The Multifaceted Role of Perivascular Macrophages in Tumors

Abstract

Evidence has emerged for macrophages in the perivascular niche of tumors regulating important processes like angiogenesis, various steps in the metastatic cascade, the recruitment and activity of other tumor-promoting leukocytes, and tumor responses to frontline therapies like irradiation and chemotherapy. Understanding the mechanisms controlling the recruitment, retention, and function of these cells could identify important targets for anti-cancer therapeutics.

Figure 1. The Roles of Perivascular Macrophages in Tumor Progression

In primary tumors. Recruitment and regulation of other tumor-promoting leukocytes – the two images, with and without vessels (blue) included, show that neutrophils (red, N) extravasate in inflamed tissues in close proximity to perivascular (PV) macrophages (green, M). [Reprinted with permission: Abtin et al., 2014.] Intravasation of tumor cells: the images show a triad of a PV TIE2⁺VEGFA⁺ TAM (blue, M), cancer cells (green, TC), and endothelial cells (red). [Reprinted with permission: Harney et al., 2015.] Angiogenesis stimulation: the image shows TIE2⁺ TAMs (green, M) located near blood vessels (red, V) in tumors. [Reprinted with permission: De Palma et al., 2003.] Relapse of tumors after therapy: the images show a subcutaneous Lewis lung carcinoma after treatment with cyclophosphamide (TIE2⁺ blood vessels [red, V]; TIE2⁺MRC1⁺ TAMs [white/pink, M]; and cell nuclei [blue]). Inset: a single, TIE2⁺MRC1⁺ TAM (white/red). [Reprinted with permission: Hughes et al., 2015.] In metastatic sites. Extravasation of cancer cells: the image shows a cancer cell (blue, TC), PV macrophages (green, M), and blood vessels (red, V) in the lungs of mice. [Reprinted with permission: Qian et al., 2009.] Dormancy: the image shows a dormant cancer cell (green, TC; white asterisk) located close to a blood vessel (red, V) in the brain. Cell nuclei are shown in blue. [Reprinted with permission: Ghajar et al., 2013.] Many of the above functions involve the release of soluble factors by PV macrophages (green), and often activated by factors expressed by neighboring endothelial cells (red). Scale bars, 20 μm.