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Identifying and Understanding the Functional Significance of Cancer Stem Cells in Prostate and Pancreatic Cancer Initiation and Chemoresistance

  • Author(s): Hindoyan, Antreas Agop
  • Advisor(s): Wu, Hong
  • et al.
Abstract

The functional heterogeneity of cancer phenotypes and responses to therapeutics is a huge obstacle to clinical cures and an intense area of study. A relatively new hypothesis posits the existence of a subpopulation of tumor cells, termed cancer stem cells, which are primarily responsible for tumor propagation and resistance to therapy. Identification of such cells may be important to develop targeted therapies for more effective cancer treatment. This dissertation focuses on the validation and functional study of cancer stem cells associated with human prostate and pancreatic cancers. By leveraging the fact that surgical castration leads to enrichment of stem/progenitor cells in the prostate, we idenitifed CD166 as a novel marker for prostate stem cells. We show that CD166 can further enrich and refine the established prostate stem/progenitor cell and cancer stem cell population in both murine and human systems. While genetic deletion of CD166 would not inhibit the development of the prostate gland or the formation of prostate cancer in our genetically engineered model systems, this protein may serve as an attractive marker for identifying and targeting prostate cancer stem cells. Further attempts were made at identifying stem/progenitor populations for prostate and pancreatic cancer through various discovery and targeted approaches. We found that Lgr5, a marker of stem cells in the gut and skin, is not expressed in prostate and pancreatic epithelial tissue, but only in prostatic stroma. Novel surface markers such as CD138 were found to be highly upregulated in pancreatic tumors, but specificity for cancer stem cells was lacking. Lastly, we studied the functional role of cancer stem cells in gemcitabine therapy resistance in a human pancreatic cancer model. We found that the PI3K and ubiquitin-mediated proteosomal degradation pathways can be used to stratify gemcitabine treatment response in patient tumors. Inhibition of Skp2 expression and therapeutic treatment with PI3K inhibitors proved to be effective sensitiziers to gemcitabine treatment. Importantly, cancer stem cell content and function did not mediate gemcitabine relapse. As such, our studies reveal the cancer stem cell paradigm may be more complicated and cancer context-dependent, and must be rigorously functionally proven prior to clinical adoption.

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