Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 23

cells, has largely been investigated and was shown that macrophages deple-
tion decreases tumor angiogenesis and progression ( Lin et al., 2001 , 2006 ),
thus pointing at TAMs as a potential target for cancer therapies. Moreover,
increasing evidence suggest that macrophage polarization away from the
M2 phenotype to the M1 phenotype can be regarded as another impor-
tant strategy for cancer therapies ( Sica et al., 2008 ). Recent studies indicate
that HRG functions in vivo to repress M2 macrophage skewing, which
results in both tumor angiogenesis inhibition and vessel normalization,
while PlGF displays the opposing effects ( Rolny et al., 2011 ). A number of
findings support the concept that TAMs are educated by tumor cells and
tumor microenvironment, and “re-education” of TAMs is now emerging
as a novel strategy for cancer therapies via tumor angiogenesis inhibi-
tion and vessel normalization ( Fig. 1.4 ). However, much work remains
Figure 1.4 Cancer therapeutic strategy by targeting TAM polarization to inhibit tumor
angiogenesis and normalize tumor vessels . TAMs exhibit the proangiogenic M2 phe-
notype, which not only promotes tumor angiogenesis but also leads to the abnormal
tumor vessels. Conversely, M1 macrophages are considered as antiangiogenic and have
the opposing effect in the modulation of vascular network. The phenotype of macro-
phages can be shifted based on the tumor microenvironment. For example, HRG and
AMA, an antagonist of ADM receptors, or MENK can polarize TAMs away from the M2 to
the M1 phenotype, which in turn inhibits tumor angiogenesis and/or normalizes tumor
vessels. By contrast, proangiogenic factors such as PlGF, VEGF, ADM and CCL2 have the
opposing effects. New cancer therapeutic strategies are being developed not only for
inhibiting tumor angiogenesis but also for normalizing tumor vessels by the “re-educa-
tion” of TAM polarization from an M2 phenotype to an M1 phenotype. For color version
of this igure, the reader is referred to the online version of this topic.