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et al., 2011 ). Both pharmacological and genetic approaches indicate that HRG
inhibits tumor angiogenesis, growth and metastasis by promoting immune
responses ( Rolny et al., 2011 ; Tugues et al., 2012 ), especially by skewing TAM
polarization away from the M2 phenotype to a tumor-inhibiting M1 pheno-
type via downregulation of PlGF ( Rolny et al., 2011 ). Adrenomedullin22-52
(AMA), an antagonist of ADM receptors, inhibits tumor growth by inducing
M2 macrophages polarization to M1 phenotype through downregulation of
ADM expression in an autocrine manner ( Chen et al., 2011 ). Cyclooxygen-
ase-2 (COX-2) is constitutively expressed in various tumors, and TAMs are
considered as the major source of COX-2 ( Inaba et al., 2003 ). It has been
shown that celecoxib, an inhibitor of COX-2, induces TAM polarization from
M2 to M1 phenotype in intestinal tumors ( Nakanishi et al., 2011 ). Met-
enkephalin (MENK) is an endogenous neuropeptide, which has the ability to
inhibit tumor growth and metastasis ( Kuniyasu et al., 2010 ). The expression
of MENK in tumors, such as colorectal cancer, is associated with tumor-
infiltrating immune cells ( Ohmori et al., 2009 ). It was recently demonstrated
that MENK induces TAM polarization to M1 phenotype, as indicated by the
downregulation of CD206 and arginase I ( Chen et al., 2012a ). Taken together,
these evidences provide novel insights into potential targets for efficient tumor
therapeutic strategies through TAM polarization from M2 to M1 phenotype.
4.2.2. Molecular Mechanisms of Macrophage Polarization in the
Tumor Microenvironment
Nuclear factor-kappaB (NF-κB) signaling is a key regulator that links
inflammation and cancer ( Ben-Neriah and Karin, 2011 ; Grivennikov et al.,
2010 ). The potential role of NF-κB signaling in macrophages polarization
was validated in both in vitro and in vivo experiments. It was shown that
macrophages polarization to M2 phenotype requires NF-κB activation.
When NF-κB signaling is specifically inhibited by blocking IκB kinase
(IKK)β, the major activator of NF-κB, TAMs are switched to M1 pheno-
type, which in turn inhibits tumor growth ( Hagemann et al., 2008 ). On the
other hand, overexpression of p50 NF-κB overexpression in TAMs inhibits
M1 inflammatory responses and antitumor resistance ( Saccani et al., 2006 ).
It was recently demonstrated that Wnt5a induces a negative feedback loop
of NF-κB activation in macrophages and has the ability to skew macro-
phage polarization to M2 phenotype in breast cancer patients ( Bergenfelz
et al., 2012 ). Notch signaling is another important mediator in the deter-
mination of M1 versus M2 polarization of TAMs. Notch signaling activa-
tion induces macrophage polarization to M1 phenotype, whereas blockade
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