225fibronectin) to promte EMT in SCC-9 cells. Moreover, it increased the level of
Twist and ZEB and promoted expression of CSCs surface markers, self-renewal
ability, resistance to therapies and apoptosis (Yang et al. 2013 ). A disintegrin and
metalloproteinase domain-containing protein 17 (ADAM17) is recently reported to
be associated with metastasis in oral cancer. Increased levels of ADAM17 expres-
sion and concomitant CD44 cleavage is shown to be regulating CD44 cleavage
which is critical for orasphere formation or stemness and HNSCC tumorigenesis
(Fig. 11.3) (Kamarajan et al. 2013 ).
11.5.2 Cancer Stem Cells Remodel Tumor Microenvironment
Dynamic interplay between CSCs and TAMs modulates the molecular, functional
and phenotypic identities of both types of cell. The bidirectional interaction of polar-
ized macrophages with stem and progenitor cells plays a significant role in tissue
repair and remodeling by tumor-promoting conditions in the TME (Fig. 11.3). The
tumor cell produces CSF-1, IL-10, chemokines (CCL2, CCL18, CCL17 and
CXCL4) and ECM components and induces M2-like polarization of macrophages
promoting cancer progression (Fig. 11.3) (Raggi et al. 2016 ). In HNSCC, CSCs
overexpresses IL-6 R which upon interaction with IL-6 promotes tumorigenesis
(Nör et al. 2014 ). CSCs releases Peristonin that act on α 3 βv integrin to recruit TAMs.
Moreover, it is also reported that M-CSF secreted by CSCs promotes the differentia-
tion of MDSCs to TAMs (Fig. 11.3) (Raggi et al. 2016 ). It also shows that CSCs
secrete VEGF to promote neoangiogensis and support a local vascular environment
(Gilbertson and Rich 2007 ). The CSCs are reported to remodel the extracellular
matrix by promoting the degradation of matrix protein via various proteinases which
facilitates the migration of CSCs to distant sites. Hyaluronic acid (HA), an ECM
component upon interaction with stem cell surface marker CD44 initiates multiple
signaling cascades augmenting the oral tumor progression. The transmembrane pro-
tein CD44 is also a co-receptor for several receptor tyrosine kinases (RTKs) includ-
ing c-MET and EGFR. In oral cancer, ERK1/2 interaction with CD44 induces tumor
aggressiveness (Judd et al. 2012 ). Moreover, HA synthesizing enzyme hyaluronan
synthase 2 (HAS2) are highly synthesized in oral cancer and HAS2 down regulation
leads to CD44 dependent decrease of tumor cell migration (Wang et al. 2013 ). The
CSCs in HNSCC are characterized as high CD44 expressing phenotypes which
is a docking receptor necessary for MMP-9 (Zhang et al. 2012 ). Over expression of
transcription factor Snail promotes EMT in cancer cells to endorse stem-like proper-
ties and in this context snail mediated overexpression of MMPs is shown to be asso-
ciated with the high invasion capacity in UMSCC1 cell lines (Lin et al. 2011 ).
Moreover, EMMPRIN or CD147 (Extracellular matrix metallo-protease inducer) is
a cell surface protein and oral stem cell marker which mediates ECM remodeling
during invasion and metastasis via MMP induction (Huang et al. 2013 ). In HNSCC,
EMMPRIN-2 overexpression induces secretion of MMP-2, uPA, Cathepsin which
in turn promotes ECM remodelling and angiogenesis thereby paving the way
towards invasion and metastasis (Huang et al. 2014 ).
11 Oral Cancer Stem Cells Microenvironment