Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 22

a mechanism where TAMs regulates vessel normalization by the distinct
expression and production of VEGF in M1 or M2 macrophages. Further
studies suggest that VEGF inhibition induces tumor vessel normalization in
part by the remodeling of the vascular basement membrane and the sur-
rounding ECM ( Vosseler et al., 2005 ; Winkler et al., 2004 ). It is well estab-
lished that ECM influences tumor growth and progression and regulates
vascular morphogenesis in tumors ( Bauer et al., 2009 ). Integrins is a family of
heterodimeric receptors that link the surface of cells to different ECM com-
ponents, thus mediating the transduction of cell-ECM signals. Some integ-
rins, such as α5β3, α5β5, α5β1 and α6β5, are upregulated in tumors ( Joyce,
2005 ). β3-intergrin is a promoter of endothelial cell survival during tumor
angiogenesis ( Brooks et al., 1994 ), and it is expressed in macrophages ( Frig-
geri et al., 2010 ; Zhang et al., 2012a ). Additionally, β3-intergrin seems to play
a significant role in macrophage polarization, as demonstrated by findings
that β3-intergrin knockout mice display impaired muscle regeneration and
increased fibrosis due to the infiltration of macrophages that are polarized
to M2 phenotype ( Zhang et al., 2012a ). Furthermore, β3-intergrin-binding
peptide has the ability to induce vessel normalization in spinal cord injury
mouse mode ( Han et al., 2010 ). However, more studies are needed to clarify
if TAMs produce β3-intergrin, and the significance of TAM-derived β3-
intergrin for macrophage polarization and vessel normalization in tumors.
7. CONCLUDING REMARKS
Given the significant role of angiogenesis in solid tumor growth
and metastasis, antiangiogenic strategies offered a promising perspective
for cancer therapies. Bevacizumab, a monoclonal antibody targetingVEGF,
is the first antiangiogenic agent used in clinic. When administered as a
single agent in patients with solid tumors, bevacizumab produces modest
responses ( Cobleigh et al., 2003 ; Yang et al., 2003 ), but this treatment does
not have the benefits of long-term survival ( Mayer, 2004 ). Interestingly,
when administered in combination with chemotherapeutic agents, bevaci-
zumab can produce an unprecedented increase in cancer patients survival
compared with chemotherapy alone ( Hurwitz et al., 2004 ). These findings
highlight the relevance of anti-VEGF activity in tumor angiogenesis inhi-
bition and vessel normalization, and also pave the way for the development
of new strategies in antiangiogenic therapies. Tumor progression is modu-
lated by the synergistic effects coming from both tumor cells and stromal
cells. Tumor angiogenesis regulation by TAMs, the most abundant stromal