Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 14

of this signaling causes macrophage polarization to M2 phenotype ( Wang
et al., 2010 ). These studies support the important function for NF-κB and
Notch signaling pathways in macrophage polarization. Furthermore, several
transcription factors, such as signal transducer and activator of transcription
6 (Stat6), peroxisome proliferator-activated receptor-gamma (PPARγ), and
c-Myc, also play important roles in this process ( Bouhlel et al., 2007 ). Stat6
is a facilitator of PPARγ-regulated gene expression in macrophages ( Szanto
et al., 2010 ), which is responsible for epigenetic changes mediated by the
histone demethylase Jumonji domain containing 3 (Jmjd3), which in turn
leads to M2 polarization ( Ishii et al., 2009 ). c-Myc is required for the polar-
ization of macrophages into M2 phenotype by inducing a significant set of
M2-related genes through Stat6 and PPARγ pathways ( Pello et al., 2012 ).
Autophagy is a key cellular process widely occurring in eukaryotic cells
( Reggiori and Klionsky, 2002 ). In macrophages, autophagy is an important
regulator of innate immunity ( Xu et al., 2007 ). Moreover, the induction
of autophagy is pivotal for the survival and differentiation of monocytes
( Zhang et al., 2012b ). CCL2 and IL-6 treatment induces macrophages
skewing to M2 phenotype, a process that is also accompanied by induction
of autophagy. Inhibition of caspase-8 can mimic similar functions in mac-
rophages. However, combination treatment with autophagy inhibitors or
lysosomal protease inhibitors, and caspase-8 inhibitor results in a significant
decrease in CD206+ and CD14+/CD206+ cell populations when com-
pared with caspase-8 inhibitor treatment alone, in agreement with the con-
cept that autophagy plays a significant role in M2 macrophage polarization
( Roca et al., 2009 ). The mTOR kinase is a major regulator of autophagy
( Jung et al., 2010 ), and mTOR positively regulates immune cell activation
( Weichhart and Saemann, 2008 ). The TSC2-mTOR signaling pathway is
critical for macrophage polarization, as demonstrated by the fact that when
this pathway is inhibited by rapamycin or activated by TSC2 knockdown,
LPS-stimulated monocytes are induced to differentiate into M1 or M2
macrophages, respectively ( Chen et al., 2012b ).
These findings highlight that the characterization of the molecular
mechanisms involved in macrophage polarization within the tumor micro-
environment is essential for improving our understanding of cancer biology.
In summary, upon stimulation by different factors in the tumor microen-
vironment, macrophage gene transcription is regulated through specific
signaling pathways and transcription factors, thus leading to macrophage
polarization to M1 or M2 phenotypes to exert different functions in tumor
angiogenesis, growth and progression ( Fig. 1.1 ).