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 · 发表于：International Journal of Oral Science · 年份：2024 · DOI：10.1038/s41368-024-00308-w · 被引用次数：18 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Nerve injury and regeneration、Adenosine and Purinergic Signaling

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 A 2A receptor (A 2A R) on trigeminal ganglia. Antagonism of trigeminal A 2A R with a selective A 2A R inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A 2A R 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....