Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity)

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.

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

“…In this context, it is suggested that the Warburg effect reveals that some cancer undergoes a loss of mitochondrial activity (i.e. loss of endosymbiotic relationship between mitochondrion and the cell), and so most probably are returning to a primitive state (primitive microorganisms) 1 . Diminishing the mitochondrial activity has evolutionarily advantaged such as keeping cancer cell survival through inhibition of apoptosis [23][24][25] .…”

“…MCT is a symporter that transports H + and L-lactate or pyruvate bidirectionally 48 . Lactate is extruded continuously from transformed cells due to a switch from the Pasteur effect to the Warburg effect 1 . The presence of lactate extracellularly preserves a favorable habitat for malignant cells and an unfavorable environment for normal cells, so it offers and evolutionary advantage to tumor cells 50 .…”

“…In the early 1920s, a technician at Otto Warburg's lab spilled NaHCO 3 by accident and created an opportunity for Otto Warburg to observe that those cancer cells became highly fermentative. This has led to the development of the Warburg hypothesis that states that the driver for tumor development is a mitochondrial insult that leads to insufficient cellular respiration, explaining why even in the presence of adequate oxygen tumor cells preferentially turn to fermentation of lactic acid for an energy supply ''Warburg Effect'' 1 . While in yeast the fermentation results in the formation of ethanol, in eukaryotic cells glycolysis results in the formation of lactate.…”

“…While in yeast the fermentation results in the formation of ethanol, in eukaryotic cells glycolysis results in the formation of lactate. Cancer cells are unique in the way by which they switch to anaerobic glycolysis in the presence of a plentiful supply of oxygen 1,2 . Glycolysis occurs through the glycolysis pathway or the pentose phosphate pathway (PPP; Figure 1).…”

Connections between Warburg’s and Szentgyorgyi’s Approach about the Causes of Cancer

“…This phenomenon is the simple unicellular development. In this context, it looks like the evolutional return to simpler life, and so cancer could be regarded as "dismantling of multicellularity" [74]. This was the starting point of Szentgyorgyi is an aetiological approach: the disappearance of cellular collectivity [35].…”