CGRP-mediated Cancer Pain Mechanisms and Targeted Therapeutic Approaches
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摘要: 降钙素基因相关肽（calcitonin gene-related peptide，CGRP）在癌性疼痛的发生与维持过程中发挥中枢-外周协同放大作用。其机制涉及激活NGF、BMP2等信号通路，增强感觉神经兴奋性，促进外周和中枢敏化，并与肿瘤微环境共同形成“疼痛-肿瘤进展”正反馈循环。临床前研究表明，CGRP拮抗剂在乳腺癌、口腔癌及胰腺癌等模型中展现出显著的镇痛及抗肿瘤潜力。此外，CGRP水平与癌痛强度密切相关，提示其作为靶向癌痛治疗的潜在标志物与干预靶点。对CGRP在癌性疼痛及肿瘤进展中的作用机制及相关治疗研究进展进行综述，并探讨未来通过靶向CGRP通路联合现有治疗手段，作为癌痛管理的新策略。Abstract: Calcitonin gene-related peptide （CGRP） exerts a central-peripheral synergistic amplification effect in the development and maintenance of cancer pain. This effect is mediated through the activation of signaling pathways, including NGF and BMP2, leading to increased sensory nerve excitability, the promotion of peripheral and central sensitization, and the formation of a "pain-tumor progression" positive feedback loop with the tumor microenvironment. Preclinical evidence has demonstrated the significant analgesic and anti-tumor potential of CGRP antagonists in models including breast cancer, oral cancer, and pancreatic cancer, among others. Furthermore, CGRP levels are closely correlated with cancer pain intensity, suggesting its potential value as a biomarker and intervention target for targeted cancer pain therapy. This review summarizes the mechanistic roles of CGRP in cancer pain and tumor progression, as well as recent advances in related therapeutic research, and explores future strategies for cancer pain management through targeting the CGRP pathway in combination with existing treatment modalities.
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Key words:
- CGRP /
- Cancer-related pain /
- Tumor microenvironment /
- Targeted therapy /
- Clinical translation
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图 1 CGRP分布
α-CGRP主要表达于感觉神经系统，其神经元胞体主要分布于DRG和TG。而β-CGRP则主要分布于运动神经元。在胃肠道中，包括肠道各层结构以及血管内，两种CGRP亚型的分布情况如图所示。图中以α>β或β>α标示了不同核团或结构中两种亚型的相对表达优势。
Figure 1. Distribution of CGRP
图 2 CGRP“疼痛-肿瘤进展”循环
DRG与TG中的感觉神经元在肿瘤微环境炎症因子刺激下被激活，促进CGRP释放增多，进而触发外周与中枢敏化过程。外周层面，CGRP通过激活TRPV1/Nav1.8等通道降低痛阈、诱发痛觉过敏；中枢层面，CGRP增强谷氨酸释放与NMDA受体活化，进一步放大疼痛信号。同时，CGRP通过cAMP/PKA通路提升神经元兴奋性并形成自分泌正反馈，而BMP2/Smad1通路则与CGRP表达形成正向互馈，协同促进肿瘤进展、免疫逃逸与疼痛加剧，最终构成“疼痛-肿瘤进展”的恶性循环。
Figure 2. The "pain-tumor progression" cycle of CGRP
图 3 CGRP在乳腺癌神经-肿瘤正反馈环路中的核心作用及靶向干预示意图
CGRP在乳腺癌组织中显著高表达。癌细胞可诱导DRG轴突生长并增强肿瘤内神经纤维浸润，促进CGRP释放，形成持续的神经-肿瘤正反馈环路。CGRP通过激活PKA/PKC通路增强DRG神经元兴奋性，与NGF协同加剧疼痛传导，并与骨转移相关疼痛加重有关。此外，CGRP通过激活ERK/YAP等促癌信号通路，促进肿瘤增殖、迁移、血管生成和免疫逃逸，且CGRP拮抗剂可缓解癌痛并抑制肿瘤生长。
Figure 3. Core role of CGRP in the neuro-tumor positive feedback loop in breast cancer and a schematic diagram of targeted intervention
表 1 CGRP在癌性疼痛中的作用机制
Table 1. The role of calcitonin gene-related peptide in oncologic pain
机制类别 关键机制 效应 / 临床表现 关键分子与通路 肿瘤微环境-疼痛相互作用 1.促炎介质（IL-6、TNF-α、NGF）刺激外周感觉神经元
2.CGRP/SP释放1.神经元敏化（痛阈↓）
2.痛觉过敏 / 自发性疼痛
3.CGRP 通过旁分泌信号
促进肿瘤进展
4.通过TG神经元激活增强疼痛传导1.CLR/RAMP1受体的激活
2.NGF/TrkA通路介导神经敏化
3.BMP2/BMPR/Smad轴
调控CGRP表达
4.cAMP/PKA通路增强神经元兴奋性外周敏化 1.触发因素：
炎症介质（缓激肽、NGF、PGE2；
酸性微环境（H⁺浓度↑）
2.直接激活：伤害性感受器阈值↓
3.轴突反射： CGRP/SP 释放→正反馈环路1.痛觉过敏
2.痛觉超敏1.NGF/TrkA信号增强神经元反应性，促进CGRP分泌与TRPV1受体表达
2.PKA/PKC磷酸化离子通道（如Nav1.8），降低兴奋阈值
3.前列腺素E2通过EP受体
增强敏化状态中枢敏化 1.启动：突触前：谷氨酸 / CGRP/SP 释放↑；突触后：N-甲基-D-天冬氨酸受体（NMDA-R）激活、Ca²⁺内流
2.维持：转录调控（环磷腺苷反应元件结合蛋白（CREB）→受体上调）1.痛觉过敏/痛觉超敏
2.继发性痛觉过敏
3.广动力范围（WDR）
神经元过度激活（自发放电↑）1.cAMP/PKA/PKC通路介导NMDA
受体磷酸化，增强突触后反应
2.pERK/MAPK通路调控c-Fos、BDNF等基因表达，维持中枢敏化
3.CGRP通过正反馈促进谷氨酸释放，加剧突触传递效能
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表 2 CGRP在癌症疼痛和肿瘤进展中的作用-临床前与临床研究
Table 2. Role of CGRP in cancer pain and tumor progression – preclinical and clinical insights
癌症类型 模型 / 方法 关键发现 机制 / 通路 治疗靶点 / 策略 骨癌 1.骨癌疼痛大鼠模型
2.鞘内注射CGRP8-37
3.BMP2-siRNA 干预
4.BMPR抑制剂 （LDN193189） 处理1.CGRP在DRG显著上调，诱发机械性痛觉过敏
2.干预BMP2/Smad1 通路可下调CGRP表达，缓解疼痛1.BMP2/BMPR/Smad1 信号通路调控CGRP 表达
2.CGRP通过激活PKA/PKC 通路增强神经元兴奋性1.靶点：BMP2/Smad1/CGRP轴
2.策略：使用 CGRP受体拮抗剂
（CGRP8-37）、BMP2-siRNA、
BMPR抑制剂（LDN193189）乳腺癌 1.乳腺癌动物模型
2.CGRP拮抗剂（Rimegepant）干预1.CGRP在乳腺癌组织（尤其三阴性乳腺癌 TNBC）中上调，与预后不良相关
2.CGRP促进肿瘤神经浸润及骨转移癌痛1.CGRP激活 PKA/PKC 通路增强 DRG 兴奋性
2.CGRP激活 ERK/YAP信号通路，促进肿瘤增殖、迁移、血管生成及免疫逃逸1.靶点：CGRP 通路
2.策略：使用 CGRP拮抗剂（Rimegepant），兼具缓解癌痛与抗肿瘤潜力口腔癌 1.舌鳞癌小鼠模型
2.CGRP拮抗剂（BIBN4096、Oleegepant）干预
3.A2AR拮抗剂（SCH58261、伊曲茶碱）干预1.CGRP受体（RAMP1/CALCRL）高表达，促进肿瘤生长与淋巴结转移
2.CGRP水平与疼痛评分呈正相关1.A2AR激活促进 CGRP释放
2.CGRP通过受体激活ERK1/2-CD44及 Hippo-YAP通路
3.CGRP抑制 CD4⁺/CD8⁺ T细胞功能1.靶点：A2AR-CGRP 轴、ERK/YAP通路
2.策略：使用 CGRP受体拮抗剂（BIBN4096、Oleegepant、Fremanezumab、Rimegepant）、A2AR拮抗剂胰腺癌 1.胰腺癌细胞与 DRG共培养实验
2.sHH抑制剂（Cyclopamine）干预
3.TrkA抑制剂（GW441756）干预1.胰腺癌细胞通过 sHH 信号上调DRG中 CGRP合成
2.血清CGRP水平与疼痛程度相关1.肿瘤分泌sHH激活 DRG 中 Gli1/Gli2，上调 CGRP
2.NGF通过 TrkA/p75增强CGRP 释放1.靶点：sHH-CGRP 轴、NGF/TrkA 通路
2.策略：使用 sHH 抑制剂、TrkA 抑制剂、CGRP 靶向药物，探索联合治疗通用 /
多癌种1.CGRP受体拮抗剂（小分子 gepants）
2.抗CGRP单克隆抗体（anti-CGRP MAbs）1.CGRP拮抗剂通过多靶点机制缓解癌症疼痛
2.抗CGRP单克隆抗体安全性高、给药便利（长半衰期）1.外周：阻断CGRP 与受体结合，抑制伤害性感受器敏化
2.中枢：减少谷氨酸释放
3.抑制神经炎症（IL-6、TNF-α）及血管生成1.靶点：CGRP 或其受体（CALCRL/RAMP1）
2.策略：使用 CGRP受体拮抗剂、抗CGRP单克隆抗体（如 Fremanezumab）
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