Dedifferentiation of stromal smooth muscle as a factor in prostate carcinogenesis.

We had earlier established an animal model of prostate carcinogenesis using a combination of testosterone (T) and 17beta-estradiol benzoate (E2) on Noble rats (Wang and Wong, 1998). In the present study we examined the changes in a number of smooth muscle differentiation markers including smooth muscle alpha-actin and myosin, vinculin, desmin, laminin and vimentin as well as changes in fine structure by electron microscopy. Our immunohistochemical (IHC) studies revealed that smooth muscle cells (SMCs) subjacent to dysplastic (precancerous) sites and carcinoma usually exhibited a preferential loss of myosin, desmin and laminin. However, the expression of alpha-actin and vinculin appeared to be more persistent in most dysplastic or neoplastic sites. The study reaffirmed our earlier observation that there was a concurrent dedifferentiation of surrounding SMCs during the development and progression of prostate carcinogenesis. The structural study revealed that SMC subjacent to epithelial dysplasia displayed a spectrum of derangements. These included the loosening of muscular layers with SMC characterized by their highly irregular external contours with numerous spine-like cytoplasmic projections. There was also a reduction in density of myofilaments and presence of many enlarged caveolae in muscle cells. Additionally, focal discontinuity or disruptions of muscular layer were often observed together with an increase in abundance of fibrous connective tissue. Moreover, the amount of smooth muscle appeared to be inversely correlated with the histologic grade of prostate tumors. In most instances, SMCs were totally absent in the moderately or poorly differentiated tumors and in metastatic tumors in the lung and the small intestine. Stromal muscular deformity was associated with concurrent changes in epithelial cells. Dysplastic epithelial cells were characterized by a reduction in abundance of secretory organelles such as reduction in size of Golgi apparatus, paucity of granular endoplasmic reticulum and secretory vesicles. The nuclei showed typical deformity characterized by deep nuclear membrane foldings. The basal lamina of dysplastic or tumor cells was present although focal structural abnormalities such as reduplication, disruption and smearing were sometimes observed. The present data indicate that derangements of epithelial cells during prostate carcinogenesis are associated with a reduction or dedifferentiation of stromal SMCs. Our results lend support to the hypothesis that transformed epithelium is incapable of maintaining normal differentiation of adjacent muscle. In turn, abnormal stromal, resulting from dedifferentiation or reduction of SMC, may lead to loss of stromal control over epithelial proliferation and differentiation. Consequently, a loss of differentiation in both epithelium and stromal SMCs may be critically involved in hormone-induced prostate carcinogenesis.