title: Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer.
abstract: The CXCL4 paralog CXCL4L1 is a less studied chemokine that has been suggested to exert an antiangiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines, and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic ductal adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell coculture experiments, murine, and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues. CXCL4L1 gene expression was increased greatly in primary and metastatic PDAC. We found that myofibroblasts triggered cues in the tumor microenvironment, which led to induction of CXCL4L1 in tumor cells. CXCL4L1 expression was also controlled by epigenetic modifications at critical CpG islands, which were mapped. CXCL4L1 inhibited angiogenesis but also affected tumor development more directly, depending on the tumor cell type. In vivo administration of an mAb against CXCL4L1 demonstrated a blockade in the growth of tumors positive for CXCR3, a critical receptor for CXCL4 ligands. Our findings define a protumorigenic role in PDAC development for endogenous CXCL4L1, which is independent of its antiangiogenic function. Cancer Res; 76(22); 6507-19. ©2016 AACR.
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Quemener
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Baud
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Boyé
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.|INSERM U1037, Toulouse, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Billottet
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Soulet
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Darlot
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Dumartin
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sire
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Grepin
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daubon
authors.affiliation: Université Bordeaux, Pessac, France.|CNRS UMR 5234, Pessac, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rayne
authors.affiliation: Université Bordeaux, Pessac, France.|CNRS UMR 5234, Pessac, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Wodrich
authors.affiliation: Department of Pathology, Hôpital Bichat, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Pineau
authors.affiliation: Department of Visceral Surgery, University Homburg/Saar, Homburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schilling
authors.affiliation: Department of Pathology, University of Liège, Liège, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.affiliation: Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Shih-Che
authors.initials: SC
authors.lastname: Sue
authors.affiliation: Department of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Kim
authors.initials: K
authors.lastname: Clarke
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Lomri
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
authors.affiliation: INSERM U1029, Pessac, France.|Université Bordeaux, Pessac, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Hagedorn
authors.affiliation: INSERM U1037, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Prats
authors.affiliation: INSERM U1029, Pessac, France. andreas.bikfalvi@u-bordeaux.fr.|Université Bordeaux, Pessac, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bikfalvi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010978:Platelet Factor 4; D054367:Receptors, CXCR3 / Q000235:genetics*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C515187:CXCR3 protein, human; D018925:Chemokines; D054367:Receptors, CXCR3; D010978:Platelet Factor 4