217poor prognosis in many cancers (Bhowmick et al. 2004 ). Other markers includes
tenascin-C, periostin, NG-2, PDGF receptor-a/b, FSP (S100A4), FAP vimentin, type
I collagen, prolyl 4-hydroxylase and fibroblast surface protein. For the first time, in
2004, CAFs in stroma of oral SCC were reported (Barth et al. 2004 ) and since then,
massive studies have emphasized their importance in disease progression. High fre-
quency of CAFs in OSCCs is significantly correlated with invasion, disease progres-
sion, tumor recurrence and poor patient prognosis (Kawashiri et al. 2009 ; Vered
et al. 2010 ). The growth factors, matrix proteins and proteases secreted by fibro-
blasts and tumor cells create a tumor microenvironment that facilitates tumor main-
tenance, invasion and metastasis via the paracrine interaction of epithelial tumor
cells and stromal cells (Mueller and Fusenig 2002 ). Moreover, in HNSCC CAFs are
also characterized by expression of integrin α6, an important molecule in cell adhe-
sion and surface signaling. Integrin α6 is reported to bind with ECM component
laminins and interacts with CDKN1A, which alters the cell cycle progression. Also,
upregulation of α-SMA and integrin-α6 was demonstrated to be highly correlated
with poor clinical outcome in oral cancer (Lim et al. 2011 ). The CAFs secrete vari-
ous cytokines like TGF-β, CXCL12, paracrine motility factor and hepatocyte growth
factor (HGF) (Leef and Thomas 2013 ). The TGF-β promotes immune suppression
whereas upon binding with CXCR4, CXCL12 upregulates MMP9 and HIF-1α
expression that promotes EMT (Ishikawa et al. 2009 ; De Wever et al. 2008 ). Recently,
it is proposed that fibroblast-derived HGF and SDF-1 seem to portray a crucial role
in the mutual interactions between oral SCC cells and underlying stromal fibroblasts
that consequents in the local invasion (Daly et al. 2008 ). Moreover, report elucidates
that the paracrine interaction between oral carcinoma cells SCC-25 and CAFs pro-
vides a mechanistic background for the gene regulation of MMPs which causes to
poor clinical outcome in head and neck cancer (Fullár et al. 2012 ). Furthermore, the
presence of MMP-1 (Collagenase 1) expression in the stromal compartment of inva-
sive head and neck cancer suggests that its expression in peritumoral fibroblasts is
induced in paracrine manner by tumor cells and tumor- infiltrating inflammatory
cells (Johansson et al. 1997 ; Westermarck et al. 2000 ). Comparison of the secretome
profiles between CAFs and normal oral fibroblasts (NOF) using mass spectrometry-
based proteomics and biological network analysis reveals that proteins engaged in
ECM organization and disassembly and collagen metabolism are highly upregu-
lated. Moreover, the expression of type I collagen N-terminal propeptide (PINP) was
found to associate in vivo with CAFs in the tumor front and promoted shortened
survival of oral cancer patients (Bagordakis et al. 2016 ).
Myofibroblasts are cells that display a phenotype between fibroblasts and smooth
muscle cells α-SMA expression (Chaponnier et al. 2006 ). Myofibroblasts secrete a
large repertoire of chemokines, cytokines, inflammatory mediators, growth factors,
neurotransmitters, hormones, adhesion proteins and most abundantly ECM proteins
(Powell et al. 2005 ). Barth et al. in 2004 for the first time produced evidence in favor
of a role for myofibroblasts in OSCC and later of this year, Lewis et al. demon-
strated that myofibroblasts when induced TGF-β1 by release HGF to promotes
OSCC invasion in vitro (Barth et al. 2004 ; Lewis et al. 2004 ). Myofibroblasts
activation in the vicinity of tumor cells in stroma encourages the setting up of recip-
11 Oral Cancer Stem Cells Microenvironment