transforming-growth-factor-beta and Nevus--Pigmented

Topics: Biomarkers; Bone Marrow Transplantation; Cytokines; Graft vs Host Disease; Humans; Hypopigmentation; Immunocompromised Host; Interleukin-1; Interleukin-6; Nevus, Pigmented; Skin Neoplasms; Transforming Growth Factor beta; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Nodal, a potent embryonic morphogen in the transforming growth factor-beta family, is a proposed key regulator of melanoma tumorigenicity. However, there has been no systematic study of Nodal expression in melanocytic lesions. We investigated Nodal expression by immunohistochemistry in 269 melanocytic lesions, including compound nevi, dysplastic nevi, congenital nevi, Spitz nevi, melanoma in situ, malignant melanoma including the variant desmoplastic melanoma, and metastatic melanoma. We found that the Nodal expression was significantly increased in malignant lesions (including melanoma in situ, malignant melanoma, and metastatic melanoma) compared with compound nevi, Spitz nevi, and dysplastic nevi. Surprisingly, congenital nevi expressed a level of Nodal comparable with malignant lesions, whereas desmoplastic melanoma showed lower expression than nondesmoplastic malignant melanoma (P<0.05). Deep melanoma (Breslow depth >1 mm) displayed a higher percentage of Nodal-positive tumor cells than did superficial melanoma (Breslow depth < or =1 mm), although there was no statistical difference in the overall staining intensity (P=0.18). Melanomas in situ showed a lower level of Nodal expression than did deep melanomas and metastatic melanomas (P<0.05). The low expression of Nodal in normal and dysplastic nevi, and its increasing expression with the progression of malignant lesions, are suggestive of a role for Nodal in melanoma progression.

Topics: Biomarkers, Tumor; Dysplastic Nevus Syndrome; Humans; Immunohistochemistry; Melanoma; Nevus, Pigmented; Nodal Protein; Precancerous Conditions; Skin Neoplasms; Transforming Growth Factor beta

We have analysed, by in situ hybridization, mRNA expression of TGF-beta 1, TGF-beta 2, TGF-beta 3, and of TGF-beta 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-beta. All skin metastases and most primary melanomas invasive to Clark's level IV-V revealed specific TGF-beta 2 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-beta 1 mRNA signals although expression of this isoform was not found in benign naevi. TGF-beta 3 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-beta 3 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-beta type II receptor mRNA signals were much more heterogeneously distributed when compared to benign melanocytic naevi, suggesting variable degrees of TGF-beta resistance among melanoma cells within individual lesions. However, melanoma progression appeared not to be correlated with a complete loss of TGF-beta type II receptor gene expression, since all skin metastases revealed clearly detectable although heterogeneous levels of TGF-beta type II receptor mRNA expression.

Topics: Disease Progression; Humans; Immunohistochemistry; In Situ Hybridization; Isomerism; Melanoma; Nevus, Pigmented; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Sensitivity and Specificity; Skin Neoplasms; Tissue Distribution; Transforming Growth Factor beta