Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization

Abstract

Angiogenesis, the formation of new capillary blood vessels from preexisting vasculature, is one of the hallmarks of cancer that is pivotal for tumor growth and metastasis. Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Thus, the combination of angiogenesis inhibition and vessel normalization is a potential strategy for anticancer therapy. The solid tumor is composed of not only cancer cells, but also the nonmalignant resident stromal cells, such as bone-marrow-derived cells (BMDCs) and cancer-associated fibroblasts (CAFs). Tumor-associated macrophages (TAMs) are the most abundant cell components of BMDCs, which play a significant role in promoting tumor progression. Accumulating evidences from both patient biopsies and experimental animal models have shown that TAMs function in tumor angiogenesis and vessel abnormalization in a density- and phenotype-dependent manner. 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.

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 critical 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 modulatory 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+ hemangiocytes, and CD11b+ myeloid cells (Du et al., 2008). In the tumor microenvironment, 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 angiogenesis and progression (Condeelis and Pollard, 2006). It was shown that the level of infiltrating macrophages is positively correlated with tumor angiogenesis 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 (CSF-1) induces the enhancement of macrophage recruitment, causing an increase of tumor angiogenesis (Lewis and Pollard, 2006; Lin et al., 2001).

Angiogenesis is well known to promote tumor growth and metastasis. However, unlike the healthy vasculature, tumor vessels are highly chaotic, poorly organized and dysfunctional (vessel abnormalization), due to the excessive production of proangiogenic factors (De et al., 2011; Jain, 2005). These abnormalities of tumor vessels result in a hypoxic tumor microenvironment and represent physiological barriers for the delivery of cancer therapeutic agents (Fokas et al., 2012). The restoration of the balance between pro- and antiangiogenic factors production in tumor microenvironment may play a pivotal role in modulating the normalization of the structure of tumor blood vessels (Jain, 2005). Some important molecules, such as vascular endothelial growth factor (VEGF) (Jain, 2005), placental growth factor (PlGF) (Fischer et al., 2007; Fokas et al., 2012; Hedlund et al., 2009; Van et al., 2010), platelet-derived growth factors (PDGFs), angiopoietins, HIF-prolyl hydroxylases (PHD) (De et al., 2011), Rgs5 (Hamzah et al., 2008), CD160 receptor (Chabot et al., 2011), nitric oxide (NO) and EGF receptor (Kashiwagi et al., 2008), derived from either tumor cells or stromal cells, were reported to participate in regulating vessel normalization. In addition, intracellular signaling pathways, such as PI3K/mTOR pathway (Fokas et al., 2012; Qayum et al., 2012), are also involved in regulating vessel normalization. Understanding molecular mechanisms of vessel normalization may ultimately lead to more effective therapeutic strategies against cancer.

Interestingly, VEGF ablation in inflammatory cells promotes vessel normalization and vessel maturation (Stockmann et al., 2008), suggesting that inflammatory cells, such as macrophages, play a significant role in these processes. Depending on the activation states induced by the microenvironment, macrophages can be designated as either classically activated (M1 phenotype) or alternatively activated (M2 phenotype) (Sica et al., 2008). The different phenotypes of macrophages may exhibit opposing effects in blood vessels modeling and tumor progression. M2, rather than M1, macrophages were defined as the proangiogenic phenotype due to their ability to secrete factors that promote angiogenesis (Lamagna et al., 2006). Moreover, M2 macrophages induce vessel abnormalization, while M1 macrophages lead to vessel normalization (Rolny et al., 2011). These evidences suggest the significant role of TAM polarization from the M2 phenotype to the M1 phenotype in the regulation of tumor angiogenesis and vessel normalization. Thus, tumor vascular network, including angiogenesis and vessel normalization, is affected by the dynamic changes in macrophages phenotypes. The current review will summarize a comprehensive overview about the basic biology of macrophages, monocytes recruitment and the polarization of macrophages in the tumor microenvironment, as well as the function and underlying mechanisms of TAM polarization in the regulation of tumor angiogenesis and vessel normalization. Furthermore, the potential of targeting TAMs in the tumor microenvironment for anticancer therapy by tumor angiogenesis inhibition and vessel normalization will also be discussed.