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oropharynx, hypopharynx, tonsils, pyriform sinus and other and ill-defined sites
of the lip, oral cavity and pharynx (Ferlay et al. 2010 ). In the year 2012, there
were approximately 300,373 new cases of lip/oral cavity cancer and 142,387 new
cases of other pharyngeal (i.e. excluding the nasopharynx) cancer worldwide as
per the most recent GLOBOCAN estimates (Ferlay et al. 2012 ). In India, the
global epicenter of oral cancer, the disease occurrence trends vary by region
and investigators estimate that the total number of new mouth cancer cases will
increase from 45,859 in 2010 to 64,525 in 2020 (Takiar et al. 2010 ). Betel quid
chewing, excessive alcohol consumption, tobacco smoke, HPV infection and radi-
ation exposure are the chief risk factors for on setting the disease (Brandwein-
Gensler et al. 2005 ; Marron et al. 2010 ; Licitra et al. 2006 ; Chen et al. 2008 ).
Along with the conventional anticancer approaches such as surgery, radiotherapy
and cytotoxic chemotherapy, several selective treatment modalities are also avail-
able which is based on the increased understanding of tumor biology and specific
tumor subtypes (Fan et al. 2011 ). Though there is availability of high end multidi-
mensional treatment regimen, the oral cancer treatment is quite unpromising with
significant functional and aesthetic deficits such as facial disfigurement aside
from functional deformity like speech impairment and difficulty in swallowing
(Naik et al. 2016 ). Near about 30% of oral cancer cases are often coupled with an
exorbitant rate of post-treatment loco- regional recurrence, ipsilateral and bilateral
lymph node metastasis due to the dissemination of neoplastic cells via abundant
lymphatic submucosal plexus present in the oral cavity, ultimately leading to
death (Fan et al. 2011 ). Further, the 5 year survival rate of oral cancer patients is
restricted to only 50–60% (Leemans et al. 1994 ).
The ever increasing failure rate of contemporary treatment motilities, rising
intrinsic and acquired therapeutic resistance, persistent recurrences and relapse of
oral cancer are mostly due to the random cytoreduction strategies that are designed
to target only the bulk tumor cells setting aside a small subpopulation of therapy
tolerant cells. Such rare and therapy tolerant subpopulation of cells with exclusive
ability of self-renewal, progeny differentiation and tumorigenicity is termed as
“Cancer Stem Cells” (CSCs). The CSCs are also reported to have the unique proper-
ties of enhanced DNA damage responses, apoptotic evasion, active drug efflux
potential and epithelial to mesenchymal transition (EMT) which offer CSCs the
supremacy to tumorigenesis, sustained growth and therapeutic resistance (Fig. 11.1)
(Costea et al. 2006 ). The tumor microenvironment (TME) imposes intense pressure
in cancer evolution in response to adverse growth conditions, resource limitation
and immune predation. Moreover, the ability of the tumor cells to organize its sur-
rounding environment in its favor along with the ability of microenvironment to
shelter tumor cells from adverse exogenous constraints determines fate of the dis-
ease progression (Sottoriva et al. 2013 ; McGranahan and Swanton 2017 ). TME var-
ies in terms of nutrients, oxygen, growth factors, cytokines, pH, extra-cellular matrix
(ECM), vascularization and stromal components including fibroblasts and immune
cells (Hjelmeland et al. 2011 ). This distinction within the tumor landscape creates
various functional niches that govern the sensitivity of the genetically similar cancer
cells to same treatment module (Almendro et al. 2013 ; Holohan et al. 2013 ).
P.P. Naik et al.