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11.5.1.3 Tumor Metabolism
The “Warburg effect”, as proposed by Otto Warburg in the 1920s, postulates that
even in presence of abundant oxygen, cancer cells are more reliant on aerobic gly-
colysis than the oxidative phosphorylation (OXPHOS). Though glycolysis is less
efficient in terms of ATP production, during the proliferation of cancer cells, it pro-
vides metabolites for the synthesis of macromolecules. However, contradictorily
“Reverse Warburg Effect” posits that tumor cells exploit normal stroma through
H 2 O 2 paracrine signaling resulting in oxidative stress in stromal fibroblasts thereby
trigger mitochondrial dysfunction, mitophagy and glycolytic metabolism. This
helps in the release of metabolic intermediate metabolites like lactate, glutamine
and ketone bodies to be used for oxidative phosphorylation in cancer cells. According
to report, the non-physiological high glucose and oxygen concentration favor a gly-
colytic phenotype. However, when patient-derived, low-passage CSCs is investi-
gated OXPHOS was found to be preferred energy metabolism of CSCs. Moreover,
it is reported that when OXPHOS is blocked CSCs are able to switch to a glycolytic
phenotype. This observed adaptive metabolic plasticity might permit the CSCs to
sustain in the microenvironments during tumor progression (Neiva et al. 2009 ;
Dong et al. 2013 ).
There exists a multicompartment model of energy metabolism in oral cancer. It
is also reported that it may be a three metabolic compartments in OSCC, where the
peripheral tumors cells relies on OXPHOS and cells in the deeper layer tumor are
more glycolytic (aerobic or anaerobic) whereas the third metabolic compartment
represented as cells in tumor stroma undergoing aerobic glycolysis. This three com-
partment metabolism was demonstrated through higher level of expression of
MCT4 in tumor stroma and deeper tumor, whereas MCT1 level was more in the
leading tumor edge. Energy metabolism through OXPHOS in the leading tumor
edge was confirmed by functional mitochondrial metabolism markers TOMM20
and LDHb (Curry et al. 2014 ). In differentiated cancer cells, the glycolytic pheno-
types predominate over OXPHOS phenotype. CSCs instead might rely more on
oxidative metabolism for their energy production. The CSCs also appear to be meta-
bolically plastic and when OXPHOS is blocked they can eventually develop resis-
tance by acquiring an intermediate glycolytic/oxidative phenotype. For the first time
Curry et al. reported the connection between cancer stemness with lactate and
ketone uptake and mitochondrial metabolism in HNSCC (Fig. 11.4). “Three com-
partment tumor metabolism” involving (1) proliferative and mitochondrial-rich can-
cer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and
mitochondrial-poor cancer cells (Ki-67/TOMM20/COX/MCT1); and (3) non-
proliferative and mitochondrial-poor stromal cells (Ki-67/TOMM20/COX/MCT1)
in HNSCC displayed metabolic symbiosis where the non-proliferative stromal cells
provide metabolites for OXPHOS in highly proliferating cancer cells (Bagordakis
et al. 2016 ). Again, metabolic stress in the confined TME is recently reported to
assist in emergence and sustenance of CSC-like phenotypes. Chronic metabolic
stress (CMS) due to long-term nutrient deprivation in the TME persuades a Wnt-
dependent phenoconversion of non-CSCs toward CSCs through stochastic state
transition (Lee et al. 2015 ).
P.P. Naik et al.