Exploration of the roles of cancer stem cells and survivin in the pathogenesis and progression of prostate cancer.

摘要

Our study of prostate cancer is centered on a conditional mouse model based on the Cre/lox recombination technology to inactivate the tumor suppressor gene Pten, whose function is frequently lost in human prostate cancer. This model proved to be a powerful tool in our investigation on the presence and characteristics of putative cancer stem cell population and its interaction with the tumor microenvironment, as well as on the role of survivin, a cancer-specific anti-apoptotic protein in prostate cancer progression. The combination of conditional Pten deletion and luciferase-expressing mouse model allowed us to non-invasively follow the tumor growth through bioluminescence imaging, permitting the collection of tumors at either the androgen-dependent (AD) primary growth phase or the recurrent phase when castration-resistant prostate cancer (CRPC) is formed after initial regression from androgen-deprivation therapy. Utilizing cell surface markers shown to enrich normal prostate epithelial stem cells (Lin -Sca-1+CD49f+), we were able to further restrict the parameters of selection to enrich putative cancer stem cells (CSCs) from both androgen-dependent and castrate-resistant prostate tumors. These populations of cells exhibited the ability to self-renew and differentiate to multiple cell types in vitro and in vivo, in concordance to known characteristics of normal prostate tissue stem cells. Along with the detection of expression of certain expected stem cell-like markers, evidence was obtained that the CSCs from the model also retain a high level of survivin expression like the cancer cells. We demonstrated the contribution of the cancer-associated fibroblasts (CAFs) of the tumor microenvironment in enhancing the putative cancer stem cells' self-renewal and differentiation potentials. We also found that in vivo growth and differentiation of CSCs from CRPC cancer were better supported by CAFs derived from CRPC cancer compared to those from AD cancer. These results suggested that signaling proteins that are secreted by stage-specific CAFs might support and potentiate the stemness and tumorigenic properties of the corresponding CSCs. This novel finding deserves to be further investigated, particularly since stromal fibroblasts remain as an understudied cellular compartment of the prostate cancer.;Our examination of the role of survivin in prostate cancer was achieved through the generation of a prostate epithelium-specific double knock-out mouse model lacking Pten and Survivin. With Survivin deletion alone, normal prostate organogenesis and growth as well as fertility of mice were not found to be impaired. Survivin homozygous deletion in conditional Pten knockout mice, however, resulted in the delay of prostate cancer progression in the sense that even up to 52 weeks of observation, no adenocarcinoma but only premalignant lesions, namely prostatic intraepithelial neoplasms (PINs) were detected. This was in contrast to adenocarcinoma formation by 36 weeks in many animals of the control tumor group or the heterozygous Survivin deletion group. Prostate tumors lacking survivin appeared to display enhanced apoptosis, decreased proliferation index, increased senescence, and a high degree of hypertrophic cells, some of these characteristics being atypical of the usual PIN lesions. Our findings from this direct in vivo genetic study demonstrate the importance of survivin in prostate cancer progression potentially via its anti-apoptotic and cell division regulatory roles, as supported by previous studies, as well as open up possibilities of survivin's association with cellular senescence and cancer stem cells that remains to be explored in the future.