The role of tumor-associated macrophages in tumor vascularization

Abstract

Tumor vascularization is a highly complex process that involves the interaction between tumors and their surrounding stroma, as well as many distinct angiogenesis-regulating factors. Tumor associated macrophages (TAMs) represent one of the most abundant cell components in the tumor environment and key contributors to cancer-related inflammation. A large body of evidence supports the notion that TAMs play a critical role in promoting the formation of an abnormal tumor vascular network and subsequent tumor progression and invasion. Clinical and experimental evidence has shown that high levels of infiltrating TAMs are associated with poor patient prognosis and tumor resistance to therapies. In addition to stimulating angiogenesis during tumor growth, TAMs enhance tumor revascularization in response to cytotoxic therapy (e.g., radiotherapy), thereby causing cancer relapse. In this review, we highlight the emerging data related to the phenotype and polarization of TAMs in the tumor microenvironment, as well as the underlying mechanisms of macrophage function in the regulation of the angiogenic switch and tumor vascularization. Additionally, we discuss the potential of targeting pro-angiogenic TAMs, or reprograming TAMs toward a tumoricidal and angiostatic phenotype, to promote normalization of the tumor vasculature to enhance the outcome of cancer therapies.

Figure 1

Targeting TAMs to disrupt or normalize tumor vasculature. Tumor cell-derived factors (MCP-1, SDF-1), multiple signaling pathways (Notch, Wnt5a, TSC2-mTOR and FLT-1) and transcription factors (HIF-1α, STAT3, Ets2) in the tumor environment recruit and/or polarize TAMs to an M2 (alternatively activated) state. TAMs produce pro-angiogenic factors and MMPs to promote the tumor vascularization during tumor growth and progression. TAMs and aberrant tumor vasculature also contribute to the failure of anticancer treatments, such as anti-angiogenesis therapy, chemotherapy and radiation therapy. TAM-targeted therapies can be designed to block the recruitment or pro-angiogenic activity of TAMs. TAMs can also be “re-educated” and reprogrammed to become antitumor effector cells with an M1-like phenotype, characterized by high expression of CD86, MHC-II and NOS2, enhanced production of IL-12, CXCL10, IFN-β and NO. These classically activated macrophages display anti-angiogenic, tumoricidal and immunostimulatory activities, facilitating the eradication of cancer cells. Targeting of TAMs may also potentially lead to the normalization of tumor vasculature, which synergizes with antitumor efficacy of other cytotoxic treatments, such as chemotherapy. HIF-1α, hypoxia-inducible factor-1α; HRG, Histidine-rich glycoprotein; IRF5, interferon regulatory factor 5; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; NO, nitric oxide; NOS2, nitric oxide synthase 2; PGE2, prostaglandin E2; SDF-1, stromal cell-derived factor-1; SRA, scavenger receptor A; STAT, Signal transducer and activator of transcription; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.