Acinar morphogenesis in nonmalignant human prostatic epithelial cells and its loss in malignant cells.

摘要

Little is known about the multiple steps in prostate carcinogenesis and tumor progression. For the present study, it was hypothesized that during prostate carcinogenesis and progression, the following changes occur: (1) that there is a progressive loss of the ability of epithelial cells to undergo acinar morphogenesis, by polarization, to form well defined acini with lumens; (2) that adhesion of cells to laminin is altered and this occurs as a result of changes in the expression of laminin integrin receptors which bind cells to laminin; (3) that the loss of abnormal expression of integrins imparts to the cells increased invasive ability; and (4) that cells show altered response to both stimulatory and inhibitory growth factors, which occurs as a result of changes in the level of expression of growth factors and their receptors.;Using a family of seven human prostate epithelial cell lines, a novel, 3-dimensional human prostate cell culture model was developed to test the hypotheses. In this model, non-tumorigenic RWPE-1 cells mimic normal epithelial acinar morphogenesis as it occurs in vivo. Immunocytochemical and confocal microscopy methods were employed. Results show that RWPE-1 cells form acini only when plated in a matrix of Matrigel or laminin, but not in collagen or fibronectin. When binding of cells to laminin is blocked by antibody to laminin, cells fail to form acini. The six tumorigenic cells lines showed a progressive loss of acini forming ability with increasing malignancy. Abnormal integrin expression showed a direct relationship to the loss of ability of cells to undergo acinar morphogenesis and their increased invasive ability.;Exposure of RWPE-1 cells to growth stimulatory exogenous EGF caused a dose-dependent decrease in acinar formation. These results suggest that, because of increased cell proliferation, malignant cells lose the ability to form acini and the degree of loss is related to abnormal integrin expression and increased invasive ability. Further, the growth inhibitory, exogenous TGF- b 1 and b 2 were more effective inhibitors of growth of RWPE-1 and WPE1-NA22 cells than that of WPE11-NB26 cells.;Taken together, these results demonstrate that during prostate carcinogenesis and tumor progression, there is a progressive loss of the normal expression of laminin integrin receptors. Changes in the expression of laminin integrins, growth factors and their receptors, contribute to the inability of cancer cells to undergo acinar morphogenesis. This is associated with increased invasive ability. These results facilitate the development of agents which may be used to restore normal acinar morphogenesis and, thus, block carcinogenesis, invasion and metastasis. (Abstract shortened by UMI.).