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.
Highlights
Depending on the tissue type, there is a wide variability in the oxygen (O2 ) levels, ranging from9.5% (72.0 mmHg) in kidneys [1], 7.6–6.8% (57.6 mmHg-51.6 mmHg) in gastrointestinal tract [2,3], 5.6% (42.8 mmHg) in lungs [4], 5.4% (40.6 mmHg) in liver [5], and 4.4% (33.8 mmHg) in the brain [6].O2 levels below these values are considered hypoxic
This review will focus on the metabolic rewiring induced by hypoxia, on the implications of such rewiring in tumor progression and chemoresistance, on the new therapeutic opportunities that may emerge with a deep knowledge of the metabolic reprogramming occurring in hypoxia
Cells of solid tumors are often glucose-addicted, the glycolytic pathway followed by lactic fermentation has a lower efficiency in terms of glucose/adenosine triphosphate (ATP) ratio, compared to the glycolysis followed by tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS)
Summary
Depending on the tissue type, there is a wide variability in the oxygen (O2 ) levels, ranging from. Hypoxia affects neoplastic cells, and implies changes in metabolism and functions of infiltrating cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) These changes may impair or favor the neoplastic growth, producing cellular quiescence, differentiation, apoptosis, or necrosis, depending on the degree, persistence, and severity of hypoxia. As a consequence of the different oxygenation, solid tumors are metabolically heterogeneous: better oxygenated regions rely on mitochondrial oxidative phosphorylation (OXPHOS), while hypoxic areas are more dependent on anaerobic metabolism [21]. This metabolic reprogramming is coordinated by the hypoxia-inducible factors (HIF) family. This review will focus on the metabolic rewiring induced by hypoxia, on the implications of such rewiring in tumor progression and chemoresistance, on the new therapeutic opportunities that may emerge with a deep knowledge of the metabolic reprogramming occurring in hypoxia
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