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Warburg Hypothesis Warburg hypothesis The Warburg hypothesis (/ˈvɑːrbʊərɡ/), sometimes known as the Warburg theory of cancer, postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria.[1] 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.[2] Contents Scientist Otto Warburg, whose research activities led to the Hypothesis formulation of the Warburg On-going research and interest hypothesis for explaining the root See also cause of cancer. References Further reading Hypothesis Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924.[3] 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.[4][5] The metabolic difference 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.[6] 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."[7] 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.[8] On-going research and interest A large number of researchers have dedicated and are dedicating their efforts to the study of the Warburg Effect that is intimately associated with the Warburg hypothesis. In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol,[9][10] rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.[11][12][13] In particular, almost 18,000 publications have been published on the matter of ATP and the Warburg effect in the period 2000 to 2015. Most of the functions of the Warburg Effect have been the object of study.[14] Thousands of publications claim to have determined its functions or causes. See also Carcinogen 2-Deoxy-D-glucose Ketogenic diet Pyruvic acid Cellular respiration Inverse Warburg Effect References 1. Warburg O (24 February 1956). "On the Origin of Cancer Cells". Science. 123 (3191): 309–14. Bibcode:1956Sci...123..309W (http://adsabs.harvard.edu/abs/1956Sci...123..309W). doi:10.1126/science.123.3191.309 (https://doi.org/10.1126%2Fscience.123.3191.309). PMID 13298683 (https://www. ncbi.nlm.nih.gov/pubmed/13298683). 2. Vazquez, A.; Liu, J.; Zhou, Y.; Oltvai, Z. (2010). "Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880972). BMC systems biology. 4: 58. doi:10.1186/1752- 0509-4-58 (https://doi.org/10.1186%2F1752-0509-4-58). PMC 2880972 (https://www.ncbi.nlm.nih.gov/pmc/articles/P MC2880972)​ . PMID 20459610 (https://www.ncbi.nlm.nih.gov/pubmed/20459610). 3. O. Warburg, K. Posener, E. Negelein: Ueber den Stoffwechsel der Tumoren; Biochemische Zeitschrift, Vol. 152, pp. 319-344, 1924. (in German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: 319-344, 1924. (in German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: Constable, London, 1930. 4. Bertram JS (2000). "The molecular biology of cancer". Mol. Aspects Med. 21 (6): 167–223. doi:10.1016/S0098- 2997(00)00007-8 (https://doi.org/10.1016%2FS0098-2997%2800%2900007-8). PMID 11173079 (https://www.ncbi.nl m.nih.gov/pubmed/11173079). 5. Grandér D (1998). "How do mutated oncogenes and tumor suppressor genes cause cancer?". Med. Oncol. 15 (1): 20–6. doi:10.1007/BF02787340 (https://doi.org/10.1007%2FBF02787340). PMID 9643526 (https://www.ncbi.nlm.nih. gov/pubmed/9643526). 6. Hsu PP & Sabatini DM (2008). "Cancer Cell Metabolism: Warburg and Beyond". Cell. 134 (5): 703–7. doi:10.1016/j.cell.2008.08.021 (https://doi.org/10.1016%2Fj.cell.2008.08.021). PMID 18775299 (https://www.ncbi.nlm .nih.gov/pubmed/18775299). 7. Brand, R. A. (2010). "Biographical Sketch: Otto Heinrich Warburg, PhD, MD" (https://www.ncbi.nlm.nih.gov/pmc/articl es/PMC2947689). Clinical Orthopaedics and Related Research. 468 (11): 2831–2832. doi:10.1007/s11999-010- 1533-z (https://doi.org/10.1007%2Fs11999-010-1533-z). PMC 2947689 (https://www.ncbi.nlm.nih.gov/pmc/articles/P MC2947689)​ . PMID 20737302 (https://www.ncbi.nlm.nih.gov/pubmed/20737302). 8. Pedersen, Peter L (February 2007). "The cancer cell's "power plants" as promising therapeutic targets: an overview". Journal of bioenergetics and biomembranes. 39 (1): 1–12. doi:10.1007/s10863-007-9070-5 (https://doi.org/10.1007% 2Fs10863-007-9070-5). ISSN 0145-479X (https://www.worldcat.org/issn/0145-479X). PMID 17404823 (https://www.n cbi.nlm.nih.gov/pubmed/17404823). 9. Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Adil HH, Elhassan GO, Ibrahim ME, David Polo Orozco J, Cardone RA, Reshkin SJ, Harguindey S (2014). "Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question" (https://www.ncbi.nlm .nih.gov/pmc/articles/PMC4303887). Oncoscience. 1 (12): 777–802. doi:10.18632/oncoscience.109 (https://doi.org/1 0.18632%2Foncoscience.109). PMC 4303887 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303887)​ . PMID 25621294 (https://www.ncbi.nlm.nih.gov/pubmed/25621294). 10. Alfarouk KO (February 2016). "Tumor metabolism, cancer cell transporters, and microenvironmental resistance". Journal of Enzyme Inhibition and Medicinal Chemistry: 1–8. doi:10.3109/14756366.2016.1140753 (https://doi.org/10. 3109%2F14756366.2016.1140753). PMID 26864256 (https://www.ncbi.nlm.nih.gov/pubmed/26864256). 11. Alfarouk KO, Muddathir AK, Shayoub ME (20 January 2011). "Tumor acidity as evolutionary spite" (http://www.mdpi.c om/2072-6694/3/1/408). Cancers. 3 (1): 408–14. doi:10.3390/cancers3010408 (https://doi.org/10.3390%2Fcancers30 10408). PMC 3756368 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756368)​ . PMID 24310355 (https://www.ncb i.nlm.nih.gov/pubmed/24310355). 12. Gatenby RA, Gillies RJ (November 2004). "Why do cancers have high aerobic glycolysis?". Nature Reviews. Cancer. 4 (11): 891–9. doi:10.1038/nrc1478 (https://doi.org/10.1038%2Fnrc1478). PMID 15516961 (https://www.ncbi.nlm.nih. gov/pubmed/15516961). 13. Kim JW, Dang CV (September 2006). "Cancer's molecular sweet tooth and the Warburg effect" (http://cancerres.aacrj ournals.org/cgi/pmidlookup?view=long&pmid=16982728). Cancer Research. 66 (18): 8927–30. doi:10.1158/0008- 5472.CAN-06-1501 (https://doi.org/10.1158%2F0008-5472.CAN-06-1501). PMID 16982728 (https://www.ncbi.nlm.nih .gov/pubmed/16982728). 14. The Warburg Effect: How Does it Benefit Cancer Cells? (http://www.cell.com/trends/biochemical-sciences/fulltext/S09 68-0004(15)00241-8) Trends in Biochemical Sciences- M.V. Liberti, J.W. Locasale. January 2016 Further reading Warburg O (24 February 1956). "On the Origin of Cancer Cells". Science. 123 (3191): 309–14. Bibcode:1956Sci...123..309W (http://adsabs.harvard.edu/abs/1956Sci...123..309W). doi:10.1126/science.123.3191.309 (https://doi.org/10.1126%2Fscience.123.3191.309). PMID 13298683 (https://www. ncbi.nlm.nih.gov/pubmed/13298683). Ristow M (July 2006). "Oxidative metabolism in cancer growth" (http://www.co-clinicalnutrition.com/pt/re/conutrition/a bstract.00075197-200607000-00003.htm). Current Opinion in Clinical Nutrition and Metabolic Care. 9 (4): 339–45. doi:10.1097/01.mco.0000232892.43921.98 (https://doi.org/10.1097%2F01.mco.0000232892.43921.98). PMID 16778561 (https://www.ncbi.nlm.nih.gov/pubmed/16778561). " "Energy Blocker" kills Big Tumors in Rats" (http://www.hopkinskimmelcancercenter.org/news/details.cfm?documenti d=673) (Press release).
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