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.
Video Warburg hypothesis
Hypothesis
Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg in 1924. 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 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. 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."
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.
Maps Warburg hypothesis
Continuing 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, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
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. 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
Further reading
- Warburg O (24 February 1956). "On the Origin of Cancer Cells". Science. 123 (3191): 309-14. Bibcode:1956Sci...123..309W. doi:10.1126/science.123.3191.309. PMID 13298683.
- Ristow M (July 2006). "Oxidative metabolism in cancer growth". Current Opinion in Clinical Nutrition and Metabolic Care. 9 (4): 339-45. doi:10.1097/01.mco.0000232892.43921.98. PMID 16778561.
- ""Energy Blocker" kills Big Tumors in Rats" (Press release). Johns Hopkins Medicine. 14 October 2004.
- Gatenby RA, Gillies RJ (2004). "Why do cancers have high aerobic glycolysis?" (reprint). Nature Reviews Cancer. 4 (11): 891-9. doi:10.1038/nrc1478. PMID 15516961.
- Pelicano H, Martin DS, Xu RH, Huang P (2006). "Glycolysis inhibition for anticancer treatment". Oncogene. 25 (34): 4633-46. doi:10.1038/sj.onc.1209597. PMID 16892078.
- Weinhouse S (1976). "The Warburg hypothesis fifty years later". Journal of Cancer Research and Clinical Oncology. 87 (2): 115-26. doi:10.1007/BF00284370. PMID 136820.
- Garber K (2004). "Energy Boost: The Warburg Effect Returns in a New Theory of Cancer". Journal of the National Cancer Institute. 96 (24): 1805-6. doi:10.1093/jnci/96.24.1805. PMID 15601632.
- Seyfried TN, Mukherjee P (Oct 2005). "Targeting energy metabolism in brain cancer: review and hypothesis". Nutr Metab (Lond). 2 (1): 30. doi:10.1186/1743-7075-2-30. PMC 1276814 . PMID 16242042.
- Pedersen PL (Jun 2007). "Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen". J Bioenerg Biomembr. 39 (3): 211-22. doi:10.1007/s10863-007-9094-x. PMID 17879147.
- Glycolytic enzyme inhibitors as novel anti-cancer drugs (3-bromopyruvate (3BP) and iodoacetate (IAA)), James C.K. Lai et al., Idaho State, June 2007
- Can a High-Fat Diet Beat Cancer? by Richard Friebe, Time magazine, Monday, Sep. 17, 2007,
- Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E (Mar 2007). "Energy metabolism in tumor cells". FEBS J. 274 (6): 1393-418. doi:10.1111/j.1742-4658.2007.05686.x. PMID 17302740.
- Pedersen PL (Feb 2007). "The cancer cell's "power plants" as promising therapeutic targets: an overview". J Bioenerg Biomembr. 39 (1): 1-12. doi:10.1007/s10863-007-9070-5. PMID 17404823.
- Aft RL, Zhang FW, Gius D (Sep 2002). "Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death". Br J Cancer. 87 (7): 805-12. doi:10.1038/sj.bjc.6600547. PMC 2364258 . PMID 12232767.
- US 6670330 Cancer chemotherapy with 2-deoxy-D-glucose
- Can Ancient Herbs Treat Cancer? Time magazine, October 15, 2007 (describes the drug trial of BZL101, a compound from the Scutellaria Barbata herb that prevents cancerous cells from undergoing glycolysis).
- Isidoro A, Casado E, Redondo A, et al. (Dec 2005). "Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis". Carcinogenesis. 26 (12): 2095-104. doi:10.1093/carcin/bgi188. PMID 16033770.
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