Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 2

This chapter will discuss the evidence for the factors and signaling pathways that are
involved in macrophage recruitment and polarization in the tumor microenvironment,
and it summarizes the role and underlying molecular mechanisms of macrophage
polarization in tumor angiogenesis and vessel normalization. In addition, an overview
of the potential of targeting TAM polarization for anticancer therapy will be provided.
1. INTRODUCTION
Angiogenesis, the formation of new capillary blood vessels from
preexisting vasculature, is one of the hallmarks of cancer ( Hanahan and
Weinberg, 2000 ). The tumor cell population gained the most attention so
far due to its capability of secreting proangiogenic factors that are criti-
cal in initiating tumor angiogenesis. However, tumor is not an island but
rather an ensemble performance of nonmalignant resident stromal cells
(also called tumor microenvironment), which includes cancer-associated
fibroblasts (CAFs), endothelial cells, bone-marrow-derived cells (BMDCs),
and extracellular matrix (ECM) ( Ahn and Brown, 2008 ; Chan et al., 2009 ;
Joyce, 2005 ). Among the tumor microenvironment, BMDCs are the major
stromal cell population, which represents about 15-20% of total cells in
solid tumors ( Du et al., 2008 ). Several findings demonstrate that BMDCs
are directly proportional to angiogenesis within the development of tumor
( Balkwill and Coussens, 2004 ; Schmid et al., 2011 ; Yang et al., 2004 , 2008 ),
thus suggesting their important role in regulating tumor angiogenesis.
BMDCs constitute extremely heterogeneous populations, which consist of
CD45+ vascular modulatory cells, endothelial progenitor cells (EPCs), and
pericyte progenitor cells (PPCs) ( De et al., 2005 ; Du et al., 2008 ; Grunewald
et al., 2006 ; Kopp et al., 2006 ; Lyden et al., 2001 ). CD45+ vascular modula-
tory cells make up the largest group of BMDCs. Such cells consist of several
subtypes, including tumor-associated macrophages (TAMs) and immature
monocytes including Tie2+ monocytes (TEMs), VEGFR1+ hemangio-
cytes, and CD11b+ myeloid cells ( Du et al., 2008 ). In the tumor micro-
environment, EPCs can incorporate into the vasculature and mature into
endothelial cells, while PPCs can envelop blood vessels and differentiate
into pericytes and vascular smooth muscle cells. Of the multiple stromal cell
types in solid tumors, TAMs are most significant for fostering tumor angio-
genesis and progression ( Condeelis and Pollard, 2006 ). It was shown that the
level of infiltrating macrophages is positively correlated with tumor angio-
genesis and poor prognosis in cancer patients ( Lewis and Pollard, 2006 ).
Macrophage depletion in mouse tumor models results in decrease of vascular
density. Conversely, overexpression of the colony-stimulating factor-1