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Figure 1.3
Role and underlying mechanisms of TAMs and their polarization away from
M2 to M1 phenotype in vessel normalization
. In established solid tumors, blood vessels
always exhibit structural and functional abnormalities, which may be induced by the
excess of proangiogenic factors derived from TAMs skewing to the M2 phenotype. Tumor
vessel normalization is emerging as a new therapeutic strategy for cancer. Myeloid cells,
such as macrophages, are involved in tumor vessel disorganization. Genetic depletion
of VEGF in myeloid cells or PlGF in macrophages induces tumor vessel normalization.
Furthermore, HRG as well as the blockade of PlGF or VEGF signals in TAMs contribute to
TAM skewing toward the M1 phenotype and tumor vessel normalization. BM, basement
membrane; EC, endothelial cell. For color version of this figure, the reader is referred to
the online version of this topic.
TAM phenotype from M2 to M1, without affecting TAM density (
Rolny
et al., 2011
).
VEGF is expressed in TAMs (usually M2 phenotype) of both human and
mouse mammary tumors (
Qian and Pollard, 2010
). Given the importance of
VEGF for angiogenesis in health and disease, it has been become the prime
target for antiangiogenic therapies in cancer (
Ellis and Hicklin, 2008
).VEGF
inhibition not only inhibits tumor angiogenesis and tumor progression
but also induces vessel normalization (
Jain, 2005
). The blockade of VEGF
expression results in increased pericyte coverage and vessel maturation, and
decreased tumor vessel permeability (
Abramovitch et al., 1999
;
Tong et al.,
2004
;
Weisshardt et al., 2012
). Interestingly, myeloid cell-derivedVEGF is also
very important in this process, as demonstrated by the fact that VEGF dele-
tion in these inflammatory cells promotes vessel normalization and matura-
tion (
Stockmann et al., 2008
). Recent studies demonstrated that VEGF-A
is a potent chemoattractant for macrophages and that the majority of mac-
rophages recruited to VEGF-A-expressing tumors exhibit M2 phenotype,
thus implying an important role of VEGF-A in macrophage recruitment
and polarization (
De, 2012
;
Linde et al., 2012
). These data strongly support
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