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.