UMLS:C0278883 - FACTA Search

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Query: UMLS:C0278883 (metastatic melanoma)
6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastatic melanoma, compared with other cancers, appears to be unusual because of its low frequency of p53 mutations and prevalence of wild-type p53 protein in advanced malignancy. Here, we examined the effects of wild-type and mutated p53 (143 Val-Ala) on tumorigenic and metastatic potential of two human melanoma cell lines. The cell line UISO-MEL-4 contains wild-type p53 and is tumorigenic, whereas UISO-MEL-6 lacks p53 and produces lung and liver metastasis upon s.c. injection into athymic mice. Our study showed that UISO-MEL-4 stably transfected with wild-type p53 cDNA driven by cytomegalovirus promoter-enhancer sequences expressed high levels of p53 and p21 and formed s.c. tumours in vivo. Mutated p53 (143 Val-Ala) expression, on the other hand, inhibited tumour growth in 50% of cases and produced significantly slower growing non-metastatic tumours. Reduced tumour growth involved necrotic as well as apoptotic cell death. Inhibition of tumour growth was abrogated by the addition of Matrigel (15 mg ml(-1)). With UISO-MEL-6 cells, stably transfected with mutant p53, tumour growth was delayed and metastasis was inhibited. In soft agar colony formation assay, both wild-type and mutant p53 transfectants reduced anchorage-independent colony formation in vitro. These data suggest that mutated (143 Val-Ala) p53, which retains DNA binding and some of the transactivation functions of the wild-type p53 protein, suppresses tumorigenic and metastatic potentials of human melanoma cell lines in vivo.
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PMID:Suppression of tumorigenic and metastatic potentials of human melanoma cell lines by mutated (143 Val-Ala) p53. 964 36

Biopsy specimens from 12 patients with metastatic melanoma were longitudinally analysed to evaluate changes in proliferation activity and CD4+/CD8+ ratios during the course of the disease. The primary tumours of the patients who subsequently had metastatic disease were also each matched with tumours from two controls whose disease remained localized, and were compared with regard to tumour proliferation. Immunohistochemistry was performed using the avidin-biotin complex (ABC) immunoperoxidase technique, using bcl-2, p53, mdm-2 and Ki-67 as the primary monoclonal antibodies, and the percentage of positively stained melanocytic cells was calculated. Frozen sections were also available from metastatic lesions excised from eight of our patients before treatment initiation and at the time of disease progression. These specimens were prepared for microscopy, and quantitative characterization of CD4+ (OKT 4a) and CD8+ (OKT 8) cells was performed. Compared with the localized melanomas bcl-2 expression was higher in those primary melanomas that later metastasized (P = 0.068, Wilcoxon; P = 0.038, median test). Mdm-2 and Ki-67 expression did not differ in the primary tumours of patients and controls, but a statistically significant trend was observed towards increasing expression with the progression of the disease (two-sided exact P-values: 0.04 and 0.05, respectively). Patients with a low Ki-67 index in their first metastasis had a better prognosis when compared with patients with high indexes (P = 0.008, log-rank). Furthermore, most patients with decreasing CD4+/CD8+ ratios had increasing p53 immunoreactivity. Our findings suggest that Ki-67 and bcl-2 may be useful for predicting the prognosis of melanoma patients. Mdm-2 is a new but promising marker in melanoma and deserves further evaluation.
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PMID:Prognostic value of biomarkers in malignant melanoma. 966 52

The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not well defined. Our recent studies have demonstrated that the two tumor suppressor genes, p53 and p16/CDKN2, do not play a major role in the acquisition of the metastatic phenotype in human melanoma. Mutations in p53 are infrequent and do not correlate with the metastatic potential of human melanoma cells while p16/CDKN2 abnormalities are frequent, but are not pre-requisite for the acquisition of the metastatic phenotype. On the other hand, the tyrosine-kinase receptor c-KIT and the cell adhesion molecule MCAM/MUC-18 play active roles in the progression of human melanoma. Metastatic melanoma cells overexpress MCAM and do not express the c-KIT receptor. Enforced c-KIT expression in metastatic cells significantly inhibited their growth and metastatic potential in nude mice. Furthermore, exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. Ectopic expression of MCAM into primary cutaneous melanoma cells enhanced their tumorigenicity and metastatic ability in vivo. We found that both genes, c-KIT and MCAM, are regulated by the transcription factor AP-2 and that metastatic melanoma cells do not express AP-2. We therefore propose that loss of AP-2 might be a crucial event in the progression of human melanoma.
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PMID:Molecular changes in human melanoma metastasis. 981 May 13

Aggregates of benign nevus cells occurring in lymph nodes are a well-described incidental finding. Nevus cell aggregates (NCAs) can mimic foci of metastatic carcinoma or other disease processes, so the surgical pathologist should be familiar with this lesion. The purpose of this report is to describe the potential diagnostic difficulties created by benign NCAs within the thymus of a 32-year-old man with dysplastic nevus syndrome and malignant melanoma involving mediastinal lymph nodes and the right lung. Morphologically, the NCAs in this case elicited the differential diagnoses of metastatic melanoma and thymoma. Immunohistochemical studies helped to establish the correct diagnosis by demonstrating reactivity for S-100 protein and negative staining for keratin and HMB-45. Unlike malignant melanomas, NCAs show no p53 protein immunoreactivity, and low proliferative activity was detected by Ki-67 antigen immunostaining. Although melanocytic cells were rarely reported in thymic neoplasms, we are not aware of any previous reports of NCAs occurring in the normal thymus.
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PMID:Benign nevus cell aggregates in the thymus: a case report. 1010 20

A case of malignant melanoma arising from a congenital dermal nevus on the right forehead of a 16-year-old female is presented. In the mole, small pigmented nevoid cells gathered around the skin appendages and between the collagen fibers. From the age of 17, a verrucous nevoid melanoma consisting of lymphoblast-like large nevoid cells, which were positive for HMB-45 and had a high Ki-67 index up to 18.7%, gradually increased in size. The melanoma cells vertically invaded the dermis to a depth of 3 mm and radially spread in the papillary dermis. Twelve years after undergoing a wide local resection and additional chemotherapy, metastatic lesions were found in the lung and the anterior mediastinum, which gradually increased in size and caused death a few months later. Metastatic melanoma cells were positive for HMB-45 and had a high Ki-67 index up to 33.7%. Most metastatic melanoma cells were positive for p53 while the primary ones were negative. Deteriorating mutations probably accumulated during the latent period.
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PMID:Small cell type malignant melanoma which developed in a 16-year-old female with a congenital dermal nevus and metastasized 12 years after excision. 1033 82

Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.
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PMID:p53-dependent apoptosis in melanoma cells after treatment with camptothecin. 1069 11

We have analyzed the expression of the CDKN1A (p21(CIP1)), CDKN1B (p27(Kip1)), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN2A (INK4-ARF, p16/p14(ARF)), CDKN2B (p15) and CDKN2C (p18) genes was determined by PCR-SSCP (single-strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico-pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 (r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 (r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P<0.001). Two mutations in the CDKN2A (p16) gene were detected, including a novel base change AAC-->ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p14(ARF) from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN2A (INK4-ARF) gene was detected in six cases. In seven cases, the 540C-->G polymorphism in the 3'UTR of the CDKN2A (p16) gene was found in linkage disequilibrium with the 74C-->A polymorphism in intron 1 of the CDKN2B gene (P < 0.0001). These cases had significantly lower expression of the TP53 protein (P = 0.0032). Both 540C-->G and 580C-->T polymorphisms in the 3'UTR of the CDKN2A (p16) gene were associated with significantly shorter progression time from primary to metastatic disease (P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G(1)/S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma.
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PMID:Analysis of G(1)/S checkpoint regulators in metastatic melanoma. 1086 49

p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.
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PMID:Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors. 1091 10

Aneuploidy and hyperploidy are often detected in malignant melanoma by cytogenetic analysis and flow cytometric analysis of DNA content. To determine the ploidy of cells in surgical specimens of melanin-producing tumors of Japanese patients, we performed fluorescence in situ hybridization (FISH) using touch smear technique to count the number of chromosomes 18 and X + Y in interphase nuclei using alpha-satellite DNA probes, D18Z1, DXZ1 and DYZ3. A normal melanocyte strain showed two D18Z1 and two [DXZ1+DYZ3] signals per nucleus, indicating 2N, and a malignant melanoma cell line showed 4 per nucleus, indicating 4N, consistent with results of cytogenetic and flow cytometric analyses. Therefore we employed this FISH method to analyze ploidy of surgical specimens. Specimens obtained from 8 patients with nevus cell nevus showed 2 FISH signals per nucleus. On the other hand, in all specimens obtained from 8 patients with malignant melanoma (6 primary and 2 metastatic melanoma), 65-90% of cells exhibited 4 signals per nucleus, indicating 4N. Histopathologically, 50-70% of cells were identified as malignant melanoma cells, indicating that our FISH method is effective to detect melanoma cells in tissue. We also analyzed allelic loss of the p53 gene by FISH with a p53 locus-specific probe and mutation of the p53 gene by immunostaining since mutation and deletion of the p53 gene may cause hyperploidy. All specimens except one obtained from a case with young-onset metastatic melanoma exhibited no allelic losses or negative p53 staining, showing the p53 gene was intact. These results indicate that tetraploidy, not caused by p53 mutation or deletion, is commonly found in malignant melanoma of Japanese patients. It is also suggested that there is no positive relationship between tetraploidy and poorer prognosis, and mutation and allelic loss of the p53 gene might be markers of aggressive form of malignant melanoma.
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PMID:High frequency of tetraploidy detected in malignant melanoma of Japanese patients by fluorescence in situ hybridization. 1099 81

Malignant melanoma is a notoriously aggressive disease that can affect relatively young individuals and whose incidence is rising at an alarming rate. Unlike many cancers, metastatic melanoma is poorly responsive to current therapies and mutations affecting p53, the retinoblastoma gene product or Ras which occur frequently in many other cancer types, appear to be rare or at least relatively late events in the progression of the disease. Recent advances in our understanding of the disease at the molecular level have indicated that in addition to the loss of cell cycle checkpoints which may be common to all cancers, malignant melanoma shares many characteristics in common with developmental precursors to melanocytes, the mature pigment producing cells of the skin and hair follicles which are responsible for skin and hair colour. This review therefore focuses on the signalling pathways that play a crucial role in the development of the melanocyte lineage which are subject to deregulation in malignant melanoma namely signalling by receptor tyrosine kinases, the Wnt signalling pathway, as well as loss of the p16INK4a cyclin-dependent kinase inhibitor. Intriguingly all three pathways impact on the expression or function of the microphthalmia-associated transcription factor which plays an essential role in melanocyte development.
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PMID:Melanocyte development and malignant melanoma. 1100 28

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