title: Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma.
abstract: The mechanisms by which the extreme desmoplasia observed in pancreatic tumors develops remain unknown and its role in pancreatic cancer progression is unsettled. Chemokines have a key role in the recruitment of a wide variety of cell types in health and disease. Transcript and protein profile analyses of human and murine cell lines and human tissue specimens revealed a consistent elevation in the receptors CCR10 and CXCR6, as well as their respective ligands CCL28 and CXCL16. Elevated ligand expression was restricted to tumor cells, whereas receptors were in both epithelial and stromal cells. Consistent with its regulation by inflammatory cytokines, CCL28 and CCR10, but not CXCL16 or CXCR6, were upregulated in human pancreatitis tissues. Cytokine stimulation of pancreatic cancer cells increased CCL28 secretion in epithelial tumor cells but not an immortalized activated human pancreatic stellate cell line (HPSC). Stellate cells exhibited dose- and receptor-dependent chemotaxis in response to CCL28. This functional response was not linked to changes in activation status as CCL28 had little impact on alpha smooth muscle actin levels or extracellular matrix deposition or alignment. Co-culture assays revealed CCL28-dependent chemotaxis of HPSC toward cancer but not normal pancreatic epithelial cells, consistent with stromal cells being a functional target for the epithelial-derived chemokine. These data together implicate the chemokine CCL28 in the inflammation-mediated recruitment of cancer-associated stellate cells into the pancreatic cancer parenchyma.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Ishan
authors.initials: I
authors.lastname: Roy
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Boyle
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Vonderhaar
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.|MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Noah P
authors.initials: NP
authors.lastname: Zimmerman
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Egal
authors.initials: E
authors.lastname: Gorse
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Mackinnon
authors.affiliation: Department of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
authors.affiliation: Cancer Biology Department, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA.
authors.forename: Janusz
authors.initials: J
authors.lastname: Franco-Barraza
authors.affiliation: Cancer Biology Department, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA.
authors.forename: Edna
authors.initials: E
authors.lastname: Cukierman
authors.affiliation: MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.|Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Tsai
authors.affiliation: MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.|Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Evans
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.|MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018925:Chemokines; D019707:Receptors, Chemokine