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Targeting cancer cell metabolism in pancreatic adenocarcinoma

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      Abstract

      Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.

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      Most cited references 176

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      The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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        On the origin of cancer cells.

         O WARBURG (1956)
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          Cancer statistics, 2010.

          Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010. Overall cancer incidence rates decreased in the most recent time period in both men (1.3% per year from 2000 to 2006) and women (0.5% per year from 1998 to 2006), largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and 2 major cancer sites in women (breast and colorectum). This decrease occurred in all racial/ethnic groups in both men and women with the exception of American Indian/Alaska Native women, in whom rates were stable. Among men, death rates for all races combined decreased by 21.0% between 1990 and 2006, with decreases in lung, prostate, and colorectal cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2006 decreased by 12.3%, with decreases in breast and colorectal cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment. Copyright 2010 American Cancer Society, Inc.
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            Author and article information

            Affiliations
            1 INSERM U728, Beaujon University Hospital (AP-HP – PRES Paris 7 Diderot), Clichy La Garenne, France
            2 Department of Medical Oncology, Henri Mondor University Hospital, Créteil, France
            3 AAREC Filia Research, Translational Department, Boulogne-Billancourt, France
            4 Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
            5 New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
            Author notes
            Correspondence to: Eric Raymond, eric.raymond@ 123456chuv.ch
            Journal
            Oncotarget
            Oncotarget
            ImpactJ
            Oncotarget
            Impact Journals LLC
            1949-2553
            10 July 2015
            10 June 2015
            : 6
            : 19
            : 16832-16847
            26164081 4627277
            Copyright: © 2015 Cohen et al.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Categories
            Review

            Oncology & Radiotherapy

            hypoxia, glycolysis, glutamine, metformin, warburg effect

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