The α6β1 and α6β4 integrins in human prostate cancer progression

Abstract

Prostatic secretions are formed by glands composed of basal and luminal cells and surrounded by a basal lamina. The normal basal cells express several integrins (extracellular matrix receptors) including alpha 2, 3, 4, 5, 6, v, beta 1 and beta 4. These integrin units are polarized 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 and the α3β1 and α6β1 integrins (laminin receptors) are retained in the early PIN lesions. Expression of the integrins α2, α4, α5, αv and β4 is lost in carcinoma. The α3β1 and α6β1 integrins remain associated with invasive carcinoma, the latter being predominant. Integrin expression in carcinoma is diffuse in the plasma membrane and not restricted to the basal aspects of the cell. The α6β1 integrin is fully functional as judged by an ability to adhere to laminin and contains the wild type α6A cytoplasmic signaling domain. The α6β1 integrin is a leading candidate for conferring the invasive phenotype in prostatic carcinoma. Tumor cells with high expression of α6 integrin are more invasive when tested in a SCID mouse model system. Following intraperitoneal injection, the human tumor cells invade the mouse diaphragm and move through the muscle on the surface of the laminin coated muscle cells. Our current working hypothesis is that the production of α6β1 and laminin in human tumor cells contributes to the invasive phenotype. Invasion could occur on the surfaces of laminin coated structures such as the nerves, blood vessels or muscle and account for the known patterns of human prostate tumor progression. Blockage of the expression or function of α6β1 or laminin or preventing the loss of β4 would be essential steps in confining the carcinoma to the prostate gland where conventional treatment has already proven effective. © 1995 Kluwer Academic Publishers.