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through the PI3k-Akt pathway and promoted the acquisition of a stem-like pheno-
type in HNSCC as shown by downregulation of epithelial markers (E-cadherin,
Desmoplakin), upregulation of mesenchymal markers (Vimentin, N-Cadherin),
induction of cell motility, upregulation of ALDH and CD44 and growth as non-
adherent orospheres. Moreover, endothelial cell-secreted factors is shown to stimu-
late Bmi-1 expression and promote the self-renewal of cancer stem cells in HNSCC
(Krishnamurthy et al. 2010 ). The endothelial cells in HNSCC tumors are shown to
secrete more IL-6 and a higher level IL-6R are expressed in CSCs. Their interaction
in turn directs the JAK/STAT to encourage survival and self-renewal of CSCs
(Fig. 11.3) (Duffy et al. 2008 ). Impeding the interaction between endothelial cells
derived IL-6 and IL-6R is found to prevent STAT-3 signaling and cisplatin induced
stemness (Neiva et al. 2009 ). It was also reported to induce stemness through the
Bmi-1 and CD44 overexpression in head and neck cancer (Nör et al. 2014 ). Factors
secreted by CSCs promote the differentiation of MDSC population into TAMs
(Raggi et al. 2016 ). Moreover, TAMs undergo the process of ‘immune edition’
where the potentially danger antitumorigenic macrophage function is switched to
protumorigenic immune suppression favoring antitumor immunity evasion
(Ramanathan and Jagannathan 2014 ). TAMs operate various paracrine signaling
loops in the microenvironment that facilitates invasion and metastasis. TAMs, in
one hand, are shown to secrete EGF that drives tumor progression whereas on the
other hand OSCC cells produce CSF-1 that urges further TAM proliferation and
tumor infiltration. TAMs are also shown to secrete macrophage migration inhibitory
factor (MMIF) that allows neutrophil chemo-attraction and activation further induc-
ing the secretion of protumorigenic chemokines like IL-4, IL-8, IL-10, IL-13, TGF-
β, TNF-α and GM-CSF that induce immunosuppression (Fig. 11.3) (Markwell and
Weed 2015 ). Furthermore, CAFs promote immunosuppression and evasion of
immune surveillance by preferentially inducing the T cell apoptosis and Treg activa-
tion in OSCC via the production of a higher level of cytokines like IL-6, CXCL8,
TNF, TGFβ1 and VEGFA along with the co-regulatory molecules like B7H1 and
B7DC (Fig. 11.3) (Takahashi et al. 2015 ). The SDF-1/CXCR4 signaling is believed
to promote metastasis and therapy resistance attributes of CSCs wherein the CSCs
overexpresses CXCR4 and responds to a chemotactic gradient of SDF-1 (Fig. 11.3).
In OSCC, SDF-1 induces lymph node metastasis via activation of both the ERK1/2
and Akt/PKB cascades (Uchida et al. 2013 ).
11.5.1.5 Matrix Remodeling Enzymes and Cancer Stem Cells
Matrix metalloproteinases (MMPs) are important class of zinc-dependent endopep-
tidases that are involved in degradation of matrix proteins that facilitates invasion
and metastasis. The over expression of MMPs is also reported to induce acquisition
of CSC-like properties in oral cancer (Fig. 11.3). Up regulation of membrane type 1
matrix metalloproteinase (MT1-MMP), a cell surface matrix degrading proteinase
decreased the expression of epithelial markers (E-cadherin, cytokeratin18 and
β-catenin) and increased the expression of mesenchymal markers (vimentin and
P.P. Naik et al.