221subpopulation. The laryngeal carcinaoma cells Hep-2 and AMC-HN-8 when grown
under hypoxic condition stimulated HIF-1α production along with the acceleration
of stemness signature gene OCT4, SOX2 and NANOG. Hypoxia also augmented
the laryngeal CSC marker CD133 expression and increased the proliferation, inva-
sion, colony formation and sphere formation capacity (Wu et al. 2014 ). Reports
also explore that hypoxia can induce stemness in laryngeal carcinoma by enriching
the percentage of CD133+ cells post radiation treatment. After 10 Gy of irradiation
for 24 h the hypoxic Hep2 cells introduced G1 cell cycle arrest and acquired stem
like characteristics by overexpressing the stemness marker CD133 in laryngeal car-
cinoma (Wang et al. 2011 ). Moreover, hypoxia is also reported enhance the
ALDH1high CSC population in a syngeneic mouse model of HNSCC (Duarte et al.
2012 ). In orthotopic immunocompetent murine models of HNSCC, hypoxia
induced autophagy is described to promote the evolution of aggressive phenotypes
(Vigneswaran et al. 2011 ).
11.5.1.2 Autophagy
Autophagy is an evolutionarily conserved catabolic pathway involving degradation
of cytoplasmic content which recycles ATP and metabolites in response to nutrient
deprivation or metabolic stress, hypoxia, chemo/radiotherapy and activated onco-
genes. Autophagy offers survival advantage to tumors by virtue of its nutrient recy-
cling capacity as tumors cells are frequently exposed to metabolic stress owing to
hypoxia and nutrient deprivation and promotes tumorigenesis (Bhutia et al. 2013 ).
The autophagic stroma model of cancer emphasizes the induction of oxidative
stress, mitochondrial dysfunction and autophagy/mitophagy in tumor invasion and
metastasis. Intriguingly, autophagy/mitophagy induction in the tumor stromal com-
partment helps the cancer cells to directly “feed off” of stromal-derived energy-rich
metabolites (glutamine, pyruvate, and ketones/BHB) and chemical building blocks
(amino acids, nucleotides) (Fig. 11.3). It is important to note that in the tumor
microenvironment, the aggressive cancer cells are “eating” the CAFs via autoph-
agy/mitophagy (Pavlides et al. 2010 ). The solid tumor core which is a hypoxic and
nutritionally challenged environment constructs a compensatory environment
around them by turning the CAFs into their “metabolic slaves” (Roy and Bera
2016 ). Interestingly, it reported that loss of caveolin-1 (Cav-1) in stromal cells
drives the activation of the metabolic reprogramming of CAFs and upregulates the
expression of pyruvate kinase M2 (PKM2), a glycolytic enzyme resulting in the
induction of autophagy and glycolysis. Enhanced glycolysis fuels the mitochondrial
metabolism of nearby cancer cells leads to high ATP generation and cell survival
(Capparelli et al. 2012 ). RAS-dependent and NF-κB–dependent HNSCC cell line
were each able to induce metabolic reprogramming of CAFs via oxidative stress
resulting in a lactate shuttling process that feeds the cancer cells fueling anabolic
growth via and MCT1/MCT4 metabolic couple between the tumor and the stroma
(Curry et al. 2014 ).
11 Oral Cancer Stem Cells Microenvironment