanoma cells. Ad12-SV40-transformed human melanocytes and nevus cells are useful tools for studying tumor progression under experimental conditions.
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PMID:Transformation of normal human melanocytes and non-malignant nevus cells by adenovirus 12-SV40 hybrid virus. 255 80

Nevus cells were isolated from the three cutaneous components, epidermis, basal layer, and dermis, of nonmalignant pigmented lesions and were cultured separately in the presence or absence of the phorbol ester 12-0-tetradecanoyl phorbol-13-acetate in medium that supports the rapid proliferation of melanocytic cells. The separation procedure used provided cultures that were essentially free from normal melanocytes (dermis) or fibroblasts (epidermis). In short term culture, nevus cells of all skin compartments expressed markers associated with differentiated melanocytes, such as presence of premelanosomes and melanosomes and elevated tyrosinase levels. Nevus cells also expressed melanoma-associated antigens, such as NGF-receptor, transferrin-related p97, proteoglycan, and HLA-DR as detected with monoclonal antibodies. After several subpassages, cells showed a decreased expression of melanoma-associated antigens, decreased tyrrosinase levels, and melanosomes could no longer be detected. Morphologically, these cells were similar to fibroblasts. The disappearance of melanoma-associated cell surface antigens was concomitant with the appearance of a melanocyte-associated 145 kd protein that might serve as a marker of fibroblast-like differentiation in nevus cells and normal melanocytes. Nevus cell cultures grown in the presence of 12-0-tetradecanoyl phorbol-13-acetate maintained a stable differentiated phenotype throughout their lifespan. As reported earlier, nevus cells in culture, irrespective of the presence or absence of 12-0-tetradecanoyl phorbol-13-acetate, have a finite lifespan in vitro, grow anchorage-independent in soft agar, but do not form tumors when xenografted to nude mice. These studies demonstrate that nevus cells isolated from the epidermal, basal layer, and dermal components of lesional skin can serve as models to characterize the initial steps of tumor progression in a human cell system.
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PMID:Growth and phenotypic characteristics of human nevus cells in culture. 282 80

Reverse transcription (RT) of the tyrosinase mRNA and specific cDNA amplification by nested polymerase chain reactin (PCR) have been reported to facilitate the early detection of circulating tumor cells in melanoma patients. The significance and practical value of this procedure for the diagnosis of tumor dissemination in melanoma patients are unclear. In the current study we analyzed peripheral blood samples of 65 melanoma patients of different clinical stages for the presence of tyrosinase mRNA by RT-PCR using nested oligonucleotide primers specific for tyrosinase cDNA. Furthermore, blood samples were evaluated for tumor cell growth by cell culture assays in vitro. No tyrosinase mRNA was detectable in blood samples of 26 patients with primary melanoma and 16 patients with regional lymph node metastases. In five of 13 patients with visceral metastases we found at least one blood sample positive for tyrosinase mRNA during a 2-to 4-mo interval. Analyses of different blood samples of patients with visceral metastases taken in a 2-h interval, furthermore, indicate that tumor cells only transiently persist in the peripheral blood. We obtained in vitro proliferating melanoma cells from two blood samples derived from different patients with visceral melanoma metastases. This demonstrates that viable melanoma cells indeed circulate in the peripheral blood with retained proliferative capacity in vitro. The analysis of blood samples by RT-PCR for tyrosinase mRNA, however, is not suitable for the early detection of tumor progression in melanoma patients.
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PMID:The analysis of tyrosinase-specific mRNA in blood samples of melanoma patients by RT-PCR is not a useful test for metastatic tumor progression. 900 29

Peptides derived from melanocyte differentiation antigens have been identified as targets for MHC class I-restricted cytolytic T lymphocytes (CTLs) in human melanoma Regression of antigen-expressing tumors as well as selection of antigen-loss variants in the presence of antigen-specific CTLs have previously been reported. In the present study, we determined the expression of the melanocyte differentiation antigens Melan A/MART-1 and tyrosinase by mRNA analysis and by immunohistochemical staining with the monoclonal antibodies (MAbs) A103 and T311. Co-expression of Melan A/MART-1 and tyrosinase was detected by both methods in 18/20 melanomas tested. However, immunohistochemistry provided additional information on intensity and microheterogeneity of antigen expression that cannot be detected by mRNA analysis as a molecular basis for the escape from CTL recognition of antigen-negative tumor cells. Comparative analysis of repeated biopsies of metastatic lesions in 5 HLA-A2+ patients showed a gradual loss of Melan A/MART-1 expression in 4/5 and of tyrosinase in 2/5 samples in association with tumor progression. However, 3 of these patients had growing antigen-positive tumors in the presence of antigen-specific CTLs. This led us to assess the expression of MHC class I, the essential restriction element for CTL recognition, and of HLA-A2. We found an unexpectedly high frequency of MHC class I-negative tumors (9/20). Loss of MHC class I expression was detected in 3/5 progressive tumors and isolated loss of HLA-A2 in 1/5 tumors. Our results suggest that strategies enhancing the expression of MHC class I and tumor-associated antigens need to be considered in attempts at making vaccination more effective.
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PMID:Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. 913 33

Expression of HLA class I molecules is essential for the recognition of tumor cells by CD8+ T cells. In this study, 48 bioptic samples of 42 patients in all stages of melanoma were investigated after short-time cultivation of tumor cells. To confirm melanocytic origin of cultured cells, samples were screened for mRNA expression of melanoma markers gp100, tyrosinase, MAGE-3, MelanA, and MUC18 by reverse transcriptase-polymerase chain reaction. Surface expression of specific HLA-A and -B allospecificities on melanoma cells were analyzed with a standard microcytotoxicity assay after stimulation with interferon (IFN)-alpha and compared with the background found in peripheral blood mononuclear cells from the corresponding patients. Immunohistochemistry and flow cytometry confirmed specific losses in cases where the appropriate monoclonal antibodies were available. The level of expression of HLA-I, HLA-II, and intercellular adhesion molecule 1 antigens on melanoma cells cultured in the presence or absence of IFN-alpha and IFN-gamma was determined cytofluorometrically. All cell cultures tested were found to be positive for one or more melanocytic markers by reverse transcriptase-polymerase chain reaction. The specific HLA-I alleles on the cultured cells were detectable in 45 of 48 samples. In 11 cases a specific loss of one HLA-I allele was observed (2 x A2, B7, B8, B18, 4XB44, B47, B49). Ten of these samples were derived from locoregional lymphnode metastases or from distant metastatic tumors. Only one sample from a primary melanoma showed a specific loss of HLA-I (B47). IFN-alpha upregulated expression of HLA-I up to 4-fold. IFN-gamma enhanced the appearance of HLA-II up to 35-fold and the expression of intercellular adhesion molecule 1 up to 40-fold. Selective loss of HLA-I allospecificities might be a major step in tumor progression.
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PMID:Higher frequency of selective losses of HLA-A and -B allospecificities in metastasis than in primary melanoma lesions. 974 Feb 47

The identification of circulating tumor cells in the peripheral blood of patients with malignant melanoma by detection of melanoma associated protein transcripts using the reverse transcriptase polymerase chain reaction (RT-PCR) technique has been introduced as a noninvasive and sensitive technique for early detection of tumor progression and metastatic disease. An alternative approach is the analysis of S-100 protein in the serum of melanoma patients by a luminoimmunometric assay (LIA). In this study, the sensitivities of RT-PCR and LIA were compared. Seventy-seven blood samples of 59 melanoma patients were analyzed for tyrosinase, Melan-A/MART-1, MAGE-3, gp100, and p97 expression by multimarker RT-PCR; 540 serum samples of 352 melanoma patients were analyzed for S-100 protein concentration by LIA. In stage III 23.8% and in stage IV 37.5% of the samples were positive for at least one marker in multimarker RT-PCR, versus 8.1% and 48.1% of elevated S-100 levels analyzed by LIA, respectively. In a direct comparison, 31 identical samples were analyzed by multimarker RT-PCR and by S-100 LIA. In stage III 18.2% and in stage IV 45% of the samples were positive by multimarker RT-PCR versus 45.5% and 80% by S-100 LIA, respectively. S-100 LIA was more sensitive in detection of metastatic disease in melanoma patients than multimarker RT-PCR and should be evaluated in further studies. RT-PCR might be more useful in the analysis of micrometastases in anatomic compartments other than peripheral blood.
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PMID:Tumor markers in peripheral blood of patients with malignant melanoma: multimarker RT-PCR versus a luminoimmunometric assay for S-100. 1054 77

In this review, we summarize the significant progress that has been made in the identification of melanoma-associated antigens (MAA) recognized by cytotoxic T-lymphocytes (CTL). These antigens belong to three main groups: tumor-associated testis-specific antigens (e.g. , MAGE, BAGE, and GAGE); melanocyte differentiation antigens (e.g., tyrosinase, Melan-A/MART-1); and mutated or aberrantly expressed molecules (e.g, CDK4, MUM-1, beta-catenin). Although strong CTL activity may be induced ex vivo against most of these antigens, often in the presence of excess cytokines and antigen, a clear understanding of the functional status of CTL in vivo and their impact on tumor growth, is still lacking. Several mechanisms are described that potentially contribute to tumor cell evasion of the immune response, suggesting that any antitumor efficacy achieved by immune effectors may be offset by factors that result ultimately in tumor progression. Nevertheless, most of these MAA are currently being investigated as immunizing agents in clinical studies, the conflicting results of which are reviewed. Indeed, the therapeutic potential of MAA has still to be fully exploited and new strategies have to be found in order to achieve an effective and long-lasting in vivo immune control of melanoma growth and progression.
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PMID:T-cell recognition of melanoma-associated antigens. 1065 98

This phase II study was performed to determine the induction of a specific T-cell response, the clinical response rate, and toxicity of vaccination with different HLA class I-binding peptide epitopes derived from the melanocyte differentiation antigen tyrosinase in patients with stage IV melanoma. The study population consisted of 16 patients with metastatic disease and two patients who were macroscopically free of disease at study entry after resection of recurrent skin lesions. Patients received intradermal injections of 200 microgram [corrected] peptide corresponding to their HLA type on day 3, and 75 or 150 microg granulocyte-macrophage colony-stimulating factor on days 1 to 4. Vaccinations were repeated at weeks 2, 4, 6, 10, and 14. Monitoring of peptide-specific T-cell frequencies in the peripheral blood was performed using an interferon gamma ELISPOT assay. Eleven of the 16 patients with metastatic disease went off the protocol within the first 10 weeks because of tumor progression. Of the five patients with metastatic disease who received all six vaccinations, one patient showed a mixed response with regression of some lung metastases; two patients with progressive disease before vaccination had stable disease for 6 and 18+ months; and two patients had progression of their disease. The two patients who had all their metastases resected before vaccination did not have relapses for 6 and 12+ months after vaccination. Induction of tyrosinase-reactive T cells was found in these two patients and in two others with metastatic disease, including the one who achieved a mixed response and one with stable disease. This study shows limited clinical and immunologic activity of HLA class 1-peptide vaccination in combination with granulocyte-macrophage colony-stimulating factor in stage IV melanoma patients.
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PMID:Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. 1074 54

Reverse-transcriptase polymerase chain reaction (RT-PCR) with multiple markers has been demonstrated to be highly sensitive in detecting metastatic cells in peripheral blood of malignant melanoma (MM) patients, and the circulating MM cells to be significantly correlated with disease stages. We further evaluated the presence of specific PCR-positive mRNA markers in peripheral blood as well as in regional nodes as an expression of tumor progression. Peripheral blood samples from 317 MM patients with either localized (n = 219) or metastatic (n = 98) disease were processed to obtain total cellular RNA. RT-PCR was performed using tyrosinase (TYR), p97, and MelanA/MART1 as mRNA markers. PCR products were analyzed by gel electrophoresis and Southern blot hybridization. In addition, paraffin-embedded samples of histologically proven tumor-negative lymph nodes from the subset of patients with localized disease were analyzed by RT-PCR, using radiolabeled primers for TYR and MelanA/MART1. The presence of mRNA markers was significantly correlated with tumor burden with a good correlation between risk of recurrence (evaluated in stage I-III patients) and increasing number of PCR-positive markers (p = 0.0002). Currently, for each patient, PCR results obtained at different times during follow-up are being analyzed, and any variation in the number of PCR-positive markers is being correlated to the clinical status. Molecular screening of histologically negative nodes for the presence of metastatic MM cells is also under evaluation. Preliminary assessment of a subset of MM patients with higher risk of recurrence will require longer follow-up in order to define the role of RT-PCR in monitoring these patients.
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PMID:Clinical significance of PCR-positive mRNA markers in peripheral blood and regional nodes of malignant melanoma patients. Melanoma Cooperative Group. 1109 47

A 49-year-old patient with primary, recurrent melanoma on the lower extremity developed metastatic leptomeningeal melanoma that did not respond to treatment with radiation therapy or intrathecal interleukin 2 (IL-2). Disease was characterized by neurological symptoms, including loss of hearing, loss of short-term memory, and gait disturbance. CD8+ CTLs were generated in vitro using autologous dendritic cells pulsed with peptides from the melanoma-associated antigens tyrosinase (145-156), Melan-A/MART-1 (26-35), and gp100/Pmel 17 (209-217). The CTLs exhibited up to 74% specific lysis against peptide-pulsed autologous EBV-transformed B cells, with Melan-A-specific CTLs yielding the greatest lytic activity. CD8+ CTLs possessed a type 1 cytokine profile, expressing tumor necrosis factor alpha and IFNgamma but not IL-4. Infusions of CTLs were supported with systemic low-dose IL-2 administration. 111In labeling and computerized gamma imaging were used to monitor the distribution of CTLs up to 48 h after infusion. Intra-arterial delivery via the right carotid artery was followed by redistribution of the CTLs to the lungs, liver, and spleen within 16 h. In contrast, delivery via an indwelling Ommaya reservoir resulted in prolonged retention of CTLs within the brain for at least 48 h after infusion. Marked but transient elevations in tumor necrosis factor alpha, IFN-gamma, and IL-6 in the cerebrospinal fluid were observed within 4 h of CTL infusion. There was no evidence of tumor progression throughout the treatment period, and clinically the patient showed some resolution of neurological symptoms.
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PMID:Intrathecal cytotoxic T-cell immunotherapy for metastatic leptomeningeal melanoma. 1130 Apr 92


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