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.