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.

Figure 1.

Describes the interaction between different key events of carcinogenesis, this figure represents the interaction of the possible three key events of carcinogenesis with potential antagonizing agents.

Figure 2.

Cancer as integrated metabolic ecosystem, This model describes the possible pathways of carcinogenesis associated with metabolic phases of transformation. The green background reflects the tumor microenvironment which represents the medium on which carcinogenesis steps have occurred. Normal metabolism occurs does not create the tumor microenvironment which is why it is presented outside of the green background.

Figure 3.

Carcinogenesis as a dismantling of multi-cellularity. Hypothetical model describes the evolutionary homeostasis between prokaryogenesis (carcinogenesis) and eukaryogenesis. The blue background reflects the tumor microenvironment which is the medium where this reverse/convergent evolution occurs.

Figure 4.

Hypothetical model describing carcinogenesis as a metabolic ladder (cascade). Bluish background represents tumor microenvironment which is the medium necessary for driving carcinogenesis.

Figure 5.

Tumor as integrated metabolic ecosystem, this model represents cancer colony as multi-layers including isthmus and/or neutral area that prevent transgress between Glycolytic phenotypic of cells and metabolic types of cells. This model is so compatible with a recent model that supported experimentally in brain tumor [54]. Because tumor cell at edge rely on lactate as energetic fuel, we suggest the term it as o “Lactate zone”. We suggest to term “multi-layers” and/or “multi-zones” to describe that tumor colony consists of several zones; each zone has distinguished energetic fuel differs from others but at the end most of these zones are in symbiotic (mutual) relationship [Cannibal zone, Warburg (glycolytic)zone, isthmus zone and Lactate zone].