The role of vascular endothelial growth factors and their receptors in malignant melanomas

Abstract

Vascular endothelial growth factors (VEGFs) have a leading role among variety of angiogenic factors. Together with their receptors, they play an important role in endothelial cell proliferation and/or elongation, migration and vascular morphogenesis. In order to determine their possible role in malignant melanoma progression, VEGF (representing VEGFA), VEGF-C and VEGFR-1, -2, -3 immunohistochemical expression on formalin-fixed, paraffin-embedded tissue sections were evaluated. A total of 196 tissue samples consisting of 130 malignant melanomas (MM) with various vertical depth of invasion, 15 metastatic melanomas, and 66 nevi including dysplastic nevi and melanocytic nevi were analysed. Production of both VEGFs were common in benign melanocytic tumors while MM exhibited significant upregulation of VEGF (p<0.0027) and VEGF-C (p<0.0001). The proteins were also detected within stromal cells surrounding tumors, particularly in fibrocytes/ fibroblasts, macrophages and endothelial cells. They also exhibited significant increase in malignant lesions (p<0.0001). VEGFRs were localized in tumor, as well in stromal cells. Although expression of VEGF receptors was significantly higher in MM versus nevi (p<0.002 for VEGFR-1, p<0.004 for VEGFR-2 and p<0.0001 for VEGFR-3), a considerable percentage of MM were negative. There were no correlations between sentinel node positivity and all investigated proteins. When clinical outcome was evaluated, progression of the disease positively correlated with VEGF (p<0,007) and VEGF-C (p<0,008) expression VEGF (p<0.001) and VEGF-C (p<0.0001) positively correlated with nestin expression in the capillary endothelium, which was used for angiogenesis detection. Our work demonstrated that upregulation of VEGFs is associated with progression of malignant melanomas. The protein expression in the tumor microenvironment highlights their importance in malignant stromal phenotype which may serve as a potential target for the anticancer therapy.