Clinical markers and driving mechanism in melanoma progression: VEGF-C, RhoC, c-Ski/SnoN and EGFR

Melanoma appears to be a complex multigenic disease which is determined by several parallel and stepwise progressive pathways. Better understanding of molecules and pathways involved in melanoma progression can contribute to better prognostic information and identification of possible new therapeutic targets. Cutaneous malignant melanoma spreads preferentially through the lymphatic vessels. Vascular Endothelial Growth Factor-C has been found to promote tumour-associated lymphatic vessel growth. We investigated VEGF-C protein expression in primary cutaneous melanoma tissues of 113 patients with known clinicopatological follow up. High VEGF-C expression levels in melanoma cells and tumour-associated macrophages were correlated with the presence of a positive sentinel lymph node. The presence of VEGF-C expression in melanoma cells was associated with reduced disease free and overall survival. RhoC belongs to the family of Ras-homologous (Rho) proteins, wich are important regulators of the organization of the actin filament system. We observed RhoC mRNA and protein expression to be upregulated in a highly metastatic melanoma cell line, whereas only low expression levels were found in a melanoma cell line with low proliferative and invasive capacity. RhoC expression in melanoma tissue was associated with high Breslow tumour thickness and the presence of ulceration. Loss of TGF-b growth control is frequently observed in several human neoplasms, including melanoma. C-Ski and SnoN have been identified as negative regulators in the TGF-b pathway. When studying the subcellular c-Ski localization in melanoma tissues, a significant association was observed between the presence of nuclear c-Ski and thicker, ulcerated melanomas indicating nuclear c-Ski might be involved in the process of melanoma growth. SnoN expression was associated with the presence of ulceration and a positive sentinel lymph node. Epidermal Growth Factor Receptor (EGFR) expression has been associated with tumour progression and poor outcome in a variety of solid tumours. We found EGFR immunoreactivity in melanoma tissue to be more frequently present in patients with a positive sentinel lymph node. The presence of EGFR gene polysomy was associated with higher Breslow tumour thickness. Treating BLM melanoma cells with different concentrations of cetuximab (anti-EGFR antibody) reduced the invasive capacity of the melanoma cells, without impact on cell viability and growth