Mechanisms of Disease: from stem cells to colorectal cancer

Over the past decade, there have been remarkable advances in our understanding of stem cell biology. Although the intestinal stem cell remains difficult to isolate, it is known to be important for the development of intestinal neoplasms. In this Review, the authors discuss the basic mechanisms behind stem cell regulation in the gut and their role in the natural history of tumor progression in the setting of colorectal cancer. Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of β-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass β-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression. Key Points Stem cells are the origin of all intestinal epithelial cells Stem cells are regulated by many intrinsic and extrinsic factors, including the WNT/β-catenin signaling pathway Stem cells have various means of protecting themselves from acquiring DNA mutations but under certain hostile environments produce dysplasia and cancer The cancer stem cell is the key target for many novel therapies