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      CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism

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          Abstract

          CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44 high cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing.

          Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development.

          Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development.

          Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients.

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          Most cited references39

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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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              Hypoxia-inducible factors, stem cells, and cancer.

              Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation. The hypoxia-inducible factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2018
                29 November 2018
                : 8
                : 22
                : 6248-6262
                Affiliations
                [1 ]School of Medicine, Nankai University, Tianjin 300071, China;
                [2 ]The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;
                [3 ]Department of Surgery, Chinese PLA General Hospital, Beijing 100071, China;
                [4 ]Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China;
                [5 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA;
                [6 ]Department of Reproductive Medicine, School of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, California 39216, USA;
                [7 ]Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin 300071, China;
                [8 ]Project Collaborative Innovation Center for Biotherapy of Ministry of Education 2011, Tianjin 300071, China.
                Author notes
                ✉ Corresponding authors: Dr. Na Luo, School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China. E-mail: luon11@ 123456nankai.edu.cn Tel. (086) 022-23509482 or Dr. Dwayne G. Stupack, Department of Reproductive Medicine, School of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, California 39216, USA. E-mail: dstupack@ 123456ucsd.edu

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov08p6248
                10.7150/thno.28721
                6299690
                30613295
                8bfc5980-bc37-44f7-930b-8b9e5b750dea
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 24 July 2018
                : 20 October 2018
                Categories
                Research Paper

                Molecular medicine
                pfkfb4,cd44icd,stemness,glucose metabolism
                Molecular medicine
                pfkfb4, cd44icd, stemness, glucose metabolism

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