166 N-MYC Downstream Regulated Gene-1 Expression Correlates with Reduced Pancreatic Cancer Growth In Vitro and In Vivo

Abstract

cells (EPCs). VEGF and SDF-1 mRNA levels were reduced in KP-1N in the presence of cyclopamine both In Vitro and In Vivo, but the number of circulating EPCs was not affected by Hh inhibition. Host derived Ang-1 and IGF-1 mRNA levels in xenografts were strongly downregulated by cyclopamine administration, which may contribute to the maintenance and maturation of tumor vasculature. In Vitro co-culture experiments demonstrated that KP1N cells induced Ang-1/IGF-1 production in BM-EPCs, and this induction was significantly attenuated either by cyclopamine or neutralizing antibody to Shh. In addition, a matrigel plug assay supports the role of Shh secreted from PDAC cells to induce migration and capillary formation of BM-derived EPCs. This “paracrine” effect of Hh seems to be a late event during pancreatic tumorigenesis, as stromal Patch1 expression was detected within PDAC lesions in Pdx-Cre;Kras;p53lox/+ mice, but not in precursor PanIN lesion in PdxCre;Kras mice. Collectively, Hh derived from cancer cells can have a profound effect on neovascularization through the regulation of EPCs during late stages of pancreatic tumorigenesis, and targeting Hh would be a novel therapeutic approach to inhibit tumor angiogenesis. This work was supported by New Energy and Industrial Technology Development Organization (NEDO) of Japan.