Abstract 468: Down-regulation of TNFSF15 (VEGI) in tumor vasculature under inflammatory conditions is a pre-requisite of tumor neovascularization

Abstract

Abstract Tumor necrosis factor superfamily-15 (TNFSF15; VEGI) is an endogenous inhibitor of neovascularization. TNFSF15 is largely produced by quiescent vascular endothelial cells in an established vasculature but is markedly down-regulated in endothelial cells undergoing proliferation such as those in tumors or at a wound site. Recombinant TNFSF15 is a potent inhibitor of endothelial cell proliferation and tumor growth. We hypothesize that TNFSF15 as a negative regulator of angiogenesis must be down-regulated prior to the initiation of angiogenesis, and that the inflammatory conditions created by cancer cells and infiltrating lymphocytes lead to TNFSF15 down-modulation in the microenvironment, permitting new blood vessel growth. We analyzed normal ovary tissues (n=12) and clinical specimens of ovarian cancer (n=86; including stages I, II, III and IV) for the expression of TNFSF15, the endothelial cell marker PECAM (CD31), and tumor-infiltrating T-cell markers CD4 and CD25. We found that the degree of T-cell infiltration increases markedly while TNFSF15 expression diminishes as the disease progresses. We then determined the influence of human ovarian cancer cell line OVCAR-3 cell conditioned media on cytokine production by human CD4+ T-cells and CD4+CD25+ Treg cells, as well as the influence of the conditioned media of the latter two cells on TNFSF15 expression in human umbilical vein endothelial cells (HUVEC). We found that the conditioned media of Th1 or Treg cells can inhibit HUVEC TNFSF15 expression only after the lymphocytes being treated with OVCAR-3 conditioned media. Interestingly, we further found that mouse ovarian cancer ID8 cells implanted subcutaneously on mice treated with TNFSF15 shRNA at the injection sites exhibit significantly greater tumor growth rates compared with control shRNA treated ones. Our findings indicate that TNFSF15 plays a critical role in the maintenance of vascular stability as its down-modulation is a pre-requisite for the initiation of tumor neovascularization, and that TNFSF15 down-regulation is carried out by tumor-infiltrating T-cells under the influence of the cancer cells in the microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 468. doi:10.1158/1538-7445.AM2011-468