Abstract 4294: Differentiated colorectal cancer cells protect tumor-initiating cells from irinotecan

Abstract

Abstract Normal colon tissue stem cells drive tissue turnover by generating daughter stem cells and a rapidly proliferating pool of progenitor cells that give rise to differentiated cell types with specialized functions. This functional hierarchy is preserved in colon tumors in which a tumor-initiating cell (or cancer stem cell) compartment drives the formation of proliferating and differentiated cell types with reduced tumorigenic potential. Normal colon stem cells possess a variety of resistance mechanisms that allow them to endure a lifetime of genotoxic insults. By inheriting these traits, tumor-initiating cells (TIC) are thought to be endowed with an intrinsic resistance to chemotherapy. However, the relationship between chemo-resistance and tumor-initiating potential in colon tumors is poorly understood. We studied this relationship using a series colonosphere cultures isolated from freshly resected primary colon tumors and liver metastases. These cultures are highly enriched for TIC, based on their high clone and tumor-forming potential and expression of the stem cell marker ALDH1. The TIC-enriched cultures display resistance to the toposomerase I inhibitor irinotecan. However, drug resistance is mediated by a small subpopulation of non-tumorigenic differentiated ALDH1-negative cells expressing the drug efflux pump ABCB1. ABCB1 is localized to the brush border of cells at the colonosphere periphery and of cells forming intra-spheroid tubules. In human colorectal liver metastases ABCB1 is predominantly localized to the luminal side of differentiated tubule-forming cells. These ABCB1 drug-resistant cells are proliferation-competent but unable to initiate tumor formation. Conversely, tumor-initiating cells are ABCB1-negative and drug-sensitive, but could generate non-tumorigenic drug-resistant offspring in vitro and in tumor xenografts. Our work shows that colorectal tumor-initiating cells do not display intrinsic resistance to irinotecan, most likely because they are derived from a normal stem cell population that does not express ABC transporters. Tumor-initiating cells generate a protective shield of drug-resistant ABCB1-positive offspring. Furthermore, the preservation of tumor-initiating capacity following irinotecan exposure requires the cooperative action of drug-sensitive tumor-initiating cells and their drug-resistant differentiated offspring. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4294.