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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

E-cadherin mediated intercellular adhesion is regulated by a family of cytoplasmic proteins that include alpha-, beta- and gamma-catenin and p120cas. Changes in expression of E-cadherin are believed to be an early event in melanoma development. Recent studies have also drawn attention to the over-expression of beta-catenin and its possible indirect role as an oncogene in melanoma. In view of these studies, we have examined the expression of cytoplasmic proteins immunohistochemically in 13 melanocytic nevi, 34 primary cutaneous melanomas and 20 metastatic melanomas. alpha-, gamma-catenin and p120cas were heterogeneously expressed in melanocytic nevi and melanomas and were frequently absent, whereas beta-catenin expression was observed in all lesions. The pattern of expression of alpha-, beta- and gamma-catenin and p120cas was characterised by cytoplasmic and membranous immunoreactivity of varying intensity. No significant difference was found in expression of these proteins between melanocytic nevi and primary melanoma. In contrast, there was an inverse correlation between alpha-catenin expression and tumor thickness and alpha-catenin was more frequently expressed in radial compared to vertical growth phase in primary melanoma. Loss of alpha-catenin expression was observed in ten of 20 metastases compared to six of 34 primaries and the expression was more marked in primaries than in metastases. These results indicated that alterations in alpha-, beta- and gamma-catenin and p120cas expression were common in melanocytic nevi and melanomas, and that loss of alpha-catenin expression was associated with melanoma invasiveness and metastasis.
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PMID:Expression of catenins and p120cas in melanocytic nevi and cutaneous melanoma: deficient alpha-catenin expression is associated with melanoma progression. 1050 70

Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e., CTNNB1 (beta-catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (beta-transducin repeat-containing protein gene, 10q24.3) and ICAT (inhibitor of beta-catenin and Tcf-4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N-terminal degradation box of beta-catenin, which is important for the regulation of beta-catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real-time RT-PCR showed markedly reduced ICAT transcript levels (<or=20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts.
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PMID:Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. 1212 4

We evaluated expression of activated nerve growth factor receptor tyrosine kinase (p-TrkA) by immunohistochemical analysis in 152 primary and 64 metastatic human melanoma biopsy specimens and 8 nevi. Membranous, cytoplasmic, and/or nuclear expression of p-TrkA was seen in 54.6% of primary melanomas and 30% of metastases. Membranous p-TrkA was detected in 21.7% of primary and 14% of metastatic melanomas and cytoplasmic immunoreactivity in 28.9% of primary tumors and in 22% of metastases. Significantly fewer metastases than primary tumors expressed nuclear p-TrkA (16% vs 39.5%; P = .006). A significantly higher percentage of nodular than superficial spreading melanomas expressed membranous (40% vs 11%; P < .0001) p-TrkA. Nevi expressed no membranous or cytoplasmic p-TrkA; 63% showed nuclear reactivity. p-TrkA expression varied significantly with thickness of primary tumors (lower expression in thinner lesions: membranous, P = .004; cytoplasmic, P = .001; nuclear, P = .031). An association between ulceration and membranous (P = .054), cytoplasmic (P < .0001), and nuclear (P = .022) p-TrkA expression was found. Membranous p-TrkA significantly predicted decreased overall survival (P = .002). A significant association between membranous p-TrkA and cyclin A (P = .004) and Ki-67 (P < .0001) and between cytoplasmic p-TrkA and cyclin A (P < .0001), Ki-67 (P = .004), and cyclin D3 (P = .027) was found. p-TrkA had no effect on MAPK(ERK1/2) activation. A significant inverse association between cytoplasmic beta-catenin and cytoplasmic p-TrkA levels (P = .006) and between nuclear p-TrkA and cytoplasmic E-cadherin (P = .022) was seen. We present the first evidence of a role for TrkA activation in a subset of melanomas as a predictor of an aggressive phenotype and poor outcome.
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PMID:Expression of activated TrkA protein in melanocytic tumors: relationship to cell proliferation and clinical outcome. 1536 72

Choriocarcinoma is traditionally described as being composed of cytotrophoblast and syncytiotrophoblast. Microscopically, these 2 types of cells are intimately associated with each other, forming a characteristic biphasic plexiform pattern, however, the nature of these 2 types of trophoblastic cells is not well understood. In this study, we used immunohistochemistry for several trophoblastic markers to analyze the trophoblastic subpopulations in 36 gestational choriocarcinomas. Eighty-one specimens including placenta, complete mole, placental site nodule, epithelioid trophoblastic tumor, and placental site trophoblastic tumor were analyzed. The antibodies included Mel-CAM, HLA-G, MUC-4, and beta-catenin. A semiquantitative assessment of positive cells and the cellular localization of these markers were recorded. We found diffuse strong membranous and cytoplasmic staining for MUC-4 in mononucleate cells in all 36 cases (100%) and a similar pattern of localization in 28 cases (78%) for HLA-G. This distribution was similar to that in normal placentas, where MUC-4 and HLA-G are expressed in the trophoblastic cells of the trophoblastic columns and implantation site. In choriocarcinoma, mononucleate trophoblastic cells showed moderate immunoreactivity for Mel-CAM, a specific marker for implantation site intermediate trophoblast, in 78% of the cases. The MUC-4, HLA-G, and Mel-CAM-positive trophoblastic cells were larger than cytotrophoblastic cells, with more abundant cytoplasm, consistent with the morphology of intermediate trophoblast. In contrast, 31% of the choriocarcinomas contained a very small proportion (<5%) of mononucleate trophoblastic cells compatible with cytotrophoblast that was positive for nuclear beta-catenin, a cytotrophoblast-associated marker. These results suggest that choriocarcinoma is composed predominantly of a mixture of syncytiotrophoblast and intermediate trophoblast with only a small proportion of cytotrophoblast. The presence of nuclear beta-catenin staining in the cytotrophoblast of choriocarcinoma is consistent with the view that choriocarcinoma develops from transformed cytotrophoblastic cells which are presumably the cancer stem cells that differentiate into either intermediate trophoblast or syncytiotrophoblast.
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PMID:Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis. 1805 30

Canonical Wnt/beta-catenin signaling regulates stem/progenitor cells and, when perturbed, induces many human cancers. A significant proportion of human breast cancer is associated with loss of secreted Wnt antagonists and mice expressing MMTV-Wnt1 and MMTV-DeltaN89beta-catenin develop mammary adenocarcinomas. Many studies have assumed these mouse models of breast cancer to be equivalent. Here we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin transgenes induce tumors with different phenotypes. Using axin2/conductin reporter genes we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin activate canonical Wnt signaling within distinct cell-types. DeltaN89beta-catenin activated signaling within a luminal subpopulation scattered along ducts that exhibited a K18(+)ER(-)PR(-)CD24(high)CD49f(low) profile and progenitor properties. In contrast, MMTV-Wnt1 induced canonical signaling in K14(+) basal cells with CD24/CD49f profiles characteristic of two distinct stem/progenitor cell-types. MMTV-Wnt1 produced additional profound effects on multiple cell-types that correlated with focal activation of the Hedgehog pathway. We document that large melanocytic nevi are a hitherto unreported hallmark of early hyperplastic Wnt1 glands. These nevi formed along the primary mammary ducts and were associated with Hedgehog pathway activity within a subset of melanocytes and surrounding stroma. Hh pathway activity also occurred within tumor-associated stromal and K14(+)/p63(+) subpopulations in a manner correlated with Wnt1 tumor onset. These data show MMTV-Wnt1 and MMTV-DeltaN89beta-catenin induce canonical signaling in distinct progenitors and that Hedgehog pathway activation is linked to melanocytic nevi and mammary tumor onset arising from excess Wnt1 ligand. They further suggest that Hedgehog pathway activation maybe a critical component and useful indicator of breast tumors arising from unopposed Wnt1 ligand.
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PMID:MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors. 1922 68

Conjunctival melanocytic lesions encompass a group of clinically diverse, benign to malignant, neoplasms that may contain overlapping histopathological features, making definitive diagnosis challenging in some cases. In this series, we compared multiple immunohistochemical (IHC) markers in 11 conjunctival nevi, 10 primary acquired melanosis (PAM) lesions, and 11 conjunctival melanomas. Immunostains included the melanocytic markers HMB-45 and Melan-A, as well as the proliferative marker Ki-67. Loss of beta-catenin expression has been associated with more aggressive clinical disease in cutaneous melanoma, but its status in conjunctival melanocytic lesions is not known, therefore we incorporated beta-catenin immunohistochemical staining in our study. In this series, conjunctival melanomas had a higher Ki-67 proliferative index and HMB-45 immunoreactivity than did PAM lesions and conjunctival nevi (P<0.001). Melan-A was highly expressed in all 3 groups. Beta-catenin was more strongly expressed in melanomas and nevi than in PAM (P<0.001). There was high inter-grader reliability (Kappa=0.53). Overall, IHC labeling of HMB-45 and Ki-67 is increased in conjunctival melanomas compared to PAM or conjunctival nevi. Beta-catenin, an IHC marker previously unstudied in conjunctival melanocytic lesions, is not preferentially expressed in benign lesions and may play a different role in conjunctival atypia than it does in cutaneous melanoma.
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PMID:Immunohistochemical profiling including beta-catenin in conjunctival melanocytic lesions. 2816 40