Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis

Abstract

Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic–Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells “revert” to “primitive” characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells’ metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a “shift” toward “atavistic” biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection.

Characterization of the Intracellular Acidity Regulation of Brain Tumor Cells and Consequences for Therapeutic Optimization of Temozolomide

“…Tumor metabolism has attracted renewed attention recently, as the acidity generated by tumor cells has been found to be responsible for increased cell aggressiveness, favoring invasion and resistance to treatment [ 71 ]. The true nature of cancer cell metabolism has become an active source of debate with respect to whether it should be considered an evolutionary specialization, an atavistic remanence [ 71 , 72 ], or a contextual adaptation to extreme conditions [ 73 , 74 , 75 ].…”

The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers

“…Indeed, emerging evidence showed a better effect of a multi-target metabolic approach for anti-tumor therapy. A multi-target approach, involving simultaneous targeting of multiple enzymes within the same or different metabolic pathways, could be more effective [163,164]. Plant extracts, such as the polyphenol resveratrol, offer a promising option due to their ability to act on multiple cellular targets and influence various metabolic pathways [165,166].…”