RETINOIC ACID INDUCES CELLS CULTURED FROM ORAL SQUAMOUS-CELL CARCINOMAS TO BECOME ANTI-ANGIOGENIC

Retinoids have shown great promise as chemopreventive agents against t he development of squamous cell carcinomas of the upper aerodigestive tract. However, the exact mechanism by which they block new tumors fro m arising is unknown. Here, we report that 13-cis- and all-trans-retin oic acid, used at clinically achievable doses of 10(-6) mol/L or less, can directly and specifically affect cell lines cultured from oral sq uamous cell carcinomas, inducing them to switch from an angiogenic to an anti-angiogenic phenotype. Although retinoic-acid-treated and untre ated tumor cells make the same amount of interleukin-8, the major indu cer of neovascularization produced by such tumor lines, they vary in p roduction of inhibitory activity. Only the retinoic-acid-treated cells produce a potent angio-inhibitory activity that is able to block in v itro migration of endothelial cells toward tumor cell conditioned medi a and to balt neovascularization induced by such media in the rat corn ea. Anti-angiogenic activity is induced in the tumor cells by low dose s of retinoids in the absence of toxicity with a kinetics that suggest that it could be contributing to the effectiveness of the retinoids a s chemopreventive agents.