Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

Abstract

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.

Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells?

“…Despite all the prosperities in chemotherapeutic drugs, it is assumed that tumor cells are one step ahead. Tumors either through acquired mutations or exploiting the vital resources essential for our normal cells, immune cells, in particular, aggressively proliferate and survive even under stressful circumstances, such as hypoxia, malnutrition, and low pH, to say the least [359] .…”

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

“…The metabolic rewiring driven by hypoxia also plays a role in chemoresistance [ 116 ]. The huge production of lactate due to the increase in glycolysis determines a strong acidification of the TME that limits the efficacy of weak bases such as anthracyclines: indeed, these drugs are easily protonated and sequestered within lysosomes [ 117 ].…”

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

“…The first marker was 2nitroimidazole and ( 18F )FMISO later it was developed further into 123 I-tracers. It is an alternative to use reduced chelated metals such as 60 Cu-compound ATSM although their sensitivity is lower as compared to FMISO. Last but not least, FDG-PET can also be used to assess the glycolysis and increased glucose transport in cancer tissues.…”