THE ALPHA-6-BETA-1 AND ALPHA-6-BETA-4 INTEGRINS IN HUMAN PROSTATE-CANCER PROGRESSION

Prostatic secretions are formed by glands composed of basal and lumina l cells and surrounded by a basal lamina. The normal basal cells expre ss several integrins (extracellular matrix receptors) including alpha 2, 3, 4, 5, 6, v, beta 1 and beta 4. These integrin units are polarize d at the base of the cells adjacent to the basal lamina. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures. The natural history of prostate cancer involves the presence of prostatic intraepithelial neoplasia (PIN) lesions (considered precursor lesions) , carcinoma in situ and invasive carcinoma. Hemidesmosomal proteins an d the alpha 3 beta 1 and alpha 6 beta 1 integrins (laminin receptors) are retained in the early PIN lesions. Expression of the integrins alp ha 2, alpha 4, alpha 5, alpha v and beta 4 is lost in carcinoma. The a lpha 3 beta 1 and alpha 6 beta 1 integrins remain associated with inva sive carcinoma, the latter being predominant. Integrin expression in c arcinoma is diffuse in the plasma membrane and not restricted to the b asal aspects of the cell. The alpha 6 beta 1 integrin is fully functio nal as judged by an ability to adhere to laminin and contains the wild type alpha 6A cytoplasmic signaling domain. The alpha 6 beta 1 integr in is a leading candidate for conferring the invasive phenotype in pro static carcinoma. Tumor cells with high expression of alpha 6 integrin are more invasive when tested in a SCID mouse model system. Following intraperitoneal injection, the human tumor cells invade the mouse dia phragm and move through the muscle on the surface of the laminin coate d muscle cells. Our current working hypothesis is that the production of alpha 6 beta 1 and laminin in human tumor cells contributes to the invasive phenotype. Invasion could occur on the surfaces of laminin co ated structures such as the nerves, blood vessels or muscle and accoun t for the known patterns of human prostate tumor progression. Blockage of the expression or function of alpha 6 beta 1 or laminin or prevent ing the loss of beta 4 would be essential steps in confining the carci noma to the prostate gland where conventional treatment has already pr oven effective.