The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer

• Published in: Oncogene Vol. 24; no. 37; pp. 5775 - 5789
• Main Authors: Mishra, Lopa, Shetty, Kirti, Tang, Yi, Stuart, August, Byers, Stephen W
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 29-08-2005
• Subjects: Animals; Bone Morphogenetic Proteins - physiology; Cancer; Cell cycle; Cell Differentiation; Cell division; Cell fate; Cell signaling; Cytoplasm; Digestive system; DNA biosynthesis; Epithelial cells; Gastrointestinal Neoplasms - etiology; Gastrointestinal tract; Gastrointestinal Tract - cytology; Hepatocytes; Humans; Intercellular Signaling Peptides and Proteins - physiology; Mutation; Parietal cells; Progenitor cells; Receptors, Transforming Growth Factor beta - genetics; Signal Transduction - physiology; Spectrin - physiology; Stem cells; Stem Cells - cytology; Transforming Growth Factor beta - physiology; Transforming growth factor-b; Wnt protein; Wnt Proteins
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208924

The past three decades have seen an unremitting quest to identify and understand gastrointestinal stem cells, their plasticity in differentiating across cell types, as well as their role in normal, regenerative, and cancer cells. A fascinating hallmark of stem cells is their ability to undergo assymetric cell division, which entails replication of the DNA followed by division of the nucleus and partitioning of the cytoplasm to yield two different daughter cells: a stem cell as well as a committed progenitor cell, the latter proliferating into differentiated progeny. We are only just beginning to understand how normally quiescent, tissue-specific stem cells interpret a vast array of signals to develop into the gastrointestinal system. These signaling pathways include the transforming growth factor-beta (TGF-beta) superfamily, Wnt, FGFs, Hedgehog, Hox proteins that originate from surrounding mesodermal/stromal tissue as well as endodermal/epithelial tissue. TGF-beta and wnt proteins are key morphogens that ultimately influence cell division and cell fate, so that gut endodermal stem cells enter the cell cycle, and undergo cell division that ultimately leads to differentiated cells such as functional hepatocytes, gastric parietal cells, or gut epithelial cells. Disruptions and errors in this process usually lead to tissue-specific gastrointestinal cancers such as hepatocellular cancers, gastric adenocarcinomas, and colonic adenocarcinomas. An increasingly complex and coherent view of stem/progenitor cell signaling networks, which coordinate cell growth, proliferation, stress management, and survival, is helping to define the fragile areas where malignancies are likely to develop and shows promise for the development of better cancer therapies.