title: Transforming Growth Factor-β Limits Secretion of Lumican by Activated Stellate Cells within Primary Pancreatic Adenocarcinoma Tumors.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC.
  
  
  METHODS
  Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment.
  
  
  RESULTS
  Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen.
  
  
  CONCLUSIONS
  Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β; once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934-46. ©2016 AACR.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of General Surgery, The University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Roife
authors.affiliation: Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yeonju
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Shihezi University, Xinjiang, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Lv
authors.affiliation: Department of Gastroenterology and Rheumatology, The Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Molecular and Cellular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ling
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mayrim V
authors.initials: MV
authors.lastname: Rios Perez
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xinqun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: BingBing
authors.initials: B
authors.lastname: Dai
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Pratt
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Truty
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Deyali
authors.initials: D
authors.lastname: Chatterjee
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.affiliation: Neurodiagnostics Laboratory, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Koay
authors.affiliation: Department of Molecular and Cellular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jbflemin@mdanderson.org.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D000071234:Lumican / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: C000604306:LUM protein, human; D000071234:Lumican; D016212:Transforming Growth Factor beta