Abstract 3440: Activation of hedgehog pathway in tumor vasculature is a late event of pancreatic tumorigenesis

Abstract

Abstract Bone marrow cells can be activated to function as instigators of tumor growth by systemic tumor-derived signals. We have identified subsets of BM cells that regulate neovascularization in pancreatic ductal adenocarcinoma (PDAC). Notably, blockade of Hedgehog (Hh) signaling markedly destabilized neovessels in PDAC xenografts by attenuating the homing and incorporation of the BM-derived cells into the neovasculature. We found IGF-1 production in the tumor stroma was regulated by the Hh ligand, Shh, and played a key role during this process. In vitro co-culture experiments demonstrated that human PDAC cell lines induced IGF-1 in c-Kit+ BM derived mononuclear cells utilized as pro-angiogenic cells, and that the induction was attenuated either by cyclopamine or expression of shRNA targeting Smo in the mononuclear cells. Shh secreted from PDAC cells induced tube formation by the mouse endothelial line MS-1, suggesting an important role for Shh in migration and capillary formation of the BM-derived pro-angiogenic cells; this induction of capillary morphogenesis was blocked by anti-IGF-1 neutralizing antibody. The “paracrine” effect of Hh seems to be a late event during pancreatic tumorigenesis, as full length Gli2 expression in neovasculatures was detected within PDAC lesions, but not in precursor PanIN lesions using a genetically engineered mouse models. We also observed upregulation of VE-cadherin, Id1, and Ptch1 mRNA in lineage-/c-Kit+ fraction of BM mononuclear cells from PDAC mice as compared to control mice or mice with PanIN, suggesting that pro-angiogenic conditions induced at the level of the BM in cancer-bearing hosts. The primitive progenitors derived from ‘activated BM’ are imported to the tumor microenvironment where they become fully activated. Overall, these studies provide insights into the cellular and molecular mechanisms by which BM-derived cells promote tumor growth and angiogenesis and have implications for the design of anti-angiogenesis therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3440.