Tumor-promoting phorbol esters induce angiogenesis in vivo

It has been hypothesized that tumor growth is dependent on the concomitant growth of its vascular supply, and thus agents that stimulate angiogenesis may help support tumor growth. Phorbol esters are potent tumor promoters that induce a variety of biochemical effects in cells, including activation of protein kinase C. The specific mechanisms responsible for tumor promotion by phorbol esters are unknown. The objective of this study was to determine whether the tumor-promoting phorbol esters can induce vascular growth. Phorbol esters were tested for their ability to stimulate angiogenesis in vivo using the chick chorioallantoic membrane and rabbit cornea assays. The active tumor promoters 12-O-tetradecanoyl phorbol-13-acetate and phorbol 12,13-didecanoate, which activate protein kinase C, were found to stimulate angiogenesis in a dose-dependent manner. In contrast, 4 alpha-phorbol 12,13-didecanoate, which is inactive as a tumor promoter and does not activate protein kinase C, did not stimulate angiogenesis. Phorbol esters may be indirect angiogenic factors, since no mitogenic effect on bovine capillary endothelial cells in culture could be detected. The results demonstrate that the tumor-promoting activity of phorbol esters may, in part, be secondary to stimulation of neovascularization to support tumor growth and suggest a role for the activation of protein kinase C in this process.