Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions

Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8) and reactivity of TGF-betaR and c-kit. Marked up-regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, TGF-beta, granulocyte-macrophage colony-stimulating factor (GMCSF) and stem cell factor (SCF), but not IL-2. Metastases showed similar expression patterns except that SCF was absent. Co-expression of ligand and receptor was observed for TGF-beta, GM-CSF and IL-6, suggesting an autocrine role for these ligands. TNF-alpha appears to be a marker of benign lesions; IL-6 and IL-8 expression is associated with biologically early malignancy; TGF-beta, GM-CSF and IL-1alpha are highly expressed in biologically late lesions; and TNF-beta is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression.