BACKGROUND AND AIMS: Pancreatic cancer is among the most dismal of human malignancies. Current therapeutic strategies are virtually ineffective in controlling advanced, metastatic disease. Recent evidence suggests that the Hedgehog signalling pathway is aberrantly reactivated in the majority of pancreatic cancers, and that Hedgehog blockade has the potential to prevent disease progression and metastatic spread. METHODS: Here it is shown that the Hedgehog pathway is activated in the Pdx1-Cre;LsL-Kras(G12D);Ink4a/Arf(lox/lox) transgenic mouse model of pancreatic cancer. The effect of Hedgehog pathway inhibition on survival was determined by continuous application of the small molecule cyclopamine, a smoothened antagonist. Microarray analysis was performed on non-malignant human pancreatic ductal cells overexpressing Gli1 in order to screen for downstream Hedgehog target genes likely to be involved in pancreatic cancer progression. RESULTS: Hedgehog inhibition with cyclopamine significantly prolonged median survival in the transgenic mouse model used here (67 vs 61 days; p = 0.026). In vitro data indicated that Hedgehog activation might at least in part be ascribed to oncogenic Kras signalling. Microarray analysis identified 26 potential Hedgehog target genes that had previously been found to be overexpressed in pancreatic cancer. Five of them, BIRC3, COL11A1, NNMT, PLAU and TGM2, had been described as upregulated in more than one global gene expression analysis before. CONCLUSION: This study provides another line of evidence that Hedgehog signalling is a valid target for the development of novel therapeutics for pancreatic cancer that might be worth evaluating soon in a clinical setting.
BACKGROUND AND AIMS: Pancreatic cancer is among the most dismal of humanmalignancies. Current therapeutic strategies are virtually ineffective in controlling advanced, metastatic disease. Recent evidence suggests that the Hedgehog signalling pathway is aberrantly reactivated in the majority of pancreatic cancers, and that Hedgehog blockade has the potential to prevent disease progression and metastatic spread. METHODS: Here it is shown that the Hedgehog pathway is activated in the Pdx1-Cre;LsL-Kras(G12D);Ink4a/Arf(lox/lox) transgenic mouse model of pancreatic cancer. The effect of Hedgehog pathway inhibition on survival was determined by continuous application of the small molecule cyclopamine, a smoothened antagonist. Microarray analysis was performed on non-malignant human pancreatic ductal cells overexpressing Gli1 in order to screen for downstream Hedgehog target genes likely to be involved in pancreatic cancer progression. RESULTS: Hedgehog inhibition with cyclopamine significantly prolonged median survival in the transgenic mouse model used here (67 vs 61 days; p = 0.026). In vitro data indicated that Hedgehog activation might at least in part be ascribed to oncogenic Kras signalling. Microarray analysis identified 26 potential Hedgehog target genes that had previously been found to be overexpressed in pancreatic cancer. Five of them, BIRC3, COL11A1, NNMT, PLAU and TGM2, had been described as upregulated in more than one global gene expression analysis before. CONCLUSION: This study provides another line of evidence that Hedgehog signalling is a valid target for the development of novel therapeutics for pancreatic cancer that might be worth evaluating soon in a clinical setting.
Authors: Nabeel Bardeesy; Kuang-Hung Cheng; Justin H Berger; Gerald C Chu; Jessica Pahler; Peter Olson; Aram F Hezel; James Horner; Gregory Y Lauwers; Douglas Hanahan; Ronald A DePinho Journal: Genes Dev Date: 2006-11-15 Impact factor: 11.361
Authors: Hideaki Ijichi; Anna Chytil; Agnieszka E Gorska; Mary E Aakre; Yoshio Fujitani; Shuko Fujitani; Christopher V E Wright; Harold L Moses Journal: Genes Dev Date: 2006-11-15 Impact factor: 11.361
Authors: Jennifer P Morton; Michelle E Mongeau; David S Klimstra; John P Morris; Yie Chia Lee; Yoshiya Kawaguchi; Christopher V E Wright; Matthias Hebrok; Brian C Lewis Journal: Proc Natl Acad Sci U S A Date: 2007-03-19 Impact factor: 11.205
Authors: Georg Feldmann; Surajit Dhara; Volker Fendrich; Djahida Bedja; Robert Beaty; Michael Mullendore; Collins Karikari; Hector Alvarez; Christine Iacobuzio-Donahue; Antonio Jimeno; Kathleen L Gabrielson; William Matsui; Anirban Maitra Journal: Cancer Res Date: 2007-03-01 Impact factor: 12.701
Authors: M Stacey Ricci; Seok-Hyun Kim; Kazuhiro Ogi; John P Plastaras; Jianhua Ling; Wenge Wang; Zhaoyu Jin; Yingqiu Y Liu; David T Dicker; Paul J Chiao; Keith T Flaherty; Charles D Smith; Wafik S El-Deiry Journal: Cancer Cell Date: 2007-07 Impact factor: 31.743
Authors: Kamel Izeradjene; Chelsea Combs; Melissa Best; Aarthi Gopinathan; Amary Wagner; William M Grady; Chu-Xia Deng; Ralph H Hruban; N Volkan Adsay; David A Tuveson; Sunil R Hingorani Journal: Cancer Cell Date: 2007-03 Impact factor: 31.743
Authors: Oliver A Kent; Raghu R Chivukula; Michael Mullendore; Erik A Wentzel; Georg Feldmann; Kwang H Lee; Shu Liu; Steven D Leach; Anirban Maitra; Joshua T Mendell Journal: Genes Dev Date: 2010-12-15 Impact factor: 11.361
Authors: David E Rosow; Andrew S Liss; Oliver Strobel; Stefan Fritz; Dirk Bausch; Nakul P Valsangkar; Janivette Alsina; Birte Kulemann; Joo Kyung Park; Junpei Yamaguchi; Jennifer LaFemina; Sarah P Thayer Journal: Surgery Date: 2012-07-06 Impact factor: 3.982
Authors: Kun Jiang; Yan-Ping Wang; Xiao-Dong Wang; Xiao-Bo Hui; Lian-Shu Ding; Ji Liu; Dai Liu Journal: Am J Cancer Res Date: 2017-05-01 Impact factor: 6.166