一种转移性前列腺癌骨痛的新型免疫活性模型。
A novel immunocompetent model of metastatic prostate cancer-induced bone pain.
机构信息
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois.
出版信息
Prostate. 2020 Jul;80(10):782-794. doi: 10.1002/pros.23993. Epub 2020 May 14.
BACKGROUND
Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model.
METHODS
The prostate cancer bone metastasis-induced pain model (CIBP) was established by transplanting a mouse prostate cancer cell line into the femur of immunocompetent mice. Pain development, gait dynamics, and the changes in emotional activities like depression and anxiety were evaluated. Animal tissues including femurs, dorsal root ganglion (DRG), and spinal cord were collected at killing and microcomputed tomography (μCT), histology/immunohistochemistry, and quantitative immunofluorescent analysis were performed.
RESULTS
Mice receiving prostate cancer cells showed a significantly lower threshold for paw withdrawal responses induced by mechanical stimulation compared with their control counterparts. Zero maze and DigiGait analyses indicated reduced and aberrant movement associated emotional activity compared with sham control at 8-weeks postinjection. The μCT analysis showed osteolytic and osteoblastic changes and a 50% reduction of the trabecular volumes within the prostate cancer group. Neurologically we demonstrated, increased calcitonin gene-related peptide (CGRP) and neuronal p75 immune-reactivities in both the projected terminals of the superficial dorsal horn and partial afferent neurons in DRG at L2 to L4 level in tumor-bearing mice. Furthermore, our data show elevated nerve growth factor (NGF) and TrkA immunoreactivities in the same segment of the superficial dorsal horn that were, however, not colocalized with CGRP and p75 .
CONCLUSIONS
This study describes a novel immunocompetent model of CIBP and demonstrates the contribution of NGF and p75 to chronic pain in bone metastasis.
背景
超过 70%至 85%的晚期前列腺癌（PCa）患者会发生骨转移，其特征为严重骨痛和骨折风险增加。这些临床特征导致生活质量下降，并成为更高死亡率的预测因素。从机制上讲，溶骨性病变和异常成骨活性等骨骼病变导致了这些症状。免疫细胞在骨癌痛中的作用仍研究不足，在此我们试图在小鼠模型中重现这种症状。
方法
通过将小鼠前列腺癌细胞系移植到免疫功能正常的小鼠股骨中来建立前列腺癌骨转移诱导的疼痛模型（CIBP）。评估疼痛发展、步态动力学以及抑郁和焦虑等情绪活动的变化。在处死时收集包括股骨、背根神经节（DRG）和脊髓在内的动物组织，并进行微计算机断层扫描（μCT）、组织学/免疫组织化学和定量免疫荧光分析。
结果
与对照组相比，接受前列腺癌细胞的小鼠对机械刺激引起的爪回缩反应的阈值明显降低。与假对照相比，零迷宫和 DigiGait 分析表明，在注射后 8 周时，运动相关的情绪活动减少且异常。μCT 分析显示溶骨性和成骨变化，以及前列腺癌组的小梁体积减少 50%。神经学上，我们在肿瘤小鼠的 L2 到 L4 水平的浅层背角的投射末端和 DRG 的部分传入神经元中均发现降钙素基因相关肽（CGRP）和神经元 p75 的免疫反应性增加。此外，我们的数据显示在同一浅层背角的同一节段中神经生长因子（NGF）和 TrkA 的免疫反应性升高，但与 CGRP 和 p75 不共存。
结论
本研究描述了一种新型的 CIBP 免疫活性模型，并证明了 NGF 和 p75 对骨转移慢性疼痛的贡献。
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