In situ analysis of transforming growth factor-βs (TGF-β1, TGF-β2, TGF-β3and TGF-3 type II receptor expression in malignant melanoma

We have analysed, by in situ hybridization, mRNA expression of TGF-β1, TGF-β2, TGF-β3, and of TGF-β type II receptor in benign melanocytic naevi, primary melanomas, and in skin metastases of malignant melanomas. Our results show that melanoma progression correlates with overexpression of TGF-β. All skin metastases and most primary melanomas invasive to Clark's level IV-V revealed specific TGF-β2 mRNA and protein expression. However, expression of this cytokine was not observed in benign melanocytic lesions and was detected only in one of five early primary melanomas investigated. Some primary melanomas and skin metastases also revealed specific TGF-β1 mRNA signals although expression of this isoform was not found in benign naevi. TGF-β3 expression, which was only barely detectable in benign melanocytic lesions, was enhanced in some skin metastases. Interestingly, the epidermis overlaying melanomas revealed lower levels of TGF-β3 mRNA expression than epidermis of healthy skin or epidermis adjacent to benign naevi, thereby suggesting that paracrine mechanisms between tumour cells and keratinocytes may influence melanoma development. In primary melanomas TGF-β type II receptor mRNA signals were much more heterogeneously distributed when compared to benign melanocytic naevi, suggesting variable degrees of TGF-β resistance among melanoma cells within individual lesions. However, melanoma progression appeared not to be correlated with a complete loss of TGF-β type II receptor gene expression, since all skin metastases revealed clearly detectable although heterogeneous levels of TGF-β type II receptor mRNA expressio