Benign prostatic hyperplasia (BPH) is a clinically significant disease characterized by excessive stromal and epithelial proliferation. This has been proposed to result from reactivation of embryonic mesenchymal- epithelial interactions. androgens are probably not the primary growth regulator because their addition or removal does not uniformly affect adult prostate growth suggesting that other factors are directly responsible for prostate cellular proliferation. Peptide growth factors may be those embryonic inducers responsible for aberrant prostate cellular proliferation leading to BPH. Thus, understanding the normal role of peptide growth factors and androgens in prostate development may provide mechanistic insights concerning the mesenchymal-epithelial interactions that are likely reiterated in BPH. Our working hypothesis is that peptide growth factors are direct mediators of androgen action on mesenchymal-epithelial cellular interactions responsible for prostate development. The adjacent mesoderm-derived seminal vesicle development will be contrasted that of the endoderm-derived prostate. The mouse model will be used to test the hypothesis through these specific aims.
Aim 1 - To determine the spatial and temporal expressions of TGFalpha and TGFBeta1-TGFBeta3 by mesenchymal and epithelial cells during the critical developmental stages for seminal vesicle and prostate with and without androgens and with transgenic mice that misexpress TGFalpha, TGFBeta, or both TGFalpha and TGFBeta. In addition to morphometric analysis, colocalization of TGFalpha and TGFBeta1-TGFBeta3 protein and mRNA expression of prostate with and without androgens and with transgenic animals will be performed during the three critical developmental stages which are 1) commitment to male structures stages (gestational day 15- 17), 2) ductal elongation stage (gestational day 18-postnatal day 3) and 3) branching morphogenesis androgen-independent (up to postnatal day 12) and androgen-dependent (after postnatal day 14).
Aim 2 - To determine if TGFalpha and TGFBeta3 may directly mediate the androgen-dependent development of the prostate and seminal vesicles in the absence of androgens. Two approaches will be used: 1) Separate the prostate into primary pure cultures of mesenchymal and epithelial cells and examine pure cell and mixed cell cultures for elaboration of TGFalpha and TGFBeta with and without androgens, 2) Utilize organ cultures of developing prostate and seminal vesicles to test whether addition of pure exogenous TGFalpha or TGFBeta may directly mimic androgen effects during critical developmental stages.
Aim 3 To investigate whether c-myc and n-myc are the molecular mechanisms by which TGFalpha and TGFBeta act on mesenchymal and epithelial cells during development of the prostate and seminal vesicle. This will be approached by conducting in situ hybridization of myc and correlating this with TGFalpha and TGFbeta mRNA and protein expression during the critical stages of development. It is the goal of this proposal to use the mouse model, both wild type and transgenics, to define the fundamental role of androgens and peptide growth factors in the development of the prostate, and thus, to provide important new information about mesenchymal-epithelial interactions that may be the basis for BPH and perhaps, prostatic neoplasia as well.
| Steiner, M S (1995) Transforming growth factor-beta and prostate cancer. World J Urol 13:329-36 |
| Barnes, J; Anthony, C T; Wall, N et al. (1995) Bone morphogenetic protein-6 expression in normal and malignant prostate. World J Urol 13:337-43 |
