Tumor blood vessel structure is different from normal blood vessel features in terms of short lumen diameter, serpentine course and poor tight junction formation. These phenomena lead to form specific tissue environment, so called tumor microenvironments (TME). The TME polarizes tumor-infiltrating macrophages towards tumor supportive phenotype. We have previously reported that prolyl-hydroxylase inhibitor (PHDi) improved blood flow, hypoxia and TME in tumor tissues. The PHDi action mechanism is PHD inhibition, resulting in increasing hypoxia-inducing factors (HIFs) expression level. But the detail of its mechanism is unclear. In this study, we investigated the effect of HIFs in tumor infiltrating macrophage on tumor growth of PHD inhibitors on tumor progression.
In this study, we have used Lewis lung carcinoma (LLC) syngeneic tumor mouse models and used macrophage-specific HIF-1 and HIF-2 knockout mice. tumor was measured and calculated the tumor volume. Tumor tissues were collected at day16 and analyzed tumor vessels and immune cells by immunofluorescence staining.
In macrophage-specific HIF-2 knockout mice, tumor growth was inhibited by PHDi administration, but in macrophage-specific HIF-1 knockout mice were not inhibited it. In addition, macrophage-specific HIF-2 knockout mice were observed blood vessel normalization after PHDi administration, whereas macrophage-specific HIF-1 knockout mice were not observed it.
These results suggest that the inhibition of tumor growth by PHDi is associate with the HIF-1 in tumor infiltrating macrophages.