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Aldehyde Dehydrogenase–Expressing Colon Stem Cells Contribute to Tumorigenesis in the Transition from Colitis to Cancer

¹ McKnight Brain Institute and ² Department of Surgery, University of Florida, Gainesville, Florida; and Departments of ³ Surgery and ⁴ Pathology, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Emina H. Huang, University of Florida, Department of Surgery, P.O. Box 100109, 1600 Southwest Archer Road, Gainesville, FL 32609. Phone: 352-265-0761; Fax: 352-265-1060; E-mail: Emina.Huang{at}surgery.ufl.edu.

Key Words: Colitis • Colon Cancer • Aldehyde dehydrogenase • Colon sphere • Xenograft • tumor microenvironment

Patients with chronic ulcerative colitis are at increased risk of developing colorectal cancer. Although current hypotheses suggest that sporadic colorectal cancer is due to inability to control cancer stem cells, the cancer stem cell hypothesis has not yet been validated in colitis-associated cancer. Furthermore, the identification of the colitis to cancer transition is challenging. We recently showed that epithelial cells with the increased expression of aldehyde dehydrogenase in sporadic colon cancer correlate closely with tumor-initiating ability. We sought to determine whether ALDH can be used as a marker to isolate tumor-initiating populations from patients with chronic ulcerative colitis. We used fluorescence-activated cell sorting to identify precursor colon cancer stem cells from colitis patients and report both their transition to cancerous stem cells in xenografting studies as well as their ability to generate spheres in vitro. Similar to sporadic colon cancer, these colitis-derived tumors were capable of propagation as sphere cultures. However, unlike the origins of sporadic colon cancer, the primary colitic tissues did not express any histologic evidence of dysplasia. To elucidate a potential mechanism for our findings, we compared the stroma of these different environments and determined that at least one paracrine factor is up-regulated in the inflammatory and malignant stroma compared with resting, normal stroma. These data link colitis and cancer identifying potential tumor-initiating cells from colitic patients, suggesting that sphere and/or xenograft formation will be useful to survey colitic patients at risk of developing cancer. [Cancer Res 2009;69(20):8208–15]