Regulation of VEGF-A in Uveal Melanoma

PURPOSE. Blood vessels are important constituents of intraocular uveal melanoma (UM), but whether angiogenesis is regulated by environmental factors such as ischemia or by genetic mechanisms is not known. This study was undertaken to examine the regulation of the proangiogenic factor vascular endothelial growth factor (VEGF-A). METHODS. Cell lines and primary tumors were tested for expression of VEGF-A, under normoxic and hypoxic conditions, using quantitative PCR, ELISA, WST-1 viability, and in-cell Western experiments. VEGF-A serum levels were determined by ELISA. RESULTS. Hypoxia induced expression of HIF-1 alpha and VEGF-A in UM cell lines and primary tumor cultures, but it did not influence proliferation. VEGF-A expression in primary tumors was variable, demonstrating no correlation with specific histologic markers or prognosis. However, VEGF-A levels were significantly raised in UM patients with metastases compared with those without metastases (P < 0.001). CONCLUSIONS. VEGF-A expression by UM cells is mainly controlled by hypoxia and involves the HIF-1 alpha pathway, thus indicating an important role for the tumor cell environment. Metastases led to increased serum VEGF-A levels, indicating that VEGF-A may be involved in the growth of metastases. (Invest Ophthalmol Vis Sci. 2010;51:2329-2337) DOI: 10.1167/iovs.09-4739