Myeloid cells in the tumor microenvironment: modulation of tumor angiogenesis and tumor inflammation

Abstract

Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy.

Figure 1

Cytokines produced in the tumor microenvironment can give rise to macrophages with distinct physiologies. Classical activated macrophages (M1) arise in response to interferon γ (IFN-γ). M1 macrophages elicit tissue disruptive reactions by producing tumor necrosis factor α (TNF-α), interleukin 12 (IL-12), reactive nitrogen, and oxygen intermediates. M1-activated macrophages are part of the polarized Th1 response. M2 macrophages are generated in response to various stimuli, including IL-4, IL-13, IL-10, and glucocorticoids. Tumor-associated macrophages have properties of M2-activated cells. They express many proangiogenic and angiogenic modulatory factors such as IL-1β, IL-6, IL-8, vascular endothelial growth factors (VEGFs), and matrix metalloproteinases (MMPs). M2 macrophages are part of the Th2 response.

Figure 2

Recruitment of diverse bone marrow-derived cell populations to the tumor microenvironment and their effects on tumor progression. Tumor and stromal cells mobilize various subpopulations of tumor promoting bone marrow-derived cells to the peripheral blood through secretion of cytokines and chemokines. Diverse chemoattractant factors promote the recruitment and infiltration of these cells to the tumor microenvironment where they suppress the antitumor immunity or promote tumor angiogenesis and vasculogenesis or raise refractoriness against anti-VEGF therapy.