The contributions of sensory nerves to bone metastasis and associated bone pain

感觉神经对骨转移和相关骨痛的贡献

• 批准号: 10596199
• 负责人: Yusuke Shiozawa
• 金额: $ 36.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596199
• 关键词: Address; Afferent Neurons; Animals; Area; Attenuated; Benign; Biopsy; Bone Development; Bone Diseases; Bone Growth; Bone Pain; Bone remodeling; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cancer Control; Cancer Model; Cancer Patient; Cause of Death; Cells; Complication; Data; Disease Progression; FLT3 gene; Goals; Growth; Harvest; Immune; Impairment; In Vitro; Ligands; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Measures; Mediating; Metastasis Induction; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular Probes; Mus; Neoplasm Metastasis; Nerve; Neuropeptides; Pain; Pathway interactions; Patients; Peptide Synthesis; Peptides; Periosteum; Plasma; Primary Neoplasm; Prognosis; Proliferating; Quality of life; Radium; Role; Scheme; Spinal Ganglia; Symptoms; System; Tissues; Work; afferent nerve; bone; calcitonin receptor-like receptor; cancer cell; cancer survival; carcinogenesis; effective therapy; ganglion cell; improved; in vivo; insight; mortality; mouse model; negative affect; nerve supply; new therapeutic target; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; pain behavior; pain signal; palliative; prostate cancer cell; prostate cancer model; prostate cancer progression; receptor; response; skeletal; soft tissue; targeted cancer therapy; treatment strategy; tumor; tumor growth; tumor progression

Project Summary Bone metastasis remains a major cause of death among patients with prostate cancer. Unfortunately, current treatments for bone metastases are mainly palliative. A major complication of bone metastasis is bone pain. Although several lines of study have suggested that nerves have a role in cancer progression, and that bone pain and overall survival are negatively correlated, the mechanisms involved remain elusive. We have found that: 1) cancer metastasis to bone or metastatic bone disease enriches sensory nerves that express the neuropeptide calcitonin gene-related peptide (CGRP) in the bone, and that causes bone pain; 2) bone-metastatic cancer cells express elevated levels of calcitonin-receptor like receptor (CRLR); 3) CGRP induces cancer proliferation through the CRLR/p38 pathway; 4) activated FMS-like tyrosine kinase 3 receptor (Flt3) is present in the dorsal root ganglia of mice presenting bone pain indicators; 5) bone-metastatic cancer cells express elevated levels of the Flt3 ligand (FL); and 6) FL induces the sprouting of sensory nerves. We therefore hypothesize that (a) FL derived from bone-metastatic prostate cancer stimulates sensory nerves through Flt3, resulting in cancer-induced bone pain; and (b) CGRP expressed by cancer-associated sensory nerves induces progression of metastatic bone disease through the CRLR/p38 pathway. In this R01 proposal, submitted in response to PAR-16-245, we will: (1) Determine whether bone-metastatic cancer cells increase sensory nerve sprouting and CGRP synthesis in sensory nerves, contributing to cancer-induced bone pain, through the FL/Flt3 axis; and (2) Determine whether CGRP expressed by sensory nerves in bone-metastatic lesions stimulate bone metastatic outgrowth through CRLR/p38. Using an in vitro primary dorsal root ganglia culture system and a unique mouse model of cancer-induced bone pain, will allow us to measure within the same animal: (i) tumor growth, (ii) skeletal innervation, (iii) bone remodeling, and (iv) resultant pain behaviors. Using bone biopsies from patients, we will probe the molecular mechanisms whereby the crosstalk between bone metastatic cancer and sensory nerves controls both progression of bone metastases and development of associated pain. We will use these results to develop a new therapeutic strategy targeting cancer/nerve interactions. In the short term, this study will elucidate new mechanisms of bone metastasis and cancer-induced bone pain. In the long run, a better understanding of how metastatic progression and pain signals influence one another to worsen disease progression will aid in discovering new therapeutic targets for both cancer-induced bone pain and bone metastatic cancer – areas in which current therapies are wanting – to decrease suffering and improve the survival of cancer patients with bone metastases.

项目摘要 骨转移仍然是前列腺癌患者死亡的主要原因。不幸的是，目前 骨转移的治疗主要是姑息性的。骨转移的主要并发症是骨痛。 尽管有几项研究表明，神经在癌症进展中发挥作用， 疼痛和总生存率呈负相关，但相关机制仍不清楚。我们发现 1）癌症转移到骨或转移性骨疾病富集了表达 神经肽降钙素基因相关肽（CGRP）在骨，并导致骨痛; 2）骨转移 癌细胞表达升高水平的降钙素受体样受体（CRLR）; 3）CGRP诱导癌症 通过CRLR/p38途径增殖; 4）存在激活的FMS样酪氨酸激酶3受体（Flt 3） 在呈现骨痛指标的小鼠的背根神经节中; 5）骨转移癌细胞表达 Flt 3配体（FL）水平升高;和6）FL诱导感觉神经发芽。因此我们 假设（a）源自骨转移性前列腺癌的FL通过Flt 3刺激感觉神经， 导致癌症诱导的骨痛;和（B）由癌症相关感觉神经表达的CGRP诱导 通过CRLR/p38途径的转移性骨疾病的进展。在提交的R 01提案中， 对PAR-16-245的反应，我们将：（1）确定骨转移癌细胞是否增加感觉神经 感觉神经中的出芽和CGRP合成，通过FL/Flt 3促进癌症诱导的骨痛 （2）确定骨转移病灶中感觉神经表达的CGRP是否刺激骨 通过CRLR/p38转移性生长。采用体外原代背根神经节培养系统， 独特的癌症诱导骨痛小鼠模型，将允许我们在同一动物内测量：（i）肿瘤 生长，（ii）骨骼神经支配，（iii）骨重建，和（iv）由此产生的疼痛行为。利用来自 对于患者，我们将探讨骨转移癌与骨转移癌之间相互影响的分子机制。 感觉神经控制骨转移的进展和相关疼痛的发展。我们将使用 这些结果开发了一种针对癌症/神经相互作用的新治疗策略。短期内这 研究将阐明骨转移和癌症引起的骨痛的新机制。从长远来看，更好的 了解转移进展和疼痛信号如何相互影响，使疾病恶化 这一进展将有助于发现癌症引起的骨痛和骨关节炎的新治疗靶点。 转移性癌症--目前的治疗方法所需要的领域--以减少痛苦和提高生存率 癌症骨转移患者的情况。