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 and according to Warburg, cancer should be interpreted as a mitochondrial dysfunction. 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.
It is now known that cancer is caused by mutations in the genome of the cells in a process called malignant transformation, resulting in an uncontrolled growth of cells. The metabolic differences observed by Warburg are now thought to be an adaption of cancer cells to the hypoxic (oxygen-deficient) conditions inside solid tumors, and therefore not the cause, as he claimed, but an effect of cancer.
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 evidence in support of the claim that anaerobiosis was a primary cause of cancerous cells. 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."
In recent years, 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 mitochondrion frataxin may inhibit cancer growth in mammals.
Subsequent work has shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors. The drug dichloroacetic acid, which promotes respiration and the activity of mitochondria, has 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. According to one hypothesis, the reactivation of mitochondria in cancer cells might also restart their apoptosis program.
- O. Warburg, K. Posener, E. Negelein: Ueber den Stoffwechsel der Tumoren; Biochemische Zeitschrift, Vol. 152, pp. 319-344, 1924. (German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: Constable, London, 1930.
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- Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Spain; December 2005de:Warburg-Hypothese