Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of malignant melanoma has been intensely studied over the last decade. Much of the recent work focuses on oncongenes and tumour suppressor genes and the role of apoptosis in melanoma. Loss of tumour suppressor proteins such as p16 has been documented in melanoma and correlates with tumour progression. Mutations in the tumour suppressor p53 have also been documented in melanoma. The proto-oncongene Bcl-2 encodes a protein that inhibits apoptosis. Bcl-2 is found in normal melanocytes and benign nevi. However, lower levels are seen in melanoma. To investigate the relationship between melanoma and nevi, in our Basic and Clinical Science section, Dr. Radhi examines the expression of p53, p16, and Bcl in malignant melanoma arriving in benign nevi. P53 immunoreactivity was found only in the malignant component, with no expression being seen in the benign components of the lesion. This suggests that this tumour suppressor gene is involved in the pathogenesis of melanoma.
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PMID:The etiology of malignant melanoma. 1057 55

Tumor-infiltrating lymphocytes (TIL) have been shown to be an independent prognostic factor in melanomas. To better characterize the host immune response, we have classified TIL by their immunoreactivity against lymphoid markers in formalin-fixed, paraffin-embedded tissue. Monoclonal antibodies to leukocyte common antigen (LCA) and TIA-1 (a granule-associated protein of cytotoxic T cells and NK cells) were used to immunostain a series of benign nevi, nontumorigenic radial growth phase, and tumorigenic vertical growth phase melanomas and metastases. Among nine nevi, few LCA+ TIL were found, among which rare cells were positive for TIA-1 (mean, 2.0). Five nontumorigenic radial growth phase melanomas also had few total TIL and rare TIA-1+ TIL (mean, 3.4); the nontumorigenic radial growth phase component of seven tumorigenic vertical growth phase melanomas had higher numbers of TIA-1+ TIL (mean, 11). Twelve cases of tumorigenic vertical growth phase melanoma showed a variable but significantly greater number of both LCA+ TIL and TIA-1+ TIL (mean, 30.6). Nine cases of metastatic melanoma had a wide range of variation in LCA as well as in TIA-1+ TIL (mean, 46). Although the mean total number of TIA-1+ TIL increased from nontumorigenic radial growth phase to tumorigenic vertical growth phase to metastases, TIA-1+ as a percentage of TIL declined across these categories of tumor progression (42%, 31%, and 26%, respectively). Our results show that these attributes of TIA-1+ TIL, both increasing total number but decreasing percentage, appear to be a marker of tumor progression of malignant melanomas. In addition, there was significant variability in the number of TIA-1+ TIL among advanced melanomas, raising the possibility that an assessment of TIA-1+ TIL may prove a useful prognostic tool for the evaluation of primary melanomas.
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PMID:TIA-1 positive tumor-infiltrating lymphocytes in nevi and melanomas. 1065 10

Cutaneous malignant melanoma is not among the most frequent cancer types at an incidence of 10-12/100,000 persons/year in Central Europe. However, the number of melanomas has doubled within the last 10-15 years. This increase is higher than that of most other malignancies. It has been attributed to an increased UV-light exposure, whereby the latency period probably reaches decades. Persons at high risk for melanoma were identified in various studies: those from families with other melanoma patients and those who have more than 50 benign nevi, atypical nevi and actinic freckles. The majority of melanomas develops de novo and not from preexisting nevi. Treatment of choice is complete surgical excision of the tumors. Prognosis of these patients is mainly determined by tumor thickness. Metastatic spread occurs most frequently within lymph vessels, local recurrences as well as regional metastases significantly impairing the prognosis. From long-term experience in Australia it is evident that the dilemma "melanoma" can only be addressed effectively by rigorous prophylaxis and early diagnosis of the tumors.
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PMID:[Malignant melanoma of the skin. Pathogenesis, clinical aspects and prognosis]. 1071 85

Malignant melanoma (MM) is considered to be a chemotherapy-refractory tumor. New anti-cancer drugs (e.g. etoposide) that target DNA topoisomerases (e.g. topoisomerase II-alpha (topo IIalpha)) show activity against a wide variety of solid tumors. In this study, we investigated the frequency and rate of labeling for topo IIalpha in 163 MMs (primary and metastatic) and 67 melanocytic nevi to determine whether topo IIalpha expression is elevated in MM. Primary MM exhibited significantly more frequent topo IIalpha expression compared to benign nevi (86% vs. 56%, p=0.0001). The rate of topo IIalpha labeling in dysplastic melanocytic nevi, radial growth phase MM, vertical growth phase MM and metastatic MM revealed significant differences amongst groups and a positive covariance with advancing stage (means: 0.3, 0.5, 5, and 8 '+' cells/hpf, respectively; r=0.3, all p < or = 0.02). Topo IIalpha labeling significantly correlated with increasing mitotic activity, depth of invasion and Clark's level, diminishing tumor infiltrating lymphocytes, and poor outcome (all p < or = 0.01) in primary MM. For metastatic MM, a minority (30%) exhibited marked elevation of topo IIalpha expression. These findings indicate topo IIalpha as a potential therapeutic target and marker for MM. Immunohistochemical analysis of disseminated MM may allow for correlation with clinical response and enable selection of candidates sensitive for specific chemotherapy.
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PMID:Topoisomerase II-alpha expression in melanocytic nevi and malignant melanoma. 1084 49

Apoptosis is an important cofactor in the pathogenesis of a plethora of malignancies. However, little is known about modulation of the expression of bcl gene family in melanocytic tumors. To determine the role of bcl-2, bcl-x and bax in melanocytic tumors we investigated the differential expression of these genes via RT-PCR in tissue samples from human benign nevi, primary melanomas and melanoma metastases in comparison with normal skin. Bcl-2 was strongly expressed in 14/16 metastases (87.5%), whereas only 7/13 primary melanomas (53%), 7/15 nevi (46%) and 7/16 normal tissue samples (43%) showed expression of bcl-2 (P < 0.05). There was a strong indication of a correlation between tumor thickness and bcl-2 expression in nodular malignant melanomas. Expression of bcl-x was found in 16/16 melanoma metastases (100%), 11/13 primary melanomas (84%), 12/15 nevi (80%) and 10/16 normal tissue samples (62%) (P < 0.05). Bcl-xL expression increased from primary melanoma to melanoma metastases, whereas bcl-xS showed a decreasing expression level during melanoma progression. No differences in bax expression were seen between melanoma metastases, primary melanoma, nevi and normal tissue. Immunohistochemical investigations of another 53 tissue samples showed similar results. Our results strongly indicate that bcl-2 and bcl-xL gene expression increases with progression of malignant melanoma. Bcl-2 and bcl-xL expression could reflect an increased malignant potential caused by an inhibition of apoptosis and growth advantage for metastatic melanoma cells.
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PMID:Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. 1086 10

To investigate the possible role of mast cells (MC) in the angiogenic process in cutaneous melanoma, we examined tissue samples from 35 adult patients with primary malignant melanoma and compared with 20 intradermal benign nevi. MC were identified by anti-tryptase, microvessels by anti-CD34, and vascular endothelial growth factor (VEGF) expression by standard immunohistochemical methods. Tryptase-positive MC expressing VEGF were identified by double immunostaining. The numbers of MC and microvessels around the tumor were determined by the point counting method. MC density was significantly greater in melanoma compared with benign nevi (197.6 +/- 19.4 v 95.7 +/- 5.0/mm2, P < .001). Vascular density was also significantly higher in melanoma than in benign lesions (3.6-fold, P < .001). Double immunostaining showed the presence of VEGF in the cytoplasm of tryptase-positive peritumoral MC. The percentage of this MC-subtype was significantly higher in melanoma than in nevus tissues (71.9 +/- 2.4% v 30.6 +/- 2.5%, P < .001). A strong significant correlation was shown between the number of VEGF+ MC and microvessel density (r = .811, P < .001). MC count and VEGF+ MC count, as well as microvessel density were significantly higher in aggressive (metastasizing) melanomas (P < .001). Our results suggest that peritumoral accumulation of MC and the subsequent release of potent angiogenic factor such as VEGF may thus represent a tumor-host interaction that may favor progression of this tumor.
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PMID:Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. 1098 56

The protein encoded by the microphthalmia (mi) gene is a transcription factor essential for the development and survival of melanocytes. Using a monoclonal antibody generated against human Mi transcription factor protein (Mitf) the authors previously demonstrated that Mitf expression is conserved in primary and metastatic malignant melanomas, and appears to be a highly sensitive and specific melanocytic marker. Mitf expression in various cutaneous nevi and cutaneous nonmelanocytic tumors has not been documented systematically. The authors evaluated Mitf immunostaining in 62 benign nevi, 58 primary cutaneous melanomas, and 53 nonmelanocytic tumors. Mitf immunostaining was conserved in all benign nevi, with Spitz nevi and neurotized nevi demonstrating decreased staining intensity. With the exception of desmoplastic melanomas, all primary cutaneous melanomas were immunopositive regardless of the cell type. Only one of 14 desmoplastic melanomas was Mitf positive. None of the nonmelanocytic tumors was immunopositive, including those lesions that may resemble melanoma histologically (spindle cell carcinomas, atypical fibroxanthomas, and leiomyosarcomas). The results demonstrate that Mitf antibody expression is conserved in the majority of benign and malignant melanocytic lesions, and that it may be helpful in the diagnosis of primary melanocytic skin lesions. Its use in desmoplastic melanomas is limited and is reflective of other melanocyte-associated antigens. Mitf discriminates between spindle cell nonmelanocytic tumors and melanomas with a spindle cell morphology, and is useful in a panel with other appropriate antibodies.
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PMID:Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors. 1114 51

Differentiation between malignant melanomas and benign nevi can sometimes be difficult by conventional histopathology, and additional diagnostic markers may be helpful. This study investigated the immunoreactivity of the cell proliferation marker MIB1-Ki67 in 23 compound nevi, 17 dysplastic nevi, 8 Spitz nevi (SN), and 24 malignant melanomas (MMs) and evaluated its ability in separating benign nevi from MMs. In each lesion, the average number (percentage) of MIB1-positive nuclei (%MIB1-Mean) and the maximal number (percentage) of MIB1-positive nuclei (%MIB1-Max) were determined from each of the superficial, middle, and deep dermal zones of the lesion as well as from the entire lesion. The %MIB1-Max was determined from subjectively selected area(s) of high count. Malignant melanomas had a significantly greater %MIB1-Mean and %MIB1-Max than all benign nevi in all individual zones and in the entire lesion (p < 0.05). Discriminant analysis showed that the %MIB1-Mean and %MIB1-Max counted from the whole lesions had better discriminating abilities than from the individual zones. By using the %MIB1-Mean from all zones, all lesions except 1 SN and 3 MMs could be correctly classified as benign or malignant. When using the %MIB1-Max from all zones, all but 2 SN could be correctly separated as benign or malignant. Thus, MIB1-Ki67 immunoreactivity closely correlates with the benignancy or malignancy of melanocytic lesions and may assist in the differentiation of benign nevi from MMs.
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PMID:A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions. 1119 Apr 39

Cyclooxygenase (COX)-2 is an inducible enzyme involved in production of prostaglandins in inflammatory processes. There is now increasing evidence that a constitutive expression of COX-2 plays a role in development and progression of malignant epithelial tumors. In the present study we investigated expression and function of COX-2 in malignant melanoma. Expression of COX-2 was determined by immunohistochemistry in 28 cases of primary skin melanoma and 4 benign nevi. We show that COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. A constitutive expression of COX-2 mRNA and protein was found in five melanoma cell lines (A375, MeWo, SK-Mel-13, SK-Mel-28, and IGR-37) by using Northern blot as well as immunoblotting. All melanoma cell lines produced prostaglandin (PG) E2 between 468 and 3500 pg/ml as determined by ELISA. Treatment with NS-398 (50 microM), a specific inhibitor of COX-2, suppressed PGE2 production of all melanoma cell lines by 50-96%. The IC50 for inhibition of PGE2 production by NS-398 was determined as 4 microM, indicating that NS-398 acts via inhibition of the COX-2 isoenzyme. We could show that proliferation of melanoma cell lines was not influenced by treatment with NS-398 in concentrations up to 100 microM. However, NS-398 reduced Matrigel invasion of all five malignant melanoma cell lines by 50-68%. Our results indicate that COX-2 is expressed in malignant melanomas and may be involved in regulation of melanoma invasion. It remains to be investigated whether selective inhibitors of COX-2 might be useful for prevention or treatment of malignant melanoma.
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PMID:Expression of cyclooxygenase 2 in human malignant melanoma. 1119 78

We have investigated several molecular characteristics of common acquired melanocytic nevi to clarify their relationship to malignant melanoma, which is characterized by clonality and the progressive accumulation of DNA deletions. Twenty-four common acquired nevi were subjected to analysis for loss of heterozygosity at four loci on chromosome 9p and six loci on 10q that are commonly deleted in melanoma, but no deletions were seen. X inactivation analysis was performed in lesions from females, using the methylation-sensitive restriction HpaII site in the CAG microsatellite repeat (HUMARA) in exon 1 of the androgen receptor (AR) gene. In 14 melanomas, 11 (92%) were confirmed to have skewed X inactivation, consistent with monoclonality, as were 16 (80%) of 20 benign nevi. One nevus (5%) and 4 (33%) of 12 melanomas also showed loss of heterozygosity at HUMARA. One nevus showed an additional allele, consistent with low level microsatellite instability, at one of the 11 loci that were examined. Common melanocytic nevi, therefore, arise by apparently clonal proliferation, but they do not share chromosomal deletions that are characteristic of melanoma. However, skewed X inactivation patterns were seen in some samples of adjacent microdissected normal epidermis.
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PMID:X inactivation, DNA deletion, and microsatellite instability in common acquired melanocytic nevi. 1175 1


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