Emerging data suggests that many human cancers including breast, brain, lung, colon, pancreatic and head and neck cancer are maintained by a subpopulation of self-renewing cells characterized as cancer stem cells that contribute to tumor growth and metastasis. Cancer stem cells have become an important target for new treatment paradigms as they may hold the key to solving treatment resistance and tumor recurrence. Paramount to the development of new therapies that preferentially target cancer stem cells is having predictable and clinically relevant models that accurately represent stem cell behavior and the tumor microenvironment. Examination of cancer stem cells both as a homogenous population and as a heterogeneous population interacting with other tumor cells is required for the development of effective treatments for stem cell driven tumor types. To address this we developed in vitro and in vivo cancer stem cell models of breast and pancreatic cancers to provide a comprehensive approach for preclinical research in these areas. Using the MDA-MB-231 and BxPC3 human cancer cell lines we are able to show the differential responses of cancer stem cells isolated from the parent lines to the standard chemotherapeutic agents docetaxel and gemcitabine with and without the small molecule inhibitor Reparixin specifically designed to inhibit cancer stem cells. Treatment response differences between homogeneous cancer stem cell versus heterogeneous populations were revealed in their growth, differentiation and invasiveness as determined by 2D and 3D tumorsphere assays. This response is also recapitulated in vivo using IVIS imaging to compare orthotopic tumor growth of isolated cancer stem cells and the parent lines treated with standard chemotherapeutics agents with or without combination Reparixin treatment. These results emphasize the need to employ a multifaceted approach to specifically target cancer stem cells in preclinical drug development to identify successful therapies for use as part of an overall treatment regimen in recurring or treatment resistant cancers.
Citation Format: Maria L. Mancini. Modeling the differential responses of cancer stem cells (CSCs) as heterogeneous versus homogenous populations in human cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2043. doi:10.1158/1538-7445.AM2014-2043