IMMUNOHISTOCHEMICAL STUDY OF THE RETINOIC ACID RECEPTOR-ALPHA IN NORMAL VERSUS NEOPLASTIC HUMAN TISSUES

The molecular basis of transcription regulation by retinoic acid recep tors (RARs) has been well studied, but the histologic distribution of these receptors in normal and neoplastic human tissues is not well def ined, despite the frequent use of retinoic acid in medicine. We descri be here the microanatomical distribution of RAR alpha in such tissues and discuss its biologic implications. A monoclonal antibody directed against the RAR alpha protein was used in an alkaline phosphatase anti -alkaline phosphatase (APAAP) technique applied to frozen sections of benign and neoplastic human tissues. Staining was confined to the nucl eus except among glial tissues where there was intense, focal cytoplas mic staining, RAR alpha expression was nearly absent in mitotically ac tive benign cell populations but was strongly expressed in populations undergoing terminal differentiation. Nonproliferating, long-lived cel ls such as neurons, myocytes, chondrocytes, and hepatocytes had little to no expression of this receptor. Among the malignant tumors there w as marked variability of nuclear staining intensity. Lung carcinomas w ere strongly labelled, while nuclear staining in glial tumors was weak , although there was intense, focal cytoplasmic staining. In contrast to benign tissues, RAR alpha expression paradoxically correlated with the amount of cellular proliferation as determined by immunostaining w ith the Ki67 monoclonal antibody among lung tumors, and by mitotic rat es among all of the tumors studied. These results suggest that RAR alp ha plays a role in controlling cellular proliferation and terminal dif ferentiation in benign tissues and that this regulation is markedly al tered in the malignant tissues that were examined.