Cancer-induced bone pain (CIBP) is the most common and devastating symptom of bone metastatic cancer that substantially disrupts patients’ quality of life. Currently, there are few effective analgesic treatments for CIBP other than opioids which come with severe side effects. In order to better understand the factors and mechanisms responsible for CIBP it is essential to have clinically relevant animal models that mirror pain-related symptoms and disease progression observed in patients with bone metastatic cancer.

In the current study, we characterize a syngeneic mouse model of prostate cancer induced bone pain. We transfected a prostate cancer cell line (RM1) with green fluorescent protein (GFP) and luciferase reporters in order to visualize tumor growth longitudinally in vivo and to assess the relationship between sensory neurons and tumor cells within the bone microenvironment. Following intra-femoral injection of the RM1 prostate cancer cell line into male C57BL/6 mice, we observed a progressive increase in spontaneous guarding of the inoculated limb between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. Daily running wheel performance was evaluated as a measure of functional impairment and potentially movement evoked pain. We observed a progressive reduction in the distance traveled and percentage of time at optimal velocity between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. We utilized histological, radiographic and μCT analysis to examine tumor induced bone remodeling and observed osteolytic lesions as well as extra-periosteal aberrant bone formation in the tumor bearing femur, similar to clinical findings in patients with bone metastatic prostate cancer. Within the tumor bearing femur, we observed reorganization of blood vessels, macrophage and nerve fibers within the intramedullary space and periosteum adjacent to tumor cells. Tumor bearing mice displayed significant increases in the injury marker ATF3 and upregulation of the neuropeptides SP and CGRP in the ipsilateral DRG as well as increased measures of central sensitization and glial activation in the ipsilateral spinal cord. This immunocompetent mouse model will be useful when combined with cell type selective transgenic mice to examine tumor, immune cell and sensory neuron interactions in the bone microenvironment and their role in pain and disease progression associated with bone metastatic prostate cancer.

癌症引起的骨痛 (CIBP) 是骨转移癌最常见、最具破坏性的症状，严重影响患者的生活质量。目前，除了具有严重副作用的阿片类药物外，几乎没有有效的 CIBP 镇痛治疗方法。为了更好地了解 CIBP 的影响因素和机制，有必要建立能够反映骨转移癌患者中观察到的疼痛相关症状和疾病进展的临床相关动物模型。

在当前的研究中，我们描述了前列腺癌引起的骨痛的同基因小鼠模型。我们用绿色荧光蛋白（GFP）和荧光素酶报告基因转染前列腺癌细胞系（RM1），以便观察体内肿瘤纵向生长并评估骨微环境内感觉神经元和肿瘤细胞之间的关系。将 RM1 前列腺癌细胞系股骨内注射到雄性 C57BL/6 小鼠中后，我们观察到，与假手术小鼠相比，接种后 12 至 21 天之间，荷瘤小鼠的接种肢体的自发防御逐渐增加。日常跑轮性能被评估为功能障碍和潜在运动引起的疼痛的衡量标准。我们观察到，与假手术小鼠相比，接种后 12 至 21 天，荷瘤小鼠的移动距离和最佳速度的时间百分比逐渐减少。我们利用组织学、放射学和 μCT 分析来检查肿瘤诱导的骨重塑，并观察到荷瘤股骨中的溶骨性病变以及骨膜外异常骨形成，类似于骨转移性前列腺癌患者的临床发现。在带有肿瘤的股骨内，我们观察到邻近肿瘤细胞的髓内空间和骨膜内的血管、巨噬细胞和神经纤维的重组。荷瘤小鼠的同侧背根神经节中损伤标记物 ATF3 显着增加，神经肽 SP 和 CGRP 上调，同侧脊髓中枢敏化和神经胶质细胞活化测量值增加。当与细胞类型选择性转基因小鼠结合时，这种免疫活性小鼠模型将非常有用，以检查骨微环境中的肿瘤、免疫细胞和感觉神经元相互作用以及它们在与骨转移性前列腺癌相关的疼痛和疾病进展中的作用。