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Cell Mol Life Sci. 2017 Nov;74(22):4231-4243. doi: 10.1007/s00018-017-2579-9. Epub 2017 Jun 27.

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

Nigri J1,2,3,4, Gironella M5, Bressy C1,2,3,4, Vila-Navarro E5, Roques J1,2,3,4, Lac S1,2,3,4, Bontemps C6, Kozaczyk C6, Cros J7, Pietrasz D8,9, Maréchal R10, Van Laethem JL10, Iovanna J1,2,3,4, Bachet JB8,9,11,12, Folch-Puy E13, Tomasini R14,15,16,17,18.

Author information

1
CRCM, INSERM, U1068, 13009, Marseille, France.
2
Paoli-Calmettes Institute, 13009, Marseille, France.
3
Aix-Marseille University, UM 105, 13009, Marseille, France.
4
CNRS, UMR7258, 13009, Marseille, France.
5
Gastrointestinal and Pancreatic Oncology, Hospital Clinic of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain.
6
DYNABIO S.A.S, Luminy Biotech Entreprises, 13288, Marseille, France.
7
Department of Pathology, INSERM U1149, Hospital Beaujon, F-92110, Clichy, France.
8
INSERM UMR-S1147, University Paris Descartes, Paris, France.
9
Department of Hepatobiliary and Digestive Surgery, Hospital Pitié Salpêtrière, Paris, France.
10
Gastrointestinal Cancer Unit, University Clinic of Bruxelles, Erasme Hospital, 1070, Brussels, Belgium.
11
Sorbonne University, UPMC University, Paris 06, France.
12
Department of Hepatogastroentérology, Groupe Hospitalier Pitié Salpêtrière, Paris, France.
13
Experimental Pathology Department, Instituto de Investigación Biomédicas de Barcelona (IIBB-CSIC), CIBEREHD, IDIBAPS, Barcelona, Catalonia, Spain.
14
CRCM, INSERM, U1068, 13009, Marseille, France. Richard.tomasini@inserm.fr.
15
Paoli-Calmettes Institute, 13009, Marseille, France. Richard.tomasini@inserm.fr.
16
Aix-Marseille University, UM 105, 13009, Marseille, France. Richard.tomasini@inserm.fr.
17
CNRS, UMR7258, 13009, Marseille, France. Richard.tomasini@inserm.fr.
18
, 163 Avenue de Luminy, Parc scientifique de Luminy, Case 915, 13288, Marseille Cedex 9, France. Richard.tomasini@inserm.fr.

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

PMID:
28656348
DOI:
10.1007/s00018-017-2579-9
[Indexed for MEDLINE]

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