Natural and synthetic
vitamin A metabolites and analogs (
retinoids) were found to suppress head and neck and lung
carcinogenesis in animal models and inhibit
carcinogenesis in individuals with premalignant lesions and a high risk to develop
cancer of the aerodigestive tract. Likewise,
retinoids prevent the development of
second primary cancers in head and neck and
lung cancer patients who had been treated for the first primary. These effects are thought to result from changes in the expression of genes that regulate cell growth and differentiation. Most of the effects of
retinoids on gene expression are mediated by nuclear
retinoic acid receptors RARs (alpha, beta, and gamma) and
retinoid X receptors (RXR alpha, beta, and gamma), which function as
retinoid-activated
transcription factors. Like
vitamin A deficiency, alterations in receptor expression or function could interfere with the
retinoid signaling pathway and thereby enhance
cancer development even in
vitamin A sufficient individuals. We found that the expression of
RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without
cancer (e.g.,
oral leukoplakia and squamous
metaplasia), in dysplastic lesions adjacent to
cancer, and in malignant oral and lung
carcinomas. The expression of the other receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of
RAR gamma and RXR beta was somewhat decreased in
lung cancers. These results show that
RAR beta expression is lost at early stages of
carcinogenesis in the aerodigestive tract and support the hypothesis that the loss of
RAR beta expression may facilitate the development of some of these
cancers.