Abstract
Abstract Survivin, a member of the inhibitor of apoptosis family, is highly expressed in various cancers including prostate cancer. In the conditional Pten deletion mouse model, we showed a correlation between increased levels of survivin with the growth of the prostate tumor (Cancer Res. 66: 4285–90, 2006), and more recently described that high levels of survivin might also be associated with the cancer stem cells of this model (Cancer Res. 70: 7294–303, 2010). Here we report that homozygous deletion of the Survivin gene specifically in mouse prostate epithelium suppresses prostate tumorigenesis without affecting postnatal prostate development and growth. Mouse prostates with double conditional knockout of Survivin and Pten that were collected at 8.5 weeks of age appear to exhibit normal gross morphology, histology and cytology, in contrast to the detection of hyperplasia, dysplasia and prostatic intraepithelial neoplasia (PIN) lesions in mouse prostates with bi-allelic Pten inactivation. While the mice with Pten deletion alone uniformly develop numerous invasive adenocarcinoma lesions in all of the prostate lobes by 17–20 weeks of age, our analysis to date of a single double knockout animal at 17 weeks reveals mostly PIN lesions in the anterior and the ventral prostate lobes with the dorsolateral lobe exhibiting detectable foci of adenocarcinoma. As the animals age, increased number of animals at this age and other advancing age groups remain to be evaluated for the significance of this observation and the possibility that the isolated lesions detected in the double knockout might be related to incomplete recombination in Survivin alleles in the target cells remains to be tested. In general, we observe a dramatic reduction in the proliferation index, as assessed by Ki67 staining, in the prostate tissue with the double deletion of Pten and Survivin compared to Pten deletion alone. We propose that survival of the proliferating abnormal cells is compromised by the intracellular loss of survivin. We used adenovirus-Cre to knock-out Survivin in stem cell fractions isolated from the prostate of the normal mouse with floxed Survivin alleles. It is very interesting to find that loss of survivin significantly lowers in vitro proliferation, spheroid-forming capability and survival potential of these cells, implicating a strong cytoprotective role of survivin for the prostate stem cells. Thus, it would now be important to extend the study for evaluation of the function of survivin in the prostate cancer stem cells, a compartment that may indeed be critical to the process of prostate tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-51. doi:10.1158/1538-7445.AM2011-LB-51
Published Version
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