Cellular and Molecular Life Sciences

, Volume 74, Issue 22, pp 4231–4243 | Cite as

PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker

  • Jérémy Nigri
  • Meritxell Gironella
  • Christian Bressy
  • Elena Vila-Navarro
  • Julie Roques
  • Sophie Lac
  • Caroline Bontemps
  • Coraline Kozaczyk
  • Jérôme Cros
  • Daniel Pietrasz
  • Raphaël Maréchal
  • Jean-Luc Van Laethem
  • Juan Iovanna
  • Jean-Baptiste Bachet
  • Emma Folch-Puy
  • Richard Tomasini
Original Article

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a fatal and insidious malignant disease for which clinicians’ tools are restricted by the current limits in knowledge of how tumor and stromal cells act during the disease. Among PDA hallmarks, neural remodeling (NR) and perineural invasion (PNI) drastically influence quality of life and patient survival. Indeed, NR and PNI are associated with neuropathic pain and metastasis, respectively, both of which impact clinicians’ decisions and therapeutic options. The aim of this study was to determine the impact and clinical relevance of the peritumoral microenvironment, through pancreatitis-associated protein (PAP/REG3A) expression, on PNI in pancreatic cancer. First, we demonstrated that, in PDA, PAP/REG3A is produced by inflamed acinar cells from the peritumoral microenvironment and then enhances the migratory and invasive abilities of cancer cells. More specifically, using perineural ex vivo assays we revealed that PAP/REG3A favors PNI through activation of the JAK/STAT signaling pathway in cancer cells. Finally, we analyzed the level of PAP/REG3A in blood from healthy donors or patients with PDA from three independent cohorts. Patients with high levels of PAP/REG3A had overall shorter survival as well as poor surgical outcomes with reduced disease-free survival. Our study provides a rationale for using the PAP/REG3A level as a biomarker to improve pancreatic cancer prognosis. It also suggests that therapeutic targeting of PAP/REG3A activity in PDA could limit tumor cell aggressiveness and PNI.

Keywords

Pancreatic cancer Perineural invasion Peritumoral microenvironment 

Supplementary material

18_2017_2579_MOESM1_ESM.docx (25 kb)
Supplementary material 1 (DOCX 24 kb)
18_2017_2579_MOESM2_ESM.pdf (445 kb)
Supplementary material 2 (PDF 445 kb)

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Jérémy Nigri
    • 1
    • 2
    • 3
    • 4
  • Meritxell Gironella
    • 5
  • Christian Bressy
    • 1
    • 2
    • 3
    • 4
  • Elena Vila-Navarro
    • 5
  • Julie Roques
    • 1
    • 2
    • 3
    • 4
  • Sophie Lac
    • 1
    • 2
    • 3
    • 4
  • Caroline Bontemps
    • 6
  • Coraline Kozaczyk
    • 6
  • Jérôme Cros
    • 7
  • Daniel Pietrasz
    • 8
    • 9
  • Raphaël Maréchal
    • 10
  • Jean-Luc Van Laethem
    • 10
  • Juan Iovanna
    • 1
    • 2
    • 3
    • 4
  • Jean-Baptiste Bachet
    • 8
    • 9
    • 11
    • 12
  • Emma Folch-Puy
    • 13
  • Richard Tomasini
    • 1
    • 2
    • 3
    • 4
    • 14
  1. 1.CRCM, INSERM, U1068MarseilleFrance
  2. 2.Paoli-Calmettes InstituteMarseilleFrance
  3. 3.Aix-Marseille University, UM 105MarseilleFrance
  4. 4.CNRS, UMR7258MarseilleFrance
  5. 5.Gastrointestinal and Pancreatic Oncology, Hospital Clinic of BarcelonaCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPSBarcelonaSpain
  6. 6.DYNABIO S.A.S, Luminy Biotech EntreprisesMarseilleFrance
  7. 7.Department of PathologyINSERM U1149, Hospital BeaujonClichyFrance
  8. 8.INSERM UMR-S1147, University Paris DescartesParisFrance
  9. 9.Department of Hepatobiliary and Digestive SurgeryHospital Pitié SalpêtrièreParisFrance
  10. 10.Gastrointestinal Cancer UnitUniversity Clinic of Bruxelles, Erasme HospitalBrusselsBelgium
  11. 11.Sorbonne University, UPMC UniversityParis 06France
  12. 12.Department of HepatogastroentérologyGroupe Hospitalier Pitié SalpêtrièreParisFrance
  13. 13.Experimental Pathology Department, Instituto de Investigación Biomédicas de Barcelona (IIBB-CSIC)CIBEREHD, IDIBAPSBarcelonaSpain
  14. 14.Marseille Cedex 9France

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