| While previous studies using genetically engineered mice (GEM) have indicated potential effects of several aberrations observed in human prostate cancer, the most common early event, loss of pRb function, has not been fully assessed. Using GEMS, we show that complete inactivation of the pRb family proteins (Rb/p107/p130) is sufficient to produce prostatic intraepithelial neoplasia (PIN) lesions that consist of highly proliferative and apoptosic epithelial cells. In order to gain a full understanding of the selective pressures produced by complete pRb family inactivation and their impact on tumor progression, we studied the resulting pressures that led to altered Pten function, the most frequent change in advanced prostate tumors. Consequently it was found that Pten hemizygosity reduced apoptosis by 50%, accelerating tumor onset, and the selective progression to complete Pten loss of function yields distinct tumor properties, thereby uncovering at least one mechanism by which the observed heterogeneity of human prostate cancers can develop. In addition to Pten, we studied the effect alteration of p53 had on prostate tumorigenesis. No changes in epithelium proliferation or apoptosis were seen with p53 deficiency, hinting that if p53 does have a tumor suppressive function in the prostate, it is not in the epithelial compartment.; So far, analyses of genetic lesions in human cancers have focused on the accumulation of multiple events within the epithelial cancer cell. Yet, several studies have demonstrated clear micro-environment influences on developing tumors implicating non-tumor cell responses as a critical component of tumorigenesis. Moreover, analyses of some carcinomas have indicated the presence of tumor suppressor gene mutations within the stroma. Such observations suggest the possibility that multiple cell types selectively co-evolve through micro-environment changes during tumor progression. In our prostate cancer model, we show that selective inactivation of p53 within the mesenchyme occurs in response to epithelial tumorigenesis and indeed contributes to progression of the cancer. All of these studies have generated a preclinical animal model which both genetically and biologically models the course of human prostate cancer. |
