Inhibition of Tumor Angiogenesis by Interferon-γ by Suppression of Tumor-Associated Macrophage Differentiation

Abstract

Tumor-associated macrophages (TAMs) differentiate from monocytes and are the M2-polarized macrophages in most human tumors, secreting generous vascular endothelial growth factor (VEGF) to promote angiogenesis. Although it has been shown in vitro that interferon-γ (IFN-γ) can inhibit monocytes differentiating to M2 macrophages in the tumor microenvironment and switch TAMs from M2 into M1, suppressing the ability of secreting VEGF, its effects on TAMs in vivo remains unknown. Here we tried to examine the effects of IFN-γ on the recruitment of monocyte/macrophage differentiation of TAMs and tumor angiogenesis in vivo. We built a gallbladder cancer model by inoculating subcutaneously the human gallbladder cancer cell line (GBC-SD) into BALB/C nude mice and injected the recombinant mouse IFN-γ intratumorally. We found that in the IFN-γ group, the number of monocytes/macrophages was significantly higher than that in the control group (p < 0.01), and TAM differentiation rate, which we defined as the number of TAMs / the number of monocytes/macrophages × 100%, mice-VEGF concentration, and microvessels density (MVD) were significantly lower than those in the control group (p < 0.01, p < 0.05, and p < 0.01). Our results suggest that IFN-γ can induce monocytes/macrophages recruiting into the tumor microenvironment, but inhibit them, differentiating to TAMs in vivo, which may reduce the concentration of VEGF and angiogenesis in tumor.

Anti‐cancer therapy with TNFα and IFNγ: A comprehensive review

“…Vascular endothelial growth factor (VEGF) is an important pro‐angiogenic molecule in the tumour microenvironment, whose upregulation has been shown to contribute to tumour‐associated angiogenesis, and tumour‐associated macrophages (TAMs) are one of the main sources of VEGF . It has been found that IFNγ can reduce the expression of mouse‐VEGF, inhibit tumour angiogensis and induce blood vessel destruction and necrosis . Study also revealed that IFNγ could promote monocytes/macrophages infiltrating into tumour tissues and inhibit them to differentiate into TAMs .…”

“…It has been found that IFNγ can reduce the expression of mouse‐VEGF, inhibit tumour angiogensis and induce blood vessel destruction and necrosis . Study also revealed that IFNγ could promote monocytes/macrophages infiltrating into tumour tissues and inhibit them to differentiate into TAMs . Therefore, IFNγ reduced angiogenesis by inhibiting TAM differentiation and VEGF expression in the tumour microenvironment.…”

Interleukin-17 levels correlate with poor prognosis and vascular endothelial growth factor concentration in the serum of patients with non-small cell lung cancer

“…IL-17 has been reported to mediate angiogenesis in humans via the stimulation of vascular endothelial cell migration and cord formation and via the regulation of the production of proangiogenic factors, such as basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) (Ferrara, 2002;Takahashi et al, 2005;Toi et al, 1995). IL-17 promotes angiogenesis in tumor models (Ma et al, 2014), and IL-17 expression strongly correlates with the microvessel density (MVD) in human ovarian cancer , hepatocellular carcinoma (HCC) (Sun et al, 2014), and colorectal cancer (CRC) (Liu et al, 2011). Other reports have indicated that IL-17 significantly enhances the net angiogenic activity and in vivo growth of NSCLC by promoting CXCR-2-dependent angiogenesis (Hayata et al, 2013).…”

Targeting Angiogenesis in Biliary Tract Cancers: An Open Option

“…When IFN-γ was intratumorally administered in a GBC xenograft model subcutaneously injected with a human GBC cell line. MVD and VEGF concentration were significantly reduced [32]. …”