Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 12

Table 1.3 The factors involved in regulating TAM polarization
TAM polarization Factor types Major factors and References
M2 polarization Growth factors VEGF ( De, 2012 ; Linde et al., 2012 ); ADM
( Chen et al., 2011 ); PlGF ( Rolny et al.,
2011 ); TGF-β, GM-CSF ( Biswas and
Mantovani, 2010 ; Galli et al., 2011 )
Chemokines CCL2 ( Roca et al., 2009 )
Interleukins IL-4, IL-10, IL-13, IL-21, IL-33 ( Biswas
and Mantovani, 2010 ; Galli et al., 2011 );
IL-6 ( Roca et al., 2009 )
Others DcR3 ( Tai et al., 2012 ); ANG-2 ( Coffelt
et al., 2010 )
M1 polarization HRG ( Rolny et al., 2011 ); AMA ( Chen et al., 2011 );
Celecoxib (COX-2 inhibitor) ( Nakanishi et al., 2011 );
MENK ( Chen e t al., 2012a )
GM-CSF, granulocyte/macrophage colony stimulating factor.
Moreover, each member of this loop can induce macrophage polarization
to M2 phenotype by upregulation of CD206+ and CD14+/CD206+ cell
populations, via the inhibition of caspase-8 cleavage and enhanced autoph-
agy ( Roca et al., 2009 ).
Decoy receptor 3 (DcR3) is a soluble protein belonging to the TNF
receptor family and that is overexpressed in cancer cells. DcR3 expression
in tumors is correlated with poor prognosis in a variety of tumors. DcR3
modulates TAMs polarization to M2 phenotype by downregulating MHC
class II expression through an epigenetic mechanism ( Tai et al., 2012 ).
Angiopoietin 2 (ANG-2) is an angiogenic peptide released by endothelial
cells, which plays an essential role in modulating angiogenesis and vascular
homeostasis ( Augustin et al., 2009 ). Besides its angiogenic function, ANG-2
increases the expression of M2-like genes, such as IL-10, CD206 and CCL17,
in macrophages in vitro. Furthermore, in vivo studies showed that ANG-2
overexpression in a mouse tumor model induces higher vascular density and
M2 TAM infiltration ( Coffelt et al., 2010 ). Altogether, these findings shed
light on the critical factors skewing macrophages toward M2 phenotype in
the tumor microenvironment, which in turn promote angiogenesis, tumor
growth and metastasis, and also provide some potential targets for anticancer
therapies.
The potential molecules involved in TAMs polarization from M2 to M1
phenotype are also documented. Histidine-rich glycoprotein (HRG) is a hep-
arin-binding protein, and its expression is downregulated in tumors ( Rolny