がんの科学と治療

Paradoxical Augmentation of Tumor Angiogenesis Combined with Down-Regulation of IP-10 after Adenovirus-Mediated Transfer of Vasohibin-1 Gene in Cancer Cells

Abstract

Takanobu Nakamura, Yasuhiro Suzuki, Yoshifumi Takahashi, Susumu Satomi and Yasufumi Sato

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor produced by the endothelium. Here we examined the efficacy of local adenovirus-mediated VASH1 gene transfer for anti-angiogenic cancer treatment. When non-proliferative adenovirus vector encoding the human VASH1 gene (AdhVASH1) was injected locally into the peritoneal cavity and HM-1 ovarian cancer cells were inoculated into the peritoneal cavity thereafter, we observed a significant inhibition of tumor angiogenesis. However, to our surprise, when HM-1 cells were infected with AdhVASH1 (HM-1/hVASH1) and then inoculated in mice, we observed a paradoxical augmentation of tumor angiogenesis and tumor growth. To explore the mechanism of this augmented tumor angiogenesis, we investigated the expression of various angiogenesis regulators. The level of angiogenesis stimulators such as VEGF and FGF-2 was unchanged; however we noticed a marked down-regulation of one angiogenesis inhibitor, namely interferon- γ-inducible protein-10 (IP-10). Moreover, this down-regulation of IP-10 and augmented tumor angiogenesis were not seen when HM-1/hVASH1 cells were inoculated into severe combined immunodeficiency mice. Our present analysis reveals that there is a mutual interaction between 2 angiogenesis inhibitors; VASH1 and IP-10, and the immune reaction might be responsible for this interaction through hitherto unknown mechanism. It also discloses the importance of endogenous IP-10 in tumors, as down-regulation of IP-10 results in the paradoxical augmentation of tumor angiogenesis. Care must be taken when VASH1 gene is transiently transferred to cancer cells for the antiangiogenesis treatment.