title: Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction.
abstract: Pancreatic cancer occurs in the setting of a profound fibrotic microenvironment that often dwarfs the actual tumor. Although pancreatic fibrosis has been well studied in chronic pancreatitis, its development in pancreatic cancer is much less well understood. This article describes the dynamic remodeling that occurs from pancreatic precursors (pancreatic intraepithelial neoplasias (PanINs)) to pancreatic ductal adenocarcinoma, highlighting similarities and differences between benign and malignant disease. Although collagen matrix is a commonality throughout this process, early stage PanINs are virtually free of periostin while late stage PanIN and pancreatic cancer are surrounded by an increasing abundance of this extracellular matrix protein. Myofibroblasts also become increasingly abundant during progression from PanIN to cancer. From the earliest stages of fibrogenesis, macrophages are associated with this ongoing process. In vitro co-culture indicates there is cross-regulation between macrophages and pancreatic stellate cells (PaSCs), precursors to at least some of the fibrotic cell populations. When quiescent PaSCs were co-cultured with macrophage cell lines, the stellate cells became activated and the macrophages increased cytokine production. In summary, fibrosis in pancreatic cancer involves a complex interplay of cells and matrices that regulate not only the tumor epithelium but the composition of the microenvironment itself.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Drosos
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Revetta
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Weaver
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Buzhardt
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sosa-Pineda
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Whitehead
authors.affiliation: 1] Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Beauchamp
authors.affiliation: 1] Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA [4] Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: 1] Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Means
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D008264:Macrophages / Q000502:physiology*; D008679:Metaplasia; D051379:Mice; D010179:Pancreas / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000502:physiology*; D020239:Receptor Cross-Talk