title: Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling.
abstract: Pancreatic cancer, a hypovascular and highly desmoplastic cancer, is characterized by tumor expression of Hedgehog (HH) ligands that signal to fibroblasts in the surrounding stroma that in turn promote tumor survival and growth. However, the mechanisms and consequences of stromal HH pathway activation are not well understood. Here, we show that the HH coreceptors GAS1, BOC, and CDON are expressed in cancer-associated fibroblasts. Deletion of two coreceptors (Gas1 and Boc) in fibroblasts reduces HH responsiveness. Strikingly, these fibroblasts promote greater tumor growth in vivo that correlates with increased tumor-associated vascularity. In contrast, deletion of all three coreceptors (Gas1, Boc, and Cdon) results in the near complete abrogation of HH signaling and a corresponding failure to promote tumorigenesis and angiogenesis. Collectively, these data identify a role for HH dosage in pancreatic cancer promotion and may explain the clinical failure of HH pathway blockade as a therapeutic approach in pancreatic cancer.
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Mathew
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Holtz
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Kane
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Song
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: benallen@umich.edu.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Allen
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: marinapa@umich.edu.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018628:Gene Dosage; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C510745:Boc protein, mouse; C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D011956:Receptors, Cell Surface