Suppression of squamous cell carcinoma growth and differentiation by retinoids

The epithelium of the oral cavity is mostly nonkeratinizing. However, it undergoes an abnormal squamous differentiation with keratinization during vitamin A deficiency or oral carcinogenesis. Vitamin A analogues (retinoids) were found to be effective in preventing oral premalignant lesions and second primary cancers in the upper aerodigestive tract. Further development of retinoids for prevention and therapy of squamous cell carcinoma (SCC) requires a better understanding of their mechanism action on the growth and differentiation of SCC cells. We used cultured head and neck SCC (HNSCC) cell lines as a model system. Treatment of HNSCC cells with beta-all-trans-retinoic acid resulted in inhibition of growth (proliferation and colony formation) and suppression of squamous differentiation to varying degrees in the different cell lines. Because some of the malignant HNSCC cells recapitulate the main characteristics of keratinocyte squamous differentiation and responsiveness to retinoids, they can serve as a model for investigating the mechanism underlying the effects of retinoids on cell growth and differentiation. It is thought that nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the above effects of retinoids by acting as DNA-binding transcription-modulating factors. We found that HNSCC cell lines express several nuclear RAR and that their level could be modulated by retinoids in some cell lines. An inverse relationship was found between RAR-beta expression and squamous differentiation. An analysis of RAR mRNA expression in head and neck cancer specimens revealed a decrease in RAR-beta in premalignant and malignant tissues relative to normal mucosa. The expression of this receptor increased in vivo after treatment with 13-cis-retinoic acid. These results implicate the loss of RAR-beta expression in the development of head and neck cancer and suggest that RAR-beta could serve as an intermediate marker in prevention trials.