Abstract 3474: Ovarian cancer tumor initiating cells persist after paclitaxel and carboplatinum treatment <i>in vivo</i>
Authors: Kashmira S. Kulkarni-Datar, Sandra Orsulic, Rosemary Foster, Bo R. Rueda
Journal: Cancer Research (2012)

Abstract Recurrent ovarian cancer is believed to be due, in part, to the presence of cancer stem cells that escape the cytotoxic effects of standard chemotherapeutics and lead to relapse. Results from our laboratory and others suggest that human ovarian tumors contain rare populations of cells that are capable of initiating new tumor formation in vivo. Our objective was to analyze the effect of platinum based chemotherapy on these tumor initiating cell populations in a genetically defined mouse model of ovarian cancer. Our studies focused on a mouse ovarian cancer cell line (T2) with defined mutations in TP53, c-MYC and AKT that readily forms aggressive tumors following subcutaneous injection into non-diabetic/severe combined immunodeficient (NOD-SCID) mice. We used flow cytometry to evaluate the T2 induced tumors for expression of stem cell antigen-1 (Sca1), a known marker of murine stem cells, and CD133, an antigen which has been shown to enrich for tumor initiating cells derived from human ovarian tumors. FACS based isolation of Sca1+ and CD133+ T2 tumor-derived cells followed by injection into NOD/SCID mice assessed their relative tumor initiating capacity. Mice bearing T2-derived tumors were treated with either vehicle or paclitaxel and carboplatinum (T/C) to evaluate the effect of T/C on the Sca1+ and CD133+ tumor cell population. We consistently observed that Sca1+ and the CD133 + cells comprised 3-7% and 0.1-0.4 % of the total cell population in T2-derived tumors, respectively. Following FACS based isolation and injection into NOD/SCID mice, Sca1+ and CD133 + cells were able to form tumors much more rapidly and at lower cell numbers than their Sca1- and CD133- counterparts, suggesting that the Sca1+ and CD133+ populations are enriched in tumor initiating cells. Although, administration of T/C resulted in a significant decrease in tumor volume relative to vehicle treated tumors, we detected no significant difference in the levels of Sca1+ and CD133+ cells in tumors treated with T/C compared to vehicle controls. Furthermore, cell cycle analysis of the Sca1+ and CD133+ populations determined that these cells were enriched in the quiescent G0/G1 phase of the cell cycle. Our results provide evidence that the T2-derived Sca1+ and CD133+ tumor initiating cells are relatively quiescent, persist following standard platinum based chemotherapy and likely contribute to disease recurrence in ovarian cancer. While the specific role of these cells in post-chemotherapy tumor recurrence needs to be evaluated, our findings suggest that future studies should be directed towards targeting these cell populations which likely contribute to the resurgence of the ovarian cancer and thereby reduce the overall survival rate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3474. doi:1538-7445.AM2012-3474