Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 6

oxygen species (ROS) and NO ( Qian and Pollard, 2010 ). Conversely, M2
macrophages show high expression of mannose receptor (CD206), galac-
tose receptor, arginase I, IL-10, IL-1 decoy receptor, and IL-1RA, and low
expression of IL-12 ( Biswas and Mantovani, 2010 ; Gordon and Taylor, 2005 ;
Mantovani et al., 2002 ; Mantovani, 2008 ). Recent study demonstrated that
M2 macrophages specifically express and secrete migration-stimulating fac-
tor (MSF), a truncated isoform of fibronectin that is considered as a new
marker for M2 macrophages ( Solinas et al., 2010 ). Given their different
gene expression profiles, the functions of M1 and M2 macrophages are also
different. M1 macrophages are able to kill microorganisms and tumor cells
by activating immune responses. By contrast, M2 macrophages are gener-
ally considered as immunosuppressive cells, which promote angiogenesis,
and tissue remodeling and repair ( Mantovani et al., 2002 ). TAMs are always
biased toward the M2 phenotype ( Mantovani and Sica, 2010 ). Monocytes
recruitment into tumors, the polarization of macrophages in tumors and its
functions and underlying mechanisms in promoting tumor malignancy and
in remodeling vascular network including angiogenesis and vessel normal-
ization, are discussed below.
3. RECRUITMENT OF MONOCYTES INTO TUMORS
It has been shown that there are higher numbers of macrophages in
tumor tissues than surrounding normal tissues ( Murdoch et al., 2008 ). These
cells initially originate from monocytes that extravasate across the tumor
vessels from blood and differentiate into TAMs following their recruit-
ment into tumors. The chemoattractants including chemokines and cyto-
kines secreted from both malignant and stromal cells that contribute to
the recruitment of monocytes ( Murdoch et al., 2008 , 2004 ). Among these
chemoattractants, chemokine (C-C motif ) ligand 2 (CCL2, also known
as monocyte chemoattractant protein-1, MCP-1) is the main one ( Bot-
tazzi et al., 1983 , 1992 ; Loberg et al., 2007 ; Murdoch et al., 2008 ), which is
widely expressed in multiple types of tumors ( Bingle et al., 2002 ; Loberg
et al., 2006 ; Murdoch et al., 2008 ). Both the experimental studies using
CCL2 overexpression and knockdown approaches, and the investigation
on human tumor biopsies support the concept that CCL2 plays a pivotal
role in monocytes recruitment into tumors ( Murdoch et al., 2004 ). Recent
studies showed that CCL2 is responsible for the recruitment of inflamma-
tory monocytes (which express CCR2, the receptor for CCL2), which in
turn promotes tumor metastasis. Inhibition of CCL2-CCR2 signaling or