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      Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

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          Abstract

          Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.

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          Most cited references173

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          On the origin of cancer cells.

          O WARBURG (1956)
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            HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

            HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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              Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.

              Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 May 2015
                May 2015
                : 16
                : 5
                : 11055-11086
                Affiliations
                [1 ]Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; E-Mails: justusc11@ 123456students.ecu.edu (C.R.J.); sanderline09@ 123456students.ecu.edu (E.J.S.)
                [2 ]Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
                [3 ]Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
                [4 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mail: yangl@ 123456ecu.edu ; Tel.: +1-252-744-3419; Fax: +1-252-744-3418.
                Article
                ijms-16-11055
                10.3390/ijms160511055
                4463690
                25988385
                7c52c239-3e11-4e66-864d-445a7ca31026
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 March 2015
                : 08 May 2015
                Categories
                Review

                Molecular biology
                tumor microenvironment,cancer cell metabolism,hypoxia,acidosis,cancer therapy
                Molecular biology
                tumor microenvironment, cancer cell metabolism, hypoxia, acidosis, cancer therapy

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