INHIBITION OF SQUAMOUS-CELL CARCINOMA ANGIOGENESIS BY DIRECT INTERACTION OF RETINOIC ACID WITH ENDOTHELIAL-CELLS

Retinoic acid (RA) is a multifunctional drug that is particularly effe ctive at preventing the development of multiple primary oral squamous cell carcinomas. A portion of this activity is due to the inhibition o f tumor angiogenesis. It has been thought that RA influences tumor ang iogenesis only via its interactions with the tumor cells themselves. H ere, we test the hypothesis that the drug can also block neovasculariz ation by directly inhibiting the angiogenic activity of normal endothe lial cells. Clinically achievable doses of RA rapidly caused large- an d small-vessel endothelial cells to become refractory to stimulation o f migration either by tumor-conditioned media or purified angiogenic f actors (a-fibroblast growth factor (aFGF), bFGF, vascular endothelial GF, platelet-derived GF, TGF beta-1, and IL-8). However, RA had little effect on their proliferation. Inhibition of migration was complete w ithin 3 hours and was reversed 36 hours after drug removal. The migrat ion of human oral keratinocytes was not sensitive to RA, whereas the m igration of fibroblasts and vascular smooth muscle cells was inhibited . To determine if systemic RA affected neovascularization, rats were g iven 1 mg/kg/day of all-trans RA and their angiogenic potential was te sted by implanting pellets of tumor-conditioned media into their avasc ular corneas. This treatment rendered the rats unable to mount a neova scular response in their corneas. These data demonstrate that RA direc tly affects endothelial cells, rapidly and reversibly inhibiting their ability to migrate toward a variety of stimuli in vitro and halting t he formation of new vessels in vivo. These direct effects on vascular cells seem likely to contribute to the success of RA as a chemoprevent ive agent for oral squamous cell carcinoma.