The identification of human Colon Stem Cells and Colon Cancer Stem Cells
The inner layer of the intestinal tube, the intestinal epithelium, is in a constant process of renewal. Hundreds of millions of terminally differentiated intestinal cells are replaced by new cells every day during the life of an adult organism. This tremendous regenerative power is ultimately sustained by a small population of intestinal stem cells. It is believed that alterations in the biology of human colon stem cells (CoSCs) account for the pathophysiology of various large-bowel disorders, including colorectal cancer (CRC). Yet, the identification of human CoSCs had remained elusive. In these manuscripts we describe for the first time the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of the receptor EPHB2 allows the purification of different cell types from human normal colon mucosa biopsies. Colon epithelial cells with highest EPHB2 levels exhibit the longest telomeres and express markers characteristic of intestinal stem cells. Using culturing conditions that recreate the intestinal stem cell niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population. This discovery has profound implications for the field of regenerative medicine as it opens the possibility of using CoSCs as a therapeutic tool. In parallel, my group applied the same method of stem cell purification to human CRCs. These experiments led us to demonstrate that most human CRCs are constituted by cell populations with phenotypes similar to either CoSCs or intestinal differentiated cells organized into well-defined compartments. CoSC-like cells purified from primary CRCs generate tumors in immunodeficient mice with high efficiency and display both self-renewal and differentiation capacity. Remarkably, the expression of the CoSC gene program predicts disease relapse after intended curative therapy in CRC patients. Overall, these results imply that CRC shares a common hierarchy with the intestinal mucosa and that the acquisition of an intestinal stem cell gene program is a central process in the development of metastatic and recurrent CRC.