In situ expression of transforming growth factor ?? is associated with melanoma progression and correlates with Ki67, HLA-DR and ?? 3 integrin expression

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Abstract
Transforming growth factor-β(TGF β), which is secreted by cultured melanoma cells constitutively, inhibits the proliferation of normal melanocytes and of most melanoma cells in vitro, but some melanoma cells from advanced stages of the disease develop resistance to TGF β-dependent growth inhibition, without developing any change in TGF β cell surface binding. In vitro TGF p also downregulates the expression of HLA-DR molecules on melanoma cells, and upregulates the expression of the β 3 integrin subunit on some cell lines. Immunohistochemical analysis of 53 melanocytic lesions (12 naevi, 30 primary melanomas and 11 metastases) revealed a trend of increasing expression of TGF β and TGF β receptor type III with tumour progression, and a significantly higher expression of both TGFβ (P < 0.0001) and the receptor (P < 0.05) in metastatic and thick (P < 1 mm) primary melanomas compared with thin (> 1 mm) primary melanomas. The expression of TGF β correlated with expression of a marker of proliferation, Ki67, and with HLA-DR and β 3 integrin subunit expression. Coexpression of the four molecules was observed in all metastases and in most thick primary melanomas. These findings argue against an inhibitory effect of TGFβ on cell proliferation or HLA-DR antigen expression in melanoma, and suggest the upregulation of the β 3 subunit. TGF β protein appears to be a biological marker of melanoma progression in situ.

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