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Instead, in\n                    <jats:italic>most<\/jats:italic>\n                    <jats:italic>tumours<\/jats:italic>\n                    the Warburg effect is an essential part of a \u2018selfish\u2019 metabolic reprogramming, which results from the interplay between (normoxic\/hypoxic) hypoxia\u2010inducible factor\u20101 (HIF\u20101) overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), activated (PI3K\u2013Akt\u2013mTORC1, Ras\u2013Raf\u2013MEK\u2013ERK\u2013cMyc, Jak\u2013Stat3) or deactivated (LKB1\u2013AMPK) signalling pathways, components of the tumour microenvironment, and HIF\u20101 cooperation with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerable acceleration of glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non\u2010essential amino acids, lipids and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate, which stimulates tumour growth and suppression of anti\u2010tumour immunity \u2013 in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies; (f) cytosolic lactate being mainly exported through upregulated lactate\u2013proton symporters (MCT4), working together with other H\n                    <jats:sup>+<\/jats:sup>\n                    transporters, and carbonic anhydrases (CAII, CAIX), which hydrate CO\n                    <jats:sub>2<\/jats:sub>\n                    from oxidative metabolism to form H\n                    <jats:sup>+<\/jats:sup>\n                    and bicarbonate; (g) these proton export mechanisms, in concert with poor vascular drainage, being responsible for extracellular acidification, driving malignant progression and resistance to conventional therapies; (h) maintenance of the cellular redox homeostasis and low reactive oxygen species (ROS) formation; and (i) HIF\u20101 overexpression, mutant p53 and mutant PTEN, which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e. aerobic glycolysis in the presence of oxygen and \u2013 in principle \u2013 functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a\n                    <jats:italic>minority<\/jats:italic>\n                    of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp14502-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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