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(
Chen et al., 2011
), which not only supports the concept that macrophage
phenotypes can be changed according to different tumor microenviron-
ments but also provides a new insight into the dynamic nature of TAM phe-
notypes during the tumor growth. Given the opposing effects of M1 and
M2 macrophages for tumor progression, there is a great deal of interest in
elucidating the factors that regulate macrophage polarization in the tumor
microenvironment, as well as their underlying molecular mechanisms.
4.2.1. Macrophage Polarization-Related Factors in the Tumor
Microenvironment
Macrophage polarization-related factors have been recently reviewed, and
these include M2 phenotype polarization factors, such as IL-4, IL-10, IL-13,
IL-21, IL-33, CCL2 and transforming growth factor-β (TGF-β), and M1
phenotype polarization factors, such as IFN-γ and LPS (
Biswas and Man-
tovani, 2010
;
Galli et al., 2011
). Macrophage polarization in the tumor
microenvironment is regulated by a number of factors including growth
factors, chemokines, interleukins and other molecules (
Table 1.3
).We herein
put an emphasis on summarizing recent research progress in this topic.
VEGF plays an important role in tumor angiogenesis and progression.
A recent study demonstrated that VEGF-A-induced skin carcinogenesis
depends on the alternative activation of macrophages, suggesting a role for
VEGF-A in M2 macrophage polarization. However, this effect is indirect
since VEGF-A itself does not induce M2 macrophage polarization in vitro
(
Linde et al., 2012
). Similar to VEGF, adrenomedullin (ADM) is another
angiogenic peptide, and it is widely expressed in a variety of tumors (
Zudaire
et al., 2003
). In melanoma, TAMs are the major source of ADM, and TAM-
derived ADM upregulates CD206 expression and arginase I production,
and downregulates inducible NO synthase (iNOS) production, thus shew-
ing macrophages toward the M2 phenotype in an autocrine manner (
Chen
et al., 2011
).
As mentioned above, CCL2 is the main chemoattractant that is respon-
sible for the recruitment monocytes into the tumor sites (
Murdoch et al.,
2008
). IL-6, one of the most abundant cytokines in the tumor microenvi-
ronment, is typically expressed by cancer cells (
Siegall et al., 1990
). Interest-
ingly, expression of CCL2 and IL-6 in myeloid cells is induced in a reciprocal
manner. CCL2 expression in macrophages shows a twofold increase upon
IL-6 treatment, and IL-6 expression exhibits fivefold upregulation upon
CCL2 stimulation. Therefore, CCL2 and IL-6 induce an amplification loop
that affects tumor microenvironment, including TAMs and cancer cells.
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