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

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-06-18 DOI:10.1038/s41368-024-00308-w
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
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Abstract

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 A2A receptor (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.

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三叉神经上的痛觉腺苷 A2A 受体协调 CGRP 的释放以调节口腔鳞状细胞癌的进展
口腔鳞状细胞癌(OSCC)相关疼痛通常预示着患者的不良事件。这一临床特征表明,在恶性肿瘤的发展过程中,感觉神经元上的痛觉感受器参与其中。然而,靶向与癌细胞相关的痛觉感受器是否能阻碍 OSCC 的发展尚待确定。在这项研究中,我们报告了临床样本和小鼠肿瘤异种移植中浸润的痛觉末梢与较差的临床结果有关,并在体内推动肿瘤进展,这一点已通过临床组织芯片分析和小鼠舌神经支配得到证实。我们观察到,由于 CD73 的上调,OSCC 微环境具有过量腺苷的特征,这对 TCGA-HNSC 患者队列的临床预后具有负面预测作用。值得注意的是,这种富含腺苷的 OSCC 龛与三叉神经节上的腺苷 A2A 受体(A2AR)刺激有关。使用选择性 A2AR 抑制剂 SCH58261 拮抗三叉神经 A2AR 会阻碍 OSCC 在体内的生长。我们发现,在 OSCC 异种移植物中过度刺激三叉神经 A2AR 不会导致三叉神经节中 CGRP 的转录水平发生任何变化,但会显著引发 CGRP 的释放,SCH58261 可抵消这种效应。我们给小鼠喂食临床批准的 CGRP 受体拮抗剂 rimegepant,抑制了 ERK 和 YAP 的激活,从而进一步证明了 CGRP 的促肿瘤作用。最后,我们用异曲菲林(一种针对神经元 A2AR 的临床可用药物)减轻了 CGRP 对 OSCC 的影响。因此,我们将三叉神经A2AR介导的CGRP释放确定为治疗OSCC的一种有前景的药物回路。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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