American Association for Cancer Research
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Fig.S7 from Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer

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posted on 2023-03-30, 23:50 authored by Cathy Quemener, Jessica Baud, Kevin Boyé, Alexandre Dubrac, Clotilde Billottet, Fabienne Soulet, Florence Darlot, Laurent Dumartin, Marie Sire, Renaud Grepin, Thomas Daubon, Fabienne Rayne, Harald Wodrich, Anne Couvelard, Raphael Pineau, Martin Schilling, Vincent Castronovo, Shih-Che Sue, Kim Clarke, Abderrahim Lomri, Abdel-Majid Khatib, Martin Hagedorn, Hervé Prats, Andreas Bikfalvi

Characterization of PECAM-1 expression in pancreatic tumours

Funding

Agence Nationale de la Recherche

Association de la Recherche sur le Cancer

Ligue Nationale contre Cancer

Institut National du Cancer

ANR

INCA

Fondation pour la Recherche Médicale

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ARTICLE 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.

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