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      The Role of CD44 in the Pathogenesis, Diagnosis, and Therapy of Gastric Cancer

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          Abstract

          CD44 is a transmembrane glycoprotein and surface receptor for hyaluronan that is involved in the response of cells to their microenvironment. CD44 splice variants play roles in carcinogenesis, differentiation, and lymph node metastasis and are predictive of the prognosis for various carcinomas, including gastric cancer. Current data suggest that gastric tissue stem cells and gastric cancer stem cells both express the splice variant, CD44v9. Overall, the data regarding the alterations that occur in CD44 and its splice variants in response to acute and chronic infection with Helicobacter pylori are scant and poorly elucidated in terms of possible changes in expression that occur in gastric cancer precursor lesions, such as chronic atrophic gastritis, pyloric metaplasia and intestinal metaplasia. In this study, we discuss the available data and suggest which new data would likely be useful in clinical practice. We also discuss the potential for CD44-targeted therapeutic strategies in gastric cancer. CD44 and its splice variants are positively associated with the initiation and progression of gastric cancer and may also play important roles in diagnosis, therapy and prognosis. CD44 research has been active but fragmented, and it may offer new therapeutic approaches to gastric cancer.

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          Most cited references61

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          Identification of pancreatic cancer stem cells.

          Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.
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            CD44: from adhesion molecules to signalling regulators.

            Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes--not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
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              The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation.

              If cancer arises and is maintained by a small population of cancer-initiating cells within every tumor, understanding how these cells react to cancer treatment will facilitate improvement of cancer treatment in the future. Cancer-initiating cells can now be prospectively isolated from breast cancer cell lines and tumor samples and propagated as mammospheres in vitro under serum-free conditions. CD24(-/low)/CD44+ cancer-initiating cells were isolated from MCF-7 and MDA-MB-231 breast cancer monolayer cultures and propagated as mammospheres. Their response to radiation was investigated by assaying clonogenic survival and by measuring reactive oxygen species (ROS) levels, phosphorylation of the replacement histone H2AX, CD44 levels, CD24 levels, and Notch-1 activation using flow cytometry. All statistical tests were two-sided. Cancer-initiating cells were more resistant to radiation than cells grown as monolayer cultures (MCF-7: monolayer cultures, mean surviving fraction at 2 Gy [SF(2Gy)] = 0.2, versus mammospheres, mean SF(2Gy) = 0.46, difference = 0.26, 95% confidence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF(2Gy) = 0.5, versus mammospheres, mean SF(2Gy) = 0.69, difference = 0.19, 95% CI = -0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These findings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy.
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                Author and article information

                Journal
                Gut Liver
                GNL
                Gut and Liver
                The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Society of Pancreatobiliary Diseases
                1976-2283
                2005-1212
                December 2011
                21 November 2011
                : 5
                : 4
                : 397-405
                Affiliations
                [* ]Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA.
                []Department of Medical Oncology, University of Texas Health Science Center in Houston, Houston, TX, USA.
                Author notes
                Correspondence to: Putao Cen. Department of Medical Oncology, University of Texas Health Science Center in Houston, 6410 Fannin, Suite 722, Houston, TX 77030, USA. Tel: +1-832-325-7702, Fax: +1-713-512-7140, putao.cen@ 123456uth.tmc.edu

                Current addresses: Byung Ik Jang: Yeungnam University College of Medicine, Daegu, South Korea; Yuan Li: Department of Gastroenterology, The Third Hospital of Peking University, Beijing, China.

                Article
                10.5009/gnl.2011.5.4.397
                3240781
                22195236
                3fca573f-4081-41c2-bc8c-5af24f36486e
                Copyright © 2011 The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, the Korean Association for the Study of Intestinal Diseases, Korean Association for the Study of the Liver and Korean Society of Pancreatobiliary Diseases

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 August 2011
                : 18 September 2011
                : 30 September 2011
                Categories
                Review

                Gastroenterology & Hepatology
                cd44,chemotherapy,gastric cancer,biomarkers,helicobacter pylori
                Gastroenterology & Hepatology
                cd44, chemotherapy, gastric cancer, biomarkers, helicobacter pylori

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