Abstract PR07: Targeting CD24+ ovarian cancer stem-like cells in a transgenic murine model of ovarian cancer restrics metastasis

Abstract

Abstract The cancer stem cell (CSC) hypothesis proposes that in a heterogeneous tumor only a rare population of stem-like cells has the ability to initiate new tumors. These rare CSC are believed to be the source of resistance to therapy, recurrence, and metastasis. A better understanding of ovarian CSCs could lead to novel therapeutic approaches to specifically target CSCs. Unfortunately, the study of human CSCs is hampered by heterogeneity of patient's tumor samples, long requirements for tumor growth in vivo, and the need for tumor growth in immune-deficient mice. We have therefore characterized CSCs in a transgenic murine model of ovarian cancer. This mouse model with conditional deletion of Apc, Pten and p53 tumor suppressor genes develop advanced ovarian cancer similar to that seen patients. Study of CSC in a murine tumor model will provide a homogeneous, rapid means to systematically study CSCs in a native microenvironment. Using flow cytometry to characterize a cell line derived from this tumor model we identified the expression of several potential CSC surface markers including CD24, CD44, CD90, CD117, CD133 and ALDH. In vitro analysis demonstrates that cells defined by the expression of CD24 and CD133, but not the other CSC markers, have an increased tumor sphere forming capacity; a hallmark of CSC. We next assessed in vivo tumor initiation and growth rates. No preferential tumor initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. CD133+ cells demonstrated a trend for increased tumor initiation. CD24+ cells vs CD24- cells, had significantly greater tumor initiation and tumor growth capacity. As few as 200 CD24+ could initiate tumors. Consistent with a stem cell phenotype we have found that CD24+ cells, compared to CD24- cells, preferentially express stem cell markers Nanog and c-myc. CD24+ cells vs. CD24- cells also demonstrated preferential phosphorylation of STAT3. Suggesting an important role for STAT3 in CD24+ CSC, CD24+ cells were preferentially sensitive to either JAK2 inhibition (which prevents pSTAT3) or direct pSTAT3 inhibition. Finally, we found in vivo therapy with the JAK2 inhibitor TG101209 dramatically reduced tumor metastases, and combined with chemotherapy, prolonged overall survival. These findings indicate that CD24+ cells have a CSC phenotype and play a role in tumor migration and invasion in other organs. Moreover, these findings suggest that combination of chemotherapy and CSCs targeted therapies can potentially improve survival by inhibiting metastasis. This abstract is also presented as Poster B36. Citation Format: Daniela Burgos-Ojeda, Rong Wu, Kathleen Cho, Ronald Buckanovich. Targeting CD24+ ovarian cancer stem-like cells in a transgenic murine model of ovarian cancer restrics metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr PR07.