Retroviral transduction of transforming growth factor-β1 induces pleiotropic benign prostatic growth abnormalities in mouse prostate reconstitutions

Transforming growth factor-β1 (TGF-β1) plays an important role in the normal growth and differentiation of the mouse prostate with accumulations of extracellular TGF-β1 in fetal and neonatal prostate tissues particularly at epithelial-mesenchymal interfaces. We have demonstrated increased accumulation of TGF-β1 in areas of human prostates with benign prostatic hyperplasia and adenocarcinoma by immunohistochemistry. To study the role of TGF-β1 in pathologic processes, we constructed retroviruses that express the cDNA for murine TGF-β1 along with either a dominant selectable geneticin (G418) resistance (Neo) gene, BabeTGF-β1Neo, or a histochemically detectable β-galactosidase gene BabeTGF-β1Gal. The biologic activity of these retroviruses was evaluated in vitro in NIH3T3 fibroblasts and in vivo using the mouse prostate reconstitution (MPR) model. Expression of the retrovirus in MPR was confirmed by β-galactosidase staining and by reverse transcription followed by PCR for the virus-encoded RNA. Pathologic evaluation of hematoxylin and eosin-stained sections was complemented by immunohistochemical analysis of cytokeratin and neuronal markers. TGF-β1 transducing retrovirus infection did not have an effect on total growth of the MPR; however, changes in the growth and distribution of specific cell types were observed. A phenotype of benign hyperplasia that involved increased numbers of cytokeratin 14-positive cells characteristic of basal epithelial cells was observed. Immunohistochemical studies colocalized an increased accumulation of extracellular TGF-β1 with these cytokeratin 14 expressing hyperplastic lesions. An increase in stromal abnormalities was also observed and included a significant increase in the density of neuronal cells. The TGF-β1-induced hyperplastic response involving basal epithelial cells may be the result of paracrine stimulation of growth of specific cell types in the prostate and may represent a divergence of normal growth processes. Benign growth abnormalities of basal epithelial cells in the human prostate have also been reported. An increased density of neuronal cells and other stromal abnormalities in response to TGF-β1 retroviral transduction is also consistent with benign growth abnormalities in the human prostate.