Mw. Lingen et al., RETINOIC ACID INDUCES CELLS CULTURED FROM ORAL SQUAMOUS-CELL CARCINOMAS TO BECOME ANTI-ANGIOGENIC, The American journal of pathology, 149(1), 1996, pp. 247-258
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.