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rocal paracrine interactions between the two cell compartments. In oral SCC, αvβ6-
dependent activation of TGFβ1 mediated fibroblast–myofibroblast transdifferentiation
occurs during tumor invasion and factors released from myofibroblasts favors tumor
growth (Kellermann et al. 2008 ; Marsh et al. 2011 ). Myofibroblast-released factors
like activin A, induces invasion and triggers the release of matrix MMP by OSCC
tumor cells. Moreover, presence of myofibroblasts in OSCCs correlates with aug-
mented production of MMP-2 and MMP-9 (Sobral et al. 2011 ).
11.4.4 Tumor-Associated Endothelial Cells
Tumor angiogenesis is a multifaceted process where formation of new blood vessels
occurs in response to interactions between tumor cells and endothelial cells (ECs),
growth factors, and ECM components. Tumor vessels are reported to stimulate the
progression of many human solid tumors, including HNSCC (Zeng et al. 2005 ).
Tumor-associated ECs (TAEs) and tumor vessels vary in many respects from their
normal counterparts. Unlike normal vessels, tumor vessels possess different struc-
tural features, such as leakiness, uneven thickness of the basement membrane and
fewer pericytes (Akino et al. 2009 ). Moreover, TAEs expressed typical endothelial
cell markers like CD31. Unexpectedly, TAEs are found to be cytogenetically abnor-
mal and relatively large and heterogeneous nuclei (Hida et al. 2004 ). Substantial
reports have documented that tumor cells secrete angiogenic growth factors that
stimulate EC proliferation to induce angiogenesis (Folkman 2002 ; Sparmann and
Bar-Sagi 2004 ). New tumor vessels penetrate into neoplastic growths and enhance
nutrients and oxygen supplying and oxygen and removes waste materials (Folkman
2002 ). According to reports, the angiogenic factors like VEGF and IL-8 released by
tumor or stromal cells are documented to directly bind to their receptors on ECs to
trigger angiogenesis by encouraging endothelial sprouting, branching, differentia-
tion and survival (Folkman 2002 ; Sparmann and Bar-Sagi 2004 ). Notch ligand
Jagged1 play a critical role in angiogenesis in HNSCC. Report indicates that tumor
cells induced by growth factors via MAPK triggered Notch activation in neighbor-
ing endothelial cells which promoted capillary-like sprout formation suggesting the
direct interplay between tumor cells and ECs that promotes angiogenesis. Jagged1
enhances neovascularization and HNSCC growth in vivo and it expression is signifi-
cantly correlated with tumor blood vessel content (Zeng et al. 2005 ).
11.5 Crosstalk Between Cancer Stem Cells and Tumor
Microenvironment
Recently, two interesting model of tumor evolution was proposed by Castaño et al.
keeping an analogy with bed and bug to connect the association between the TME
and CSCs. One of models proposes that “The bed (TME) determines the bug (CSC)
P.P. Naik et al.