EXPRESSION OF THE SOLUBLE VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1 IN CUTANEOUS MELANOMA: ROLE IN TUMOUR PROGRESSION
F. Ruffini1, C. M. Failla2, A. Orecchia2, M. R. Bani3, A. S. Dorio4, C. Fortes5, G. Zambruno2, G. Graziani4, R. Giavazzi3, S. D’Atri1, P. M. Lacal1
Copyright © 2010 British Association of Dermatologists
British Journal of Dermatology
Accepted Article (Accepted, unedited articles published online for future issues)
sVEGFR-1;VEGF-A;angiogenesis;melanoma progression;angiogenic switch
Background: Vascular endothelial growth factor (VEGF)-A, placenta growth factor (PlGF), and their corresponding membrane receptors, are involved in autocrine and paracrine regulation of melanoma growth and metastasis. Besides the membrane receptors, a soluble form of the VEGFR-1 (sVEGFR-1) has been identified, that behaves both as a decoy receptor, sequestering VEGF-A and PlGF, and as an extracellular matrix (ECM) molecule, promoting endothelial cell adhesion and migration through the interaction with α5β1 integrin.
Objectives: To analyze whether sVEGFR-1 plays a role during melanoma progression.
Methods: sVEGFR-1 expression was evaluated in a panel of 36 melanoma cell lines and 11 primary human melanocyte cultures by quantitative real-time PCR analysis and in specimens of primary or metastatic melanoma lesions from 23 patients by immunohistochemical analysis.
Results: sVEGFR-1 expression was highly up-regulated in melanoma cell lines with respect to human melanocytes. Interestingly, cell lines obtained from cutaneous metastases showed a significant reduction of sVEGFR-1 expression, as compared with cell lines derived from primary tumours. These results were confirmed by immunohistochemical analysis of sections from primary skin melanomas and the corresponding cutaneous metastases, suggesting that modulation of sVEGFR-1 expression influences ECM invasion by melanoma cells and metastasis localization. Moreover, we provide evidence that adhesion of melanoma cells to sVEGFR-1 is favoured by the activation of a VEGF-A/VEGFR-2 autocrine loop.
Conclusions: Our data strongly suggest that sVEGFR-1 plays a role in melanoma progression and that low sVEGFR-1:VEGF-A and sVEGFR-1:mVEGFR-1 ratios might predict a poor outcome in melanoma patients.