title: Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma.
abstract: BACKGROUND
  Aberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells.
  
  
  METHODS
  To evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups-HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2.
  
  
  RESULTS
  When HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group.
  
  
  CONCLUSIONS
  Hepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea, younjoo282@gmail.com.
authors.forename: Younjoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Myeong-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Sun Hoo
authors.initials: SH
authors.lastname: Park
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Su Cheol
authors.initials: SC
authors.lastname: Park
authors.forename: Chul Ju
authors.initials: CJ
authors.lastname: Han
authors.forename: Ji Kon
authors.initials: JK
authors.lastname: Ryu
authors.forename: Yong Bum
authors.initials: YB
authors.lastname: Yoon
authors.forename: Yong-Tae
authors.initials: YT
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D053823:Hedgehog Proteins