Review
Macrophage regulation of tumor angiogenesis: Implications for cancer therapy

https://doi.org/10.1016/j.mam.2011.04.005Get rights and content

Abstract

This article reviews the evidence for macrophages playing an important role in the regulation of tumor angiogenesis. Findings in mouse models show that macrophages promote angiogenesis in tumors both by producing excessive amounts of proangiogenic factors and by physically assisting sprouting blood vessels to augment the complexity of the intra-tumoral vascular network. Recent studies however suggest that macrophages may be dispensable for the initiation of angiogenesis in tumors. Rather, these cells express proangiogenic programs that enhance the complexity of the tumor-associated vasculature, leading to aberrant, plethoric and dysfunctional angiogenesis. Gene expression and cell depletion studies further indicate that tumor-associated macrophages (TAMs) comprise phenotypically and functionally distinct subsets. This may reflect “education” of the macrophage phenotype by signals in some areas of the tumor microenvironment and/or TAM subsets derived from distinct macrophage precursors. Among the better characterized TAM subsets are the proangiogenic (TIE2+) and the angiostatic/inflammatory (CD11c+) macrophages, which coexist in tumors. Such antagonizing TAM subsets occupy distinct niches in the tumor microenvironment and are present at ratios that vary according to the tumor type and grade. Specifically targeting TAMs or reprogramming them from a proangiogenic to an angiostatic function may “normalize” the tumor vasculature and improve the efficacy of various anticancer therapies, including radiotherapy, chemotherapy and vascular-disrupting agents.

Section snippets

Historical findings

The first report suggesting that macrophages directly promote angiogenesis dates back to 1977 (Polverini et al., 1977). In that study, Polverini and colleagues showed that thioglycollate-activated peritoneal macrophages inoculated into the corneal stroma of guinea pigs induced robust vascular proliferation (Polverini et al., 1977). Earlier reports had described the proangiogenic activity of other hematopoietic-lineage cells, such as spleen-derived lymphocytes (Sidky and Auerbach, 1975). Sidky

Molecular pathways regulating the proangiogenic activity of TAMs

Many molecular pathways have been implicated in monocyte/macrophage-mediated promotion of tumor angiogenesis. Here, we will discuss some molecular pathways of established relevance or emerging interest in this process.

Polarization of macrophages: the M1-M2 paradigm

Tissue macrophages can display different activation states according to the stimuli present in the local microenvironment. In several microbial infections and other inflammatory conditions, the products (e.g., IFNγ) of activated T helper-1 (Th1) lymphocytes and NK cells can induce macrophages to undergo a “classical activation” (or “M1”) program that enhances their cytotoxic and antimicrobial activity. Conversely, signals produced by Th2 polarized lymphocytes (e.g., IL4, IL10 or IL13) can

Macrophage responses to cancer therapies

Several recent reports have shown that infiltrating myeloid cells may modulate tumor responses to various anticancer treatments. As discussed below, myeloid cells were shown to limit the efficacy of antiangiogenic, vascular-damaging, radiation and cytotoxic therapies in mouse tumor models (Figure 2). In several instances, TAMs have been implicated in such responses.

Reprogramming TAMs to inhibit or normalize tumor angiogenesis

From the discussion above, it is suggested that the therapeutic potential of conventional anticancer approaches may be increased by concomitantly targeting tumor-infiltrating macrophages (De Palma and Lewis, 2011). Because not all TAMs are protumoral (Movahedi et al., 2010, Pucci et al., 2009, Qian and Pollard, 2010), strategies that can specifically target protumoral TAMs or reprogram them toward an antitumoral phenotype may represent a valid approach to enhance the efficacy of conventional

Concluding remarks

Since the early studies in mice showing that TAMs promote tumor angiogenesis and progression (De Palma et al., 2003, De Palma et al., 2005), several reports have highlighted the important contribution of TAMs and other BM-derived myeloid cells to angiogenesis in various mouse tumor models (Murdoch et al., 2008). Whereas rapidly expanding mouse tumors are obviously dependent on TAMs – or subsets of these cells – to mount a proficient angiogenic response, it is not yet clear whether slowly

Acknowledgements

The authors thank all members of the Angiogenesis and Tumor Targeting Unit, and apologize to all scientists whose work could not be cited owing to space limitations. We also thank Professor Claire Lewis (Sheffield, UK) for her helpful advice on the content of this article. MDP is supported by grants from the European Research Council (Starting Grant 243128/TIE2+Monocytes) and the Associazione Italiana per la Ricerca sul Cancro (IG-2010).

Mario Leonardo Squadrito obtained his Master degree in Pharmaceutical Biotechnology from the University of L’Aquila (Italy). He then joined the San Raffaele Scientific Institute in Milan as a PhD student in Cellular and Molecular Biology. He acquired expertise in studying microRNA functions in live cells by using novel genetic tools, and is currently focusing his research interests on how microRNAs regulate the proangiogenic activity of macrophages in tumors.

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    Mario Leonardo Squadrito obtained his Master degree in Pharmaceutical Biotechnology from the University of L’Aquila (Italy). He then joined the San Raffaele Scientific Institute in Milan as a PhD student in Cellular and Molecular Biology. He acquired expertise in studying microRNA functions in live cells by using novel genetic tools, and is currently focusing his research interests on how microRNAs regulate the proangiogenic activity of macrophages in tumors.

    Michele De Palma obtained his Ph.D. in 2004 at the University of Torino Medical School (Italy), where he developed with Dr. Naldini genetic vectors and transgenic mouse models to study the role of bone marrow-derived cells in tumor angiogenesis. He then moved to the San Raffaele Scientific Institute in Milan to pursue novel cancer gene therapy strategies and to continue his studies on proangiogenic macrophages. He has been recently appointed Assistant Professor at the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland. His current research interests focus on how macrophages modulate tumor responses to antiangiogenic and cytotoxic therapies.

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