Scanlon Christina Springstead, Banerjee Rajat, Inglehart Ronald C, Liu Min, Russo Nickole, Hariharan Amirtha, van Tubergen Elizabeth A, Corson Sara L, Asangani Irfan A, Mistretta Charlotte M, Chinnaiyan Arul M, D'Silva Nisha J
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Nat Commun. 2015 Apr 28;6:6885. doi: 10.1038/ncomms7885.
Perineural invasion (PNI) is an indicator of poor survival in multiple cancers. Unfortunately, there is no targeted treatment for PNI since the molecular mechanisms are largely unknown. PNI is an active process, suggesting that cancer cells communicate with nerves. However, nerve-tumour crosstalk is understudied due to the lack of in vivo models to investigate the mechanisms. Here we developed an in vivo model of PNI to characterize this interaction. We show that the neuropeptide galanin (GAL) initiates nerve-tumour crosstalk via activation of its G protein-coupled receptor, GALR2. Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2-mediated transcription of cyclooxygenase-2 and GAL. Prostaglandin E2 promotes cancer invasion, and in a feedback mechanism, GAL released by cancer induces neuritogenesis, facilitating PNI. This study describes a novel in vivo model for PNI and reveals the dynamic interaction between nerve and cancer.
神经周围浸润（PNI）是多种癌症患者生存率低的一个指标。不幸的是，由于分子机制大多未知，目前尚无针对PNI的靶向治疗方法。PNI是一个活跃的过程，这表明癌细胞与神经之间存在交流。然而，由于缺乏用于研究其机制的体内模型，神经-肿瘤相互作用的研究较少。在此，我们建立了一个PNI体内模型来表征这种相互作用。我们发现神经肽甘丙肽（GAL）通过激活其G蛋白偶联受体GALR2启动神经-肿瘤相互作用。我们的数据揭示了一种新机制，即神经来源的GAL刺激癌细胞上的GALR2，以诱导NFATC2介导的环氧合酶-2和GAL的转录。前列腺素E2促进癌症侵袭，并且在一种反馈机制中，癌症释放的GAL诱导神经突生成，促进PNI。本研究描述了一种新的PNI体内模型，并揭示了神经与癌症之间的动态相互作用。
