PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker
- 382 Downloads
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.
KeywordsPancreatic cancer Perineural invasion Peritumoral microenvironment
We would like to thank Bruno Olivier from INSERM U1068 (Marseille, France) for his technical assistance, Laurence Borge from the U1068 Cell Culture Platform (Marseille, France), and Karim Sari and Régis Vitestelle of the animal colony facility “PSEA” (Marseille, France). This project was supported by SIRIC PACA-OUEST (Grant INCa-DGOS-Inserm 6038), the French National Institute of Cancer (INCa, PLBIO13-134), the European Research Council under the European Union’s Seventh Framework Program (FP/2007–2013)/ERC Grant Agreement No. , the Instituto de Salud Carlos III (for CIBEREHD support) and FIS Grant, PI13/01224 to EF-P and PI13/02192 to MG, co-funded by FEDER-European Union. J.N., C.B., and J.R. were supported by the European Research Council under the European Union’s Seventh Framework Program (FP/2007-2013)/ERC Grant Agreement no. . S.L. was supported by the “Programme Investissements Avenir” from Aix-Marseille University and J.R. by “Cancéropole PACA”.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- 14.Chalabi-Dchar M, Cassant-Sourdy S, Duluc C et al (2015) Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16. Gastroenterology 148:1452–1465. doi: 10.1053/j.gastro.2015.02.009 CrossRefPubMedGoogle Scholar
- 21.Barthellemy S, Maurin N, Roussey M et al (2001) Evaluation of 47,213 infants in neonatal screening for cystic fibrosis, using pancreatitis-associated protein and immunoreactive trypsinogen assays. Arch Pediatr Organe Off Soc Francaise Pediatr 8:275–281Google Scholar
- 28.Folch-Puy E, Granell S, Dagorn JC et al (2006) Pancreatitis-associated protein I suppresses NF-kappa B activation through a JAK/STAT-mediated mechanism in epithelial cells. J Immunol Baltim Md 1950 176:3774–3779Google Scholar
- 31.Hibi T, Mori T, Fukuma M et al (2009) Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer. Clin Cancer Res Off J Am Assoc Cancer Res 15:2864–2871. doi: 10.1158/1078-0432.CCR-08-2946 CrossRefGoogle Scholar
- 37.Wörmann SM, Song L, Ai J et al (2016) Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology 151(180–193):e12. doi: 10.1053/j.gastro.2016.03.010 Google Scholar