211progeny populations where the CSCs rest at the apex of positional hierarchy and
drive tumor growth and disease progression. It is highly essential to note that the
clonal evolution model and CSC models are not mutually exclusive and the progres-
sion of intratumoral heterogeneity is a highly complex process (Shackleton et al.
2009 ). Intriguingly, recent reports emphasize that the concept of intratumor hetero-
geneity not only relevant to the cancer cells but also to the interaction of cancer cells
with the diverse microenvironmental components. The intratumoral heterogeneity
and evolutionary processes happening therein are influenced by topological niches
and corresponded by functional heterogeneity (Marusyk et al. 2012 ). This alterna-
tive cancer cell plasticity model emphasizes that microenvironmental cues encour-
age self-renewal mechanisms to acquire CSC characteristics-a reversible process
that is inherently transitory allowing the interconversion of CSCs to non-CSCs
(Fig. 11.2). Cancer cell plasticity model is bidirectional involving the interconver-
sion of tumogenic and non-tumorigenic cells within tumor adding extra complexity
to the CSCs and clonal model to explain the intratumoral heterogeinity. This model
suggests that both CSCs and non-CSCs are highly adaptable populations that read-
ily switch between tumorigenic and non-tumorigenic cell states owing to appropri-
ate microenvironmental stimuli which are capable of inducing transient evolution
and plasticity (Cabrera et al. 2015 ). Moreover, a comprehensible role of microenvi-
ronment in tumorigenicity was recently demonstrated in melanoma. Quintana et al.
experimentally showed that same melanoma cells have different tumorigenic capac-
ity depending on the transplant conditions i.e. type of mouse strain, use of matrigel
and duration of experiment suggesting microenvironmental regulation of tumor
heterogeneity and tumorigenicity (Quintana et al. 2008 ).
11.3 Concept of Cancer Stem Cells in Oral Cancer
The exorbitant inefficacies of contemporary treatment modalities coupled with
increased recurrences and metastasis in oral cancer are alleged to the CSCs which
challenges the traditional concept and supports the existence of a small subpopula-
tion of intratumoral cells called as Cancer Stem Cells (CSCs) or Cancer Initiating
Cells (CICs) or Tumor Initiating Cells (TICs) with exclusive self-renewal capacity,
tumorigenesis and metastatic potential. Though the concept of cancer stem cells
was proposed in the late 1970s by a German physiologist Rodulf Virchow, who
found similarities between the embryonic tissues and cancer tissues (Visvader and
Lindeman 2008 ; Huntly and Gilliland 2005 ); Bonnet et al. (1997) were the first to
isolate CSCs from acute myeloid leukaemia samples (Dick 1997 ). The CSCs from
solid tumors were first isolated and identified in breast cancer by Al-Hajj et al.
( 2003 ). They isolated a subpopulation of CD44+/ CD24− cells within the breast
cancer tissues having the high tumorigenic capacity (Al-Hajj et al. 2003 ). The exis-
tence of CSCs is also described in other solid tumors including prostate, melanoma,
lung, colon, brain, liver, HNSCC, gastric and pancreatic cancer (Singh et al. 2003 ;
Kim et al. 2005 ; Li et al. 2007 ; Prince et al. 2007 ; Lessard and Sauvageau 2003 ).
11 Oral Cancer Stem Cells Microenvironment