Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies

Abstract

The presence of multiple areas of hypoxia (low oxygen tension) is a hallmark feature of human and experimental tumors. Monocytes are continually recruited into tumors, differentiate into tumor-associated macrophages (TAMs), and then accumulate in these hypoxic areas. A number of recent studies have shown that macrophages respond to the levels of hypoxia found in tumors by up-regulating such transcription factors as hypoxia-inducible factors 1 and 2, which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro-metastatic genes. This could explain why high numbers of TAMs correlate with poor prognosis in various forms of cancer. In this review, we assess the evidence for hypoxia activating a distinct, pro-tumor phenotype in macrophages and the possible effect of this on the growth, invasion, angiogenesis, and immune evasion of tumors. We also discuss current attempts to selectively target TAMs for destruction or to use them to deliver gene therapy specifically to hypoxic tumor sites.

Figure 1

TAM localization in hypoxic areas of murine mammary (A, B) and human breast (C, D) tumors. Tumor hypoxia was visualized by injecting mice bearing 4T1 mammary tumors or breast cancer patients with the hypoxic cell marker pimonidazole (PIMO) before surgical removal of tumors. PIMO retained by hypoxic cells in tumor sections was then detected using a rabbit anti-PIMO antibody (red staining, arrows in B and D). Macrophages were co-localized in these sections using a monoclonal antibody to the pan macrophage markers F4/80 (B) and CD68 (D) (brown staining). Although TAMs can be seen in both normoxic (A, C) and hypoxic (B, D) areas of tumors, they accumulated at highest density in the latter. Hematoxylin staining of nuclei is shown in blue. Scale bars, 50 μm.

Figure 2

Macrophage functions in a hypoxic tumor area: involvement in tumor growth, invasion, metastasis, and angiogenesis. Monocytes are recruited from the tumor vasculature by such chemoattractants released by tumors as M-CSF and CCL2. They then differentiate into TAMs and migrate into and become immobilized in areas of transient or chronic hypoxia (shown here in white) in response to VEGF, endothelins (ETs) 1 and 2, and EMAP-II, which are up-regulated in hypoxic areas. TAMs then respond to the hypoxia by up-regulating a broad array of genes encoding proteins that promote the proliferation, invasion, and metastasis of tumor cells as well as tumor angiogenesis. See text for abbreviations used.