Abstract
Carcinogenesis occurs through a series of steps from normal into benign and finally malignant phenotype. This cancer evolutionary trajectory has been accompanied by similar metabolic transformation from normal metabolism into Pasteur and/or Crabtree-Effects into Warburg-Effect and finally Cannibalism and/or Lactate-Symbiosis. Due to lactate production as an end-product of glycolysis, tumor colonies acquire new phenotypes that rely on lactate as energetic fuel. Presence of Warburg-Effect indicates that some tumor cells undergo partial (if not complete) de-endosymbiosis and so cancer cells have been become unicellular microorganism (anti-Dollo's Law) specially when they evolve to develop cannibalism as way of metabolism while oxidative types of cells that rely on lactate, as their energetic fuel, might represent extra-endosymbiosis. Thus, at the end, the cancer colony could be considered as integrated metabolic ecosystem. Proper understanding of tumor metabolism will contribute to discover potential anticancer agents besides conventional chemotherapy.
Highlights
While yeast secrete ethanol as way of competition in the so called “Crabtree effect” [1], cancer cells produce lactate via the “Warburg-effect” to increase their fitness [2]
Reshkin Pathway of Carcinogenesis: the data that came out of the papers published by the Reshkin group demonstrated that the alkalinazation produced by the up-regulation of the Na+/H+ exchanger, NHE1, during neoplastic transformation of a normal cell drives the first alterations of the cells toward glycolytic metabolism in the presence of oxygen (Warburg effect) and the first appearances of the
The normal stroma, turning it into a factory for the production of energy-rich metabolites”... this phenomenon termed as The Reverse of Warburg Effect. Targeting of these key events could be reached as follow: activity of several antitumor agents termed as Anti-Microenvironment Acidity Induced-Cancer Spite “Anti-MAICS” [2]: Where hypoxia is stimulated through the Carbonic Anhydrase inhibitor, Acetazolamide [17,18,19], and extracellular acidosis is targeted by (i) Proton Pump Inhibitors (PPIs) and (ii) systemic NaHCO3 treatment [20,21,22,23]
Summary
While yeast secrete ethanol as way of competition in the so called “Crabtree effect” [1], cancer cells produce lactate via the “Warburg-effect” to increase their fitness [2]. This raises the question: do the Warburg-effect and Crabtree-effect reflect ancestral relationships (i.e., evolution of behavior)? It would be great of interest to study the evolutionary trajectory of anaerobic metabolism from ethanol to lactic acid production This is mainly because mitochondrion has been considered to be a bacterium [3], so production of ethanol will harm mitochondrion (antiseptic agent) and inhibit cellular energy metabolism via inhibition of AMPK [4]. Carcinogenesis probably represents a delicate balance between the two processes
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