Orchestration of breast cancer osteolytic bone metastasis by MIF

描述（由申请人提供）：骨转移的发展是晚期乳腺癌病例的常见特征。骨转移通常导致病理性骨破坏和骨形成，严重削弱整体骨完整性，导致衰弱性骨痛、病理性骨折、麻痹性神经和脊髓压迫以及代谢失衡，显著降低这些患者的生活质量。重要的是，骨转移是不可治愈的，治疗仍然是姑息性的。多种致病因素已被确定为乳腺癌骨转移发展的贡献者。靶向任何单一致病因素的治疗剂可减少骨转移进展，但不会导致治愈。这种单一靶向治疗的有限成功表明，未来开发高度靶向和有效的治疗方式需要更深入地了解乳腺癌向骨扩散的机制。利用我们实验室产生的髓母细胞瘤骨转移的动物模型作为“发现工具”，巨噬细胞迁移抑制因子（MIF）被鉴定为通过乳腺癌和骨细胞之间的自促进前馈信号环的传播潜在地协调乳腺癌溶骨性骨转移的发展的因子。假设这种信号循环导致乳腺癌存活率和增殖增加，同时引发病理性骨破坏。目前的建议旨在（1）检查MIF是否调节成骨细胞和破骨细胞的存活、增殖和活性，以及（2）使用乳腺癌溶骨性骨转移的动物模型确定MIF是否促进溶骨性骨病变的形成，其中癌细胞中的MIF表达已被抑制。通过完成本提案获得的信息将为乳腺癌骨转移的MIF特异性机制提供宝贵的见解，这些机制可用于开发靶向骨转移治疗方式。此外，从这项工作中收集的信息可用于产生与破骨细胞介导的骨丢失相关的其他疾病的治疗干预，如骨质疏松症和糖尿病相关的骨疾病。

DESCRIPTION (provided by applicant): The development of bone metastases is a common feature of advanced breast cancer cases. Skeletal metastases often result in pathologic bone destruction and formation, seriously weakening overall bone integrity leading to debilitating bone pain, pathological fractures, paralyzing nerve and spinal cord compressions, and metabolic imbalances that significantly diminish the quality of life of these patients. Importantly, bone metastases are incurable and treatment remains palliative. Multiple causative factors have been identified as contributors to the development of breast cancer bone metastases. Therapeutic agents targeting any single causative factor reduce bone metastasis progression but do not lead to cure. The limited success of such single targeted therapies indicates a deeper understanding of mechanisms driving the spread of breast cancer to bone is required for the future development of highly targeted and efficacious treatment modalities. Utilizing an animal model of medulloblastoma bone metastasis generated by our laboratory as a 'discovery tool', macrophage migration inhibitory factor (MIF) was identified as a factor potentially orchestrating the development of breast cancer osteolytic bone metastasis through propagation of a self-promoting feed- forward signaling loop between breast cancer and bone cells. This signaling loop is hypothesized to result in enhanced breast cancer survival and proliferation, while instigating pathological bone destruction. The current proposal aims to (1) examine if MIF modulates osteoblast and osteoclast cell survival, proliferation, and activity, and (2) determine i MIF promotes the formation of osteolytic bone lesions using an animal model of breast cancer osteolytic bone metastasis, in which MIF expression has been suppressed in cancer cells. Information obtained through completion of this proposal will provide invaluable insight into MIF-specific mechanisms of breast cancer bone metastasis that may be used in the development of targeted bone metastasis treatment modalities. Additionally, information gleaned from this work may be used in the generation of therapeutic interventions for other diseases associated with osteoclast-mediated bone loss, such as osteoporosis and diabetes-associated bone disease.