Nigri Jérémy, Gironella Meritxell, Bressy Christian, Vila-Navarro Elena, Roques Julie, Lac Sophie, Bontemps Caroline, Kozaczyk Coraline, Cros Jérôme, Pietrasz Daniel, Maréchal Raphaël, Van Laethem Jean-Luc, Iovanna Juan, Bachet Jean-Baptiste, Folch-Puy Emma, Tomasini Richard
CRCM, INSERM, U1068, 13009, Marseille, France.
Paoli-Calmettes Institute, 13009, Marseille, France.
Cell Mol Life Sci. 2017 Nov;74(22):4231-4243. doi: 10.1007/s00018-017-2579-9. Epub 2017 Jun 27.
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.
胰腺导管腺癌（PDA）是一种致命且隐匿的恶性疾病，目前临床医生应对该疾病的手段因对肿瘤和基质细胞在疾病过程中作用的认知局限而受到限制。在PDA的诸多特征中，神经重塑（NR）和神经周围浸润（PNI）极大地影响患者的生活质量和生存。事实上，NR和PNI分别与神经性疼痛和转移相关，这两者都会影响临床医生的决策和治疗选择。本研究的目的是通过胰腺炎相关蛋白（PAP/REG3A）的表达来确定肿瘤周围微环境对胰腺癌PNI的影响及其临床相关性。首先，我们证明，在PDA中，PAP/REG3A由肿瘤周围微环境中发炎的腺泡细胞产生，进而增强癌细胞的迁移和侵袭能力。更具体地说，通过神经周围体外试验，我们发现PAP/REG3A通过激活癌细胞中的JAK/STAT信号通路促进PNI。最后，我们分析了来自三个独立队列的健康供体或PDA患者血液中PAP/REG3A的水平。PAP/REG3A水平高的患者总体生存期较短，手术结果较差，无病生存期缩短。我们的研究为将PAP/REG3A水平用作生物标志物以改善胰腺癌预后提供了理论依据。它还表明，针对PDA中PAP/REG3A活性的治疗靶向可能会限制肿瘤细胞的侵袭性和PNI。
