Prostate cancer is the most common malignant disease and second in causes of cancer death among men in Western Europe and North America. Despite improved surgical and irradiation techniques tumor relapse after therapy is not uncommon. One plausible explanation for the tumor relapse is the existence of Cancer Stem cells (CSC) or tumor initiating cells in the tumor population. CSCs, like normal stem cells have the potential to self renew and differentiate and are resistant to the currently used cytotoxic drugs. Therefore targeting various transcription factors responsible for the maintenance of self renewal ability in the stem cells is an attractive approach for new drug development. We have identified a small population of tumor initiating cells from DU145, a prostate cancer cell line. The methodology used is the collagen attachment assay in which the cells are plated on Collagen I for 5\#8217;. Rapidly adhering cells have the phenotype of CD44hi/\#945;2\#946;1hi and have higher migration and higher invasion ability than non-attached cells. When injected in nude mice,1000 CD44hi/\#945;2\#946;1hi cells can form tumors as compared to CD44low/ \#945;2\#946;1low cells. Further, by using the collagen attachment assay, we demonstrated that these cells are resistant to some commonly used chemotherapeutic drugsto treat prostate cancer, that include cisplatin and taxotere. Preliminary data also indicates that CD44hi/ \#945;2\#946;1hi cells also have increased Bmi-1 levels. Bmi-1 (B-cell specific Moloney murine leukemia virus insertion site) is a member of the polycomb family of transcription factors responsible for the maintenance of self renewal in stem cells. We found that a novel inhibitor, PTC-210 (developed by PTC therapeutics) inhibits Bmi-1 protein expression in DU145 cells and also decreases the number of collagen attached cells. Targeting expression of transcription factors necessary for stem cell maintenance, may provide new targets for inhibition of prostate cancer stem cells. These results encourage us to use this methodology to isolate human cancer stem cells from fresh prostate cancer specimens and to use the collagen assay to find novel inhibitors of prostate CSCs.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1073.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO