The Warburg Effect and the Hallmarks of Cancer.
It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. The goal of this paper is to suggest strongly that most of (if not all) the hallmarks of cancer could be the consequence of the Warburg's effect. As a result of the metabolic impairment of the oxidative phosphorylation, there is a decrease in ATP concentration. To compensate the reduced energy yield, there is massive glucose uptake, anaerobic glycolysis, with an up-regulation of the Pentose Phosphate Pathway resulting in increased biosynthesis leading to increased cell division and local pressure. This increased pressure is responsible for the fractal shape of the tumor, the secretion of collagen by the fibroblasts and plays a critical role in metastatic spread. The massive extrusion of lactic acid contributes to the extracellular acidity and the activation of the immune system. The decreased oxidative phosphorylation leads to impairment in CO2 levels inside and outside the cell, with increased intracellular alkalosis and contribution of carbonic acid to extracellular acidosis-mediated by at least two cancer-associated carbonic anhydrase isoforms. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Mitochondrial disappearance (such as seen in very aggressive tumors) is a consequence of mitochondrial swelling, itself a result of decreased ATP concentration. The transmembrane pumps, which extrude, from the mitochondria, ions, and water, are ATP-dependant. Therapy aiming at increasing both the number and the efficacy of mitochondria could be very useful.
Assistance Publique des Hopitaux de Paris,France.
Laurent
L
Schwartz
Claudiu T
CT
Supuran
Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munawarah, KSA, Center for Evolution and Cancer, University of California San Francisco, San Francisco, CA,United States.
Khalid O
KO
Alfarouk
D000138:Acidosis / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000471:Alkalosis / Q000378:metabolism; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D049109:Cell Proliferation; D002951:Citrates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010427:Pentose Phosphate Pathway; D008063:Thioctic Acid / Q000378:metabolism
D002951:Citrates; D002245:Carbon Dioxide; D008063:Thioctic Acid; D000255:Adenosine Triphosphate; C007999:hydroxycitric acid; D005947:Glucose