Nociceptive adenosine A2A receptor on trigeminal nerves orchestrates CGRP release to regulate the progression of oral squamous cell carcinoma  

作　　者：Lanxin Jiang Ying Zhou Shijie Tang Dan Yang Yixin Zhang Jiuge Zhang Fan Yang Tong Zhou Xiaoqiang Xia Qianming Chen Lu Jiang Yuchen Jiang Xiaodong Feng 

机构地区：[1]State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Research Unit of Oral Carcinogenesis and Management,Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,China [2]Key Laboratory of Oral Biomedical Research of Zhejiang Province,Affiliated Stomatology Hospital,Zhejiang University School of Stomatology,Hangzhou,China

出　　处：《International Journal of Oral Science》2024年第4期685-694,共10页国际口腔科学杂志(英文版)

基　　金：National Natural Science Foundation of China(82170971,82373187and 82002888);Fundamental Research Funds for the Central Universities(YJ201987);Sichuan Science and Technology Program(2021ZYD0090 and 2022YFS0207);Scientific Research Foundation,West China Hospital of Stomatology Sichuan University(QDJF2019-3 and RD-03-202110);CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-004)。

摘　　要：Oral squamous cell carcinoma(OSCC)associated pain commonly predicts adverse events among patients.This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy.However,it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression.In this study,we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo,as evidenced by clinical tissue microarray analysis and murine lingual denervation.We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort.Notably,such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2Areceptor(A2AR)on trigeminal ganglia.Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo.We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP,an effect counteracted by SCH58261.We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP.Finally,we diminished the impact of CGRP on OSCC with istradefylline,a clinically available drug that targets neuronal A2AR.Therefore,we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

关 键 词：TRIGEMINAL stimulation SQUAMOUS 

分 类 号：R739.8[医药卫生—肿瘤]