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: 10365974
• 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/10365974
• 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; FLT3 ligand; Goals; Growth; Harvest; Immune; Impairment; In Vitro; Ligands; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Measures; Mediating; 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; Quality of life; Radium; Role; Scheme; Spinal Ganglia; Symptoms; System; Tissues; Work; afferent nerve; bone; calcitonin receptor-like receptor; cancer cell; cancer survival; 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.

项目概要 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治疗。骨转移的主要并发症是骨痛。 尽管多项研究表明神经在癌症进展中发挥作用，并且骨骼 疼痛和总体生存率呈负相关，但所涉及的机制仍然难以捉摸。我们发现 认为：1）癌症骨转移或转移性骨病丰富了表达 骨骼中的神经肽降钙素基因相关肽（CGRP），会引起骨痛； 2）骨转移 癌细胞表达降钙素受体样受体（CRLR）水平升高； 3）CGRP诱发癌症 通过 CRLR/p38 途径增殖； 4) 存在激活的 FMS 样酪氨酸激酶 3 受体 (Flt3) 在出现骨痛指标的小鼠背根神经节中； 5)骨转移癌细胞表达 Flt3 配体 (FL) 水平升高； 6) FL 诱导感觉神经的萌芽。我们因此 假设 (a) 源自骨转移性前列腺癌的 FL 通过 Flt3 刺激感觉神经， 导致癌症引起的骨痛； (b) 癌症相关感觉神经表达的 CGRP 诱导 通过 CRLR/p38 途径进展转移性骨疾病。在这份 R01 提案中，提交于 针对PAR-16-245，我们将：（1）确定骨转移癌细胞是否增加感觉神经 感觉神经中的发芽和 CGRP 合成，通过 FL/Flt3 导致癌症引起的骨痛 轴; (2)确定骨转移病灶感觉神经表达的CGRP是否刺激骨 通过 CRLR/p38 的转移生长。使用体外原代背根神经节培养系统和 癌症引起的骨痛的独特小鼠模型，将使我们能够在同一动物内测量：（i）肿瘤 生长，(ii) 骨骼神经支配，(iii) 骨重塑，以及 (iv) 由此产生的疼痛行为。使用骨活检 对于患者来说，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 这些结果可用于开发针对癌症/神经相互作用的新治疗策略。短期来看，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 了解转移进展和疼痛信号如何相互影响以使疾病恶化 进展将有助于发现癌症引起的骨痛和骨的新治疗靶点 转移性癌症——当前治疗需要的领域——减少痛苦并提高生存率 患有骨转移的癌症患者。