MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells.
MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells.
复制标题
MMP1/PAR1/SP/NK1R旁分泌环调节胰腺癌细胞的早期神经周围侵袭
作者：
Huang C;Li Y;Guo Y;Zhang Z;Lian G;Chen Y;Li J;Su Y;Li J;Yang K;Chen S;Su H;Huang K;Zeng L
神经侵袭(PNI)的分子机制尚不清楚，体内早期PNI的检测不足阻碍了对PNI的研究。我们的目的是确定胰腺导管腺癌细胞(PDAC)细胞和神经之间的细胞因子旁分泌环路，并建立一种无创性的体内监测PNI的方法。方法：采用Matrigel/背根神经节(DRG)系统体外观察PNI，建立小鼠坐骨神经侵袭模型，观察体内PNI。用纳米氧化铁标记的磁共振成像评价PNI。我们搜索公开可用的数据集，并从30名患者获得PDAC组织，以检测MMP1在人类肿瘤和非肿瘤组织中的表达。结果：基质金属蛋白酶-1(MMP1)激活AKT，诱导表达PAR1的DRG释放P物质(SP)，进而激活表达NK1R的PDAC细胞，通过SP/NK1R/ERK促进细胞迁移、侵袭和PNI。在动物中，在神经外膜接种癌细胞约20天后，观察到后肢瘫痪和后爪宽度减少。用shRNA沉默MMP1或用PAR1或NK1R拮抗剂处理均可抑制PNI。MRI最早在PDAC细胞植入后10d即可检测到PNI。PNI还可诱导PDAC肝转移。对患者组织的生物信息学分析和病理研究证实了这些发现的临床相关性。结论：在本研究中，我们提供了MMP1/PAR1/SP/NK1R旁分泌环路在原发肿瘤形成早期参与PNI的证据。此外，我们建立了一种使用纳米氧化铁和MRI检测神经侵袭的灵敏和非侵入性的方法。
The molecular mechanism of perineural invasion (PNI) is unclear, and insufficient detection during early-stage PNI in vivo hampers its investigation. We aimed to identify a cytokine paracrine loop between pancreatic ductal adenocarcinoma (PDAC) cells and nerves and established a noninvasive method to monitor PNI in vivo. Methods: A Matrigel/ dorsal root ganglia (DRG) system was used to observe PNI in vitro, and a murine sciatic nerve invasion model was established to examine PNI in vivo. PNI was assessed by MRI with iron oxide nanoparticle labeling. We searched publicly available datasets as well as obtained PDAC tissues from 30 patients to examine MMP1 expression in human tumor and non-tumor tissues. Results: Our results showed that matrix metalloproteinase-1 (MMP1) activated AKT and induced protease-activated receptor-1 (PAR1)-expressing DRG to release substance P (SP), which, in turn, activated neurokinin 1 receptor (NK1R)-expressing PDAC cells and enhanced cellular migration, invasion, and PNI via SP/NK1R/ERK. In animals, hind limb paralysis and a decreased hind paw width were observed approximately 20 days after inoculation of cancer cells in the perineurium. MMP1 silencing with shRNA or treatment with either a PAR1 or an NK1R antagonist inhibited PNI. MRI detected PNI as early as 10 days after implantation of PDAC cells. PNI also induced PDAC liver metastasis. Bioinformatic analyses and pathological studies on patient tissues corroborated the clinical relevance of these findings. Conclusion: In this study, we provided evidence that the MMP1/PAR1/SP/NK1R paracrine loop contributes to PNI during the early stage of primary tumor formation. Furthermore, we established a sensitive and non-invasive method to detect nerve invasion using iron oxide nanoparticles and MRI.
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影响因子：
11.2
作者：
Juncker-Jensen A;Deryugina EI;Rimann I;Zajac E;Kupriyanova TA;Engelholm LH;Quigley JP
通讯作者：
Quigley JP
DOI：
10.1158/1078-0432.ccr-16-3122
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brown JM;Recht L;Strober S
通讯作者：
Strober S
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
5.7
作者：
Guo, Kun;Ma, Qingyong;Xie, Keping
通讯作者：
Xie, Keping
Sonic Hedgehog 旁分泌信号激活基质细胞促进胰腺癌神经周围侵袭
影响因子：
11.5
作者：
Li, Xuqi;Wang, Zheng;Xie, Keping
通讯作者：
Xie, Keping