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effects of M1 TAMs (Sica et al. 2006 ; Zamarron and Chen 2011 ). Higher level of
TAM infiltration is described to associate with higher tumor state and lymph node
metastasis (Li et al. 2002 ; Marcus et al. 2004 ; Liu et al. 2008 ). Furthermore, TAMs
play a protumor role in mucoepidermoid carcinoma and it is highly correlated with
angiogenesis, invasion and migration (He et al. 2014 ). Moreover, it is reported that
Axl signaling in oral cancer promotes polarizing of TAMs toward a M2 phenotype
via Axl/PI3/Akt/NF-kB pathway which subsequent in poor prognosis (Chiu et al.
2015 ). Recently, it has been proposed that infiltrating CD11b+ myeloid cells in the
vascularization showed characteristics of M2 macrophages and promoted neovas-
cularization and tumor progression in recurrence after irradiation compared to non-
irradiated tumors in oral carcinoma. Moreover, CD11b+ myeloid cells and CD206+
M2 macrophages get intensified during recurrence after radiotherapy in human oral
cancer specimens (Okubo et al. 2016 ). In HNSCC, TAMs are reported to produce
an elevated level of inflammatory cytokine called macrophage migration inhibitory
factor (MIF) that stimulates neutrophils. The neutrophils are recruited to HNSCC
tumor by MIF via a CXCR2 mechanism which further leads to tumor invasiveness
(Dumitru et al. 2011 ). The activated neutrophil induces ROS-mediated genetic
instability, increases invasion via HGF and triggers angiogenesis via MMP9 and
VEGF (Galdiero et al. 2013 ). Another report indicates that VEGF and IL-18 released
by neutrophils promote neoangiogenesis and encourage the benign tumour cells to
acquire metastatic phenotype in the early stage of oral cavity cancer (Karin and
Greten 2005 ). Expression of signal regulatory protein α (SIRPα), a surface protein
significantly correlates with the expression of CD68 and CD163 on macrophages.
Again, the inhibition of SIRPα was found to reduce the phagocytosis ability and
IL-6 and TNF-α production of macrophages (Ye et al. 2016 ). Furthermore, it is
reported that TME and the peripheral blood in HNSCC contains an increased loads
of TAMs with increased levels TGF-β which trigger immunosuppression and tumor
growth in oral cancer (Costa et al. 2013 ). Moreover, TAMs produces ROS and pros-
taglandins which support inflammation and tumorigenesis (Karin and Greten 2005 ;
Coussens and Werb 2002 ).
11.4.3 Tumor-Associated Fibroblasts Cells
Fibroblasts shape the structural framework, the tumor stroma of tissues by synthesiz-
ing ECM component (Brouty-Boyé 2005 ). Fibroblasts in tumor stroma have been
designated peritumoral fibroblasts, reactive stroma, cancer-associated fibroblasts
(CAFs) and myofibroblasts. Activated fibroblasts are prominent contributors in car-
cinogenesis of oral cancer. It reported that fibroblasts inhibit early stages of tumor
progression however at later stages in cancer CAFs promote both tumor growth and
progression. Generally, CAFs evolve from circulating fibroblasts and co-evolve
along with tumor giving rise to a distinct phenotype. A common marker indicating
CAF phenotype is the α-smooth muscle actin (α -SMA) and a greater proportion of
α-SMA-positive peritumoral fibroblasts have been demonstrated to associate with
P.P. Naik et al.