Chapter One - Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies
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.
Section snippets
Macrophages and Their Phenotypes
Macrophages are a major population in the mononuclear phagocytic lineage deriving from bone marrow progenitor cells (Doulatov et al., 2010). In contrast to the other mononuclear phagocytic lineages, such as dendritic cells (DCs), macrophages have a longer lifespan (from hours to possibly years) and display proteolytic and catabolic activities, such as phagocytosis, which allow them to be highly effective in the ingestion of pathogens, in the clearance of dead cells and debris, and in the
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 recruitment into tumors. The chemoattractants including chemokines and cytokines secreted from both malignant and stromal cells that contribute to the recruitment of monocytes (Murdoch et al., 2008, 2004). Among these
Macrophages and Cancer
Studies from patient biopsies strongly suggest that macrophages contribute to tumorigenesis. Table 1.2 lists the current knowledge on the correlation between TAM levels and patient survival in a wide range of human tumors. The clinical data suggest that TAM density is correlated with poor prognosis in most tumors. These clinical observations are well supported by experimental studies using macrophages depletion or overexpression approaches. For example, genetic ablation of the M-CSF in
Role and Mechanisms of TAMs
In most tumors, blood vessels are dramatically increased during the transition from benign to malignant states, a process regarded as an angiogenic switch and that is influenced by the tumor microenvironment (Qian and Pollard, 2010). The potential role of macrophages in modulating tumor angiogenesis was first proposed by Sunderkotter et al. in 1991 (Sunderkotter et al., 1991). After that, a variety of studies have shown that TAMs are often found in the surrounding of blood vessels of solid
Role of TAMs and Their Polarization in Vessel Normalization
In the hypoxic microenvironment, TAMs produce an excess of angiogenic molecules, which not only promote tumor angiogenesis but also induce tumor vessel abnormalization. By impairing oxygen delivery, abnormal vessels trigger a vicious cycle of nonproductive angiogenesis, which creates a hostile microenvironment from where cancer cells escape through leaky vessels, thus rendering tumors less responsive to chemoradiation (De et al., 2011; Jain, 2005). Indeed, antiangiogenic vessel normalization
Concluding Remarks
Given the significant role of angiogenesis in solid tumor growth and metastasis, antiangiogenic strategies offered a promising perspective for cancer therapies. Bevacizumab, a monoclonal antibody targeting VEGF, is the first antiangiogenic agent used in clinic. When administered as a single agent in patients with solid tumors, bevacizumab produces modest responses (Cobleigh et al., 2003; Yang et al., 2003), but this treatment does not have the benefits of long-term survival (Mayer, 2004).
Acknowledgments
This work was supported in part by the Fondazione Cariparo and the University of Padova.
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