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Gastrointestinal Cancer Cancer Stem Cells and Cancer Stem Cell Inhibitors in Gastrointestinal Cancers Joleen M Hubbard and Axel Grothey Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, US Abstract Cancer stem cells (CSCs) are a subpopulation of phenotypically distinct cancer cells that may play an important role in tumor pathogenesis. The gastrointestinal (GI) system provides a good example for investigation of the role of CSCs in tumor proliferation; GI CSCs are suitable for study due to their abundance, proliferative potential, and consistent structural arrangement that is maintained under tightly controlled signaling pathways. GI stem cells have a long lifespan and this, combined with their rapid turnover, may predispose them to forming CSCs. Alternative possible sources of GI CSCs include differentiated intestinal cells, bone marrow, and cancer cells. Therapies that specifically target CSCs present an exciting opportunity to treat patients with cancer. Enhanced understanding of CSC markers, such as CD133, CD44, and epithelial cell adhesion molecule (EpCAM), may facilitate development of therapies that target them. Among the stemness pathways that have been targeted are Wnt/β-catenin, STAT, Notch, and Nanog. Keywords Cancer therapy, cancer stem cells, CD133, CD44, epithelial cell adhesion molecule (EpCAM), focal adhesion kinase (FAK), gastrointestinal tumor, Hedgehog, Nanog, Notch, STAT3, Wnt/β-catenin Disclosure: Joleen M Hubbard receives research support from Boston Biomedical. Axel Grothey has nothing to disclose in relation to this article. Acknowledgments: Medical writing assistance was provided by Catherine Amey at Touch Medical Media, funded by Boston Biomedical. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: January 31, 2016 Accepted: March 24, 2016 Citation: Oncology & Hematology Review, 2016;12(1):41–6 Correspondence: Axel Grothey, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN55905, US. E: grothey.axel@mayo.edu Support: The publication of this article was supported by Boston Biomedical, who were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s/authors’ discretion. The publication of this article was supported by Boston Biomedical. The views and opinions expressed are those of the author and do not necessarily reflect those of Boston Biomedical. As is the case with most solid tumors, gastrointestinal (GI) tumors are treated in a variety of modalities, which are used singularly or in combination, including surgery, targeted therapies, radiation, and chemotherapy. Survival rates by stage in colon and rectal cancer are given in Table 1. Cancer stem cells (CSCs) are believed to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. 1 They are more resistant to radiation and chemotherapeutic agents than other cancer cells. 2 The presence of CSCs following cancer therapy may explain the initiation of metastasis and later recurrence of cancers, which can occur even when there is a good initial response to radiation or chemotherapy. 3 The first experiments suggesting the presence of CSCs in GI cancers were conducted in 2007. 4,5 The investigators used flow cytometry to isolate CSCs using CD133 as a marker and then demonstrated the ability of these CD133-positive cells to form xenografts in non-obese diabetic/severe combined immunodeficiency mice. Origin of cancer stem cells of the gastrointestinal system A schematic representation of an individual colon crypt is depicted in Figure 1. Stem cells lie at the bottom of the crypt and through asymmetric TOU CH MED ICA L MEDIA division are responsible for generating all epithelial cell types along the crypt–villus axis. GI stem cells may be intrinsically prone to forming CSCs because of their long lifespan combined with rapid turnover and it is widely believed that CSCs are derived from normal stem cells. 6,7 Other possible sources for GI CSCs include dedifferentiated intestinal cells, possibly via nuclear factor-kappa-B (NF-κB) modulation of Wnt signaling 7,8 and bone marrow-derived progenitor cells progressing through metaplasia and dysplasia to cancer. 9 Cancer stem cell biomarkers CD133 The CD133 molecule, which is also known as prominin-1, is a pentaspan- transmembrane glycoprotein that has been shown to be located mainly in membrane protrusions. 10 It was first identified as a surface protein marker of a subset of hematopoietic stem and progenitor cells as early as 1997, 11 but its biologic function has yet to be elucidated. In 2007, CD133-positive cells separated from colorectal tumor cells were demonstrated to possess self-renewal properties and high tumorigenic potential. 4,5 Systematic reviews have indicated that CD133 is a prognostic factor in colorectal cancer (CRC) 12 and gastric cancer. 13 Carbon nanotube-conjugated CD133- 41