Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis

SIMPLE SUMMARY: Cancer can be considered the epidemic of the third millennium, and recent projections paint a worrying scenario for the coming decades. Knowledge about the causes of neoplastic transformation remains limited, and classical genetic paradigms do not provide adequate models. Likewise, current pharmacological approaches show limited efficacy and often lead to the development of drug resistance and relapse. The limited success of cancer treatments requires a revision and, possibly, a paradigm shift in how we think about the disease. In this regard, studies of tumor cell metabolism and mechanisms of tumor cell adaptation can provide important insights. Here, we review the latest knowledge on the impact of metabolic and microenvironmental conditions on determining the phenotype of tumor cells and on how increasing this understanding could improve pharmacological options. 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.