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 alpha 3 beta 1 and alpha 6 beta 1
integrins (
laminin receptors) are retained in the early PIN lesions. Expression of the
integrins alpha 2, alpha 4, alpha 5, alpha v and beta 4 is lost in
carcinoma. The alpha 3 beta 1 and alpha 6 beta 1
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
alpha 6 beta 1 integrin is fully functional as judged by an ability to adhere to
laminin and contains the wild type alpha 6A cytoplasmic signaling domain. The
alpha 6 beta 1 integrin is a leading candidate for conferring the invasive phenotype in prostatic
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 diaphragm and move through the muscle on the surface of the
laminin coated 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 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 alpha 6 beta 1 or
laminin or preventing the loss of beta 4 would be essential steps in confining the
carcinoma to the prostate gland where conventional treatment has already proven effective.