Warburg hypothesis

Not to be confused with Warburg effect.

Scientist Otto Warburg, whose research activities led to the formulation of the Warburg hypothesis for explaining the root cause of cancer.

The Warburg hypothesis (/ˈvɑːrbʊərɡ/), sometimes known as the Warburg theory of cancer, postulates that the driver of carcinogenesis (cancer formation) is insufficient cellular respiration caused by insult (damage) to mitochondria.[1] The Warburg effect, on the other hand, describes the observation that cancer cells, and many cells grown in vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire.[2] In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis is that the Warburg effect is the root cause of cancer.

Hypothesis

The 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, carcinogenesis stems from the lowering of mitochondrial respiration. Warburg regarded the fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect.

In the somatic mutation theory of cancer, malignant proliferation 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]

See also

• Carcinogen
• Carcinogenesis
• 2-Deoxy-D-glucose
• 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. doi:10.1126/science.123.3191.309. PMID 13298683.
2. Mahla, RS; et al. (2021). "NIX-mediated mitophagy regulate metabolic reprogramming in phagocytic cells during mycobacterial infection". Tuberculosis. 126 (January): 102046. doi:10.1016/j.tube.2020.102046. PMID 33421909. S2CID 231437641.
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: 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. PMID 11173079. S2CID 24155688.
5. Grandér D (1998). "How do mutated oncogenes and tumor suppressor genes cause cancer?". Med. Oncol. 15 (1): 20–6. doi:10.1007/BF02787340. PMID 9643526. S2CID 12467031.
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. PMID 18775299. S2CID 17778749.
7. Brand, R. A. (2010). "Biographical Sketch: Otto Heinrich Warburg, PhD, MD". Clinical Orthopaedics and Related Research. 468 (11): 2831–2832. doi:10.1007/s11999-010-1533-z. PMC 2947689. PMID 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. ISSN 0145-479X. PMID 17404823. S2CID 477272.

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.