219fate” in which microenvironmental factors are believed to play critical role in niche
formation and intratumoral heterogeneity (i. e. ‘niche drives clone’). On the other
hand, another model proposes “The bug makes their own bed” in which tumor sub-
clones with certain mutations are thought to confer selective advantage to populate
the tumor (i.e. ‘clone drives niche’) (Castaño et al. 2012 ). Both the components,
TME and CSCs work synergistically in cancer progression (Fig. 11.3).
11.5.1 Tumor Microenvironment Determines Fates of Cancer
Stem Cells
According to literature, any non-stem cancer cells can spontaneously give rise to a
stem-like state in response to specific microenvironmental stimuli. Growth of can-
cer cells in a confined microenvironment leads to the alterations in metabolic and
physicochemical milieu and the reciprocal interaction between tumor cells and
TME promotes tumor progression (Chaffer et al. 2011 ). TME continuously gets
reshaped during tumor progression and prompt adaptive cellular behaviors includ-
ing dormancy, invasion and metastasis and therapy resistance. This adaptive cellular
behavior might be driven by tough tumor microenvironmental selective forces that
highly regulated alterations in the gene expression leading to the reprogramming of
signaling pathways generating stem-like characteristics (Marjanovic et al. 2013 ;
Anderson et al. 2006 ). The typical triad of tumor microenvironment that plays a
crucial role in driving malignant tumor cell behaviors consists of hypoxia, nutrient
depletion and low pH (Heddleston et al. 2010 ; Keith and Simon 2007 ). The interde-
pendence of tumor cells with their respective microenvironment and the intratu-
moral heterogeinity of cancer postulate the idea that CSCs are “bugs” that cannot
live without the “bed” i.e. the TME (Castaño et al. 2012 ).
11.5.1.1 Hypoxia
Hypoxia is one of the most common features of malignant head and neck tumor
which is also registered as a key contributor of tumor progression, metastasis and
chemo-radio therapy resistance in HNSCC. Improper vascularization, poor oxygen
transport in the intratumaoral region and necrotic areas may lead to the acute or
chronic hypoxia in the tumor microenvironment where the oxygen demand cannot
meet the oxygen supply (Vaupel and Mayer 2007 ; Jiang et al. 2011 ). As an adaptive
response to the reduced oxygenation, cancer cells may produce hypoxia inducible
factors (HIFs). HIFs comprises hypoxia-inducible factor 1α (HIF-1α), hypoxia-
inducible factor 1 (HIF-1β), hypoxia-inducible factor 2α (HIF-2α) and hypoxia
-inducible factor 3α (HIF-3α) (Brennan et al. 2005 ). Dimerization HIF-1α and
HIF-1β leads to the transcriptional activation of genes responsible for the adaption
to hypoxia which includes the genes involved in angiogenesis, metastasis and ther-
apy resistance (Li et al. 2013 ). Reports suggest that hypoxic microenvironment
11 Oral Cancer Stem Cells Microenvironment