Adhesion molecules, extracellular matrix, and proteases in prostate carcinoma

Immunohistochemical studies of prostate carcinoma reveal that most primary carcinomas, including high-grade tumors, are surrounded by a basal lamina composed of laminin, type IV collagen, and entactin. In addition to the expected laminin subchains A, B₁, B₂, subchains M and S are also found. Tenascin, found around normal glands, is seen in 60% of carcinomas. The basal cells of the normal gland express several integrin α units including α_2,3,4,5,6, and v. Both β₁ and β₄ subunits are observed. These integrin units are polarized at the base of the cells where they co-distribute with the surrounding extracellular matrix. The integrin α₆β₄ is associated with hemidesmosomal-like structures, as detected by transmission electron microscopy (TEM). In carcinoma, the β₄ is not observed and the α₆ and β₁ subunits are variably expressed. The integrin expression in carcinoma is diffuse in the cytoplasmic membrane and not restricted to the basal aspects of the cell. In addition, type VII collagen and the BP 180 protein which are associated with hemidesmosomes are lost, although the BP 230, plectin, and HD1 proteins are variably expressed. Using immunohistochemistry and northern analysis we observed three metalloproteinases in prostate carcinoma-matrilysin, gelatinase A, and gelatinase B. Western blotting and zymogram analysis reveal that of these three, only matrilysin appears to be present in its active form. Recent in situ hybridization studies reveal focal expression of the matrilysin mRNA in 25/33 primary carcinomas. Matrilysin also appears to be highly expressed in prostatic ducts and atrophic glands. Expression of the three metalloproteinases is also seen in prostatic intraepithelial neoplasia lesions. The lysosomal protease cathepsin D is focally expressed in 39/78 carcinomas. This expression shows a tendency to increase with histologic grade (p = 0.055), and is related to pathologic stage (p = 0.031). These proteases most likely participate in a cascade of enzymatic reactions which include the plasminogen activator, urokinase. During prostate tumor progression, alterations occur in the extracellular matrix, cellular surface integrins, and protease expression, suggesting a dynamic remodeling of tissue. Further analysis of these alterations are ongoing in an effort to determine the value of these factors as prognostic indicators of the disease.