title: Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; ekin.demir@tum.de gueralp.ceyhan@tum.de.
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kujundzic
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Paulo L
authors.initials: PL
authors.lastname: Pfitzinger
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Ömer Cemil
authors.initials: ÖC
authors.lastname: Saricaoglu
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Teller
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Kehl
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Carmen Mota
authors.initials: CM
authors.lastname: Reyes
authors.affiliation: ChemoCentryx, Inc., Mountain View, CA 94043.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Ertl
authors.affiliation: ChemoCentryx, Inc., Mountain View, CA 94043.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Miao
authors.affiliation: ChemoCentryx, Inc., Mountain View, CA 94043.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Tieftrunk
authors.affiliation: Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haller
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Kalliope Nina
authors.initials: KN
authors.lastname: Diakopoulos
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Magdalena U
authors.initials: MU
authors.lastname: Kurkowski
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.affiliation: Institute for Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; ekin.demir@tum.de gueralp.ceyhan@tum.de.
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D054387:Receptors, CXCR / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D054387:Receptors, CXCR; D019718:Receptors, CXCR4
keywords: CXCL12; CXCR4; CXCR7; Schwann cells; pancreatic cancer