Abstract 2382: A critical role of tumor-specific hedgehog signaling for pancreatic cancer metastasis

Abstract

Abstract The hedgehog (Hh) pathway plays a vital role in embryonic development and tissue differentiation, and aberrant activation of this pathway is found in a variety of human cancer, including pancreatic cancer. Despite the significance of Hh signaling for cancer development, it is not clear whether Hh signaling in the tumor compartment is required for tumor metastasis of pancreatic cancer. Here we show that elevated expression of hedgehog target genes is highly associated with poor outcomes of pancreatic cancer patients, but not always with elevated expression of hedgehog molecules (SHH and IHH) or the known downstream signaling molecules. Target genes of Hh signaling were expressed in the tumor as well as in the stroma. We found that elevated Hh target gene expression is associated with increased expression of snail1 or loss of E-cadherin, implying that Hh signaling may be associated with the pancreatic cancer metastasis potential. To investigate how Hh signaling may affect cancer metastasis, we established an orthotopic mouse model of pancreatic cancer. We showed in this model that Hh signaling is elevated in lymph node and liver metastasis. The role of Hh signaling for pancreatic cancer metastasis was demonstrated in an orthotopic mouse model of pancreatic cancer, which involves activated hedgehog signaling. We found that knocking down Gli2 expression in the cancer cells, which was associated with reduced Hh target gene expression, prevents tumor metastasis to liver. Based on these data, we conclude that tumor specific Hh signaling activation is required for pancreatic cancer metastasis. 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 2382. doi:10.1158/1538-7445.AM2011-2382