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The Warburg hypothesis (), sometimes known as the Warburg theory of cancer, postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. The term ''Warburg effect'' describes the observation that cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen. Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924.〔O. Warburg, K. Posener, E. Negelein: Ueber den Stoffwechsel der Tumoren; ''Biochemische Zeitschrift'', Vol. 152, pp. 319-344, 1924. . Reprinted in English in the book ''On metabolism of tumors'' by O. Warburg, Publisher: Constable, London, 1930.〕 He hypothesized that cancer, malignant growth, and tumor growth are caused by the fact that tumor cells mainly generate energy (as e.g. adenosine triphosphate / ATP) by non-oxidative breakdown of glucose (a process called glycolysis). This is in contrast to "healthy" cells which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end-product of glycolysis, and is oxidized within the mitochondria. Hence, according to Warburg, the driver of cancer cells should be interpreted as stemming from a lowering of mitochondrial respiration. Warburg reported a fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect. Cancer is caused by mutations and altered gene expression, in a process called malignant transformation, resulting in an uncontrolled growth of cells. The metabolic differences observed by Warburg adapts cancer cells to the hypoxic (oxygen-deficient) conditions inside solid tumors, and results largely from the same mutations in oncogenes and tumor suppressor genes that cause the other abnormal characteristics of cancer cells. Therefore, the metabolic change observed by Warburg is not so much the cause of cancer, as he claimed, but rather, it is one of the characteristic effects of cancer-causing mutations. Warburg articulated his hypothesis in a paper entitled ''The Prime Cause and Prevention of Cancer'' which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau, Lake Constance, Germany. In this speech, Warburg presented additional evidence supporting his theory that the elevated anaerobiosis seen in cancer cells was a consequence of damaged or insufficient respiration. Put in his own words, "the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar." Warburg's hypothesis has re-gained attention due to several discoveries linking impaired mitochondrial function as well as impaired respiration to the growth, division and expansion of tumor cells. In a study by Michael Ristow and co-workers, colon cancer lines were modified to overexpress frataxin. The results of their work suggest that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals. Studies published since 2005 have shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors. Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHC), a small-molecule inhibitor of monocarboxylate transporters (MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor pre-clinical research.〔Colen, CB, PhD Thesis (2005) http://elibrary.wayne.edu/record=b3043899~S47〕 Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.〔http://www.clinicaltrials.gov/ct2/show/NCT01791595〕 The chemical dichloroacetic acid (DCA), which promotes respiration and the activity of mitochondria, has also been shown to kill cancer cells ''in vitro'' and in some animal models. The body often kills damaged cells by apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells where the mitochondria are shut down. The reactivation of mitochondria in cancer cells restarts their apoptosis program. Besides promising human research at the Department of Medicine, University of Alberta led by Dr Evangelos Michelakis, other glycotic inhibitors besides DCA that hold promise include 3-BrOP being researched at The University of Texas M. D. Anderson Cancer Center, 2-deoxyglucose (2-DG) at Emory University School of Medicine, and lactate dehydrogenase A at Johns Hopkins University School of Medicine. == See also == * Reverse Warburg effect * Carcinogen * 2-Deoxy-D-glucose * Ketogenic diet * Pyruvic acid * Cellular respiration 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Warburg hypothesis」の詳細全文を読む スポンサード リンク
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