Osteoclast-Independent Mechanisms of Early-Stage Bone Colonization of Breast Cancer

乳腺癌早期骨定植的不依赖破骨细胞的机制

• 批准号: 10369640
• 负责人: Xiang Zhang
• 金额: $ 37.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369640
• 关键词: Accounting; Actins; Adherens Junction; Adjuvant; Adjuvant Therapy; Affect; Aging; Biology; Bone Injury; Bone Marrow; Bone Tissue; Breast; Breast Cancer Cell; Cell Communication; Cell Count; Cells; Cessation of life; Clinical; Communication; Cytoskeleton; Data; Dendritic Spines; Dependence; Development; Diagnosis; Elasticity; Epidemiology; Equilibrium; Etiology; Excision; Exhibits; Fostering; Fracture; Freezing; Frequencies; Gap Junctions; Goals; Homeostasis; Injury; Lead; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mesenchymal Cell Neoplasm; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Micrometastasis; Microscopic; Molecular; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Pathologic; Patients; Physiological; Pliability; Process; Publishing; Recurrence; Research; Rest; Risk; Role; Signal Transduction; Site; Stretching; Structure; Testing; Therapeutic; Tissues; bisphosphonate; bone; bone repair; bone turnover; cancer cell; cell motility; cell type; cofilin; design; insight; malignant breast neoplasm; migration; mouse model; neoplastic cell; osteogenic; recruit; trait; Accounting; Actins; Adherens Junction; Adjuvant; Adjuvant Therapy; Affect; Aging; Biology; Bone Injury; Bone Marrow; Bone Tissue; Breast; Breast Cancer Cell; Cell Communication; Cell Count; Cells; Cessation of life; Clinical; Communication; Cytoskeleton; Data; Dendritic Spines; Dependence; Development; Diagnosis; Elasticity; Epidemiology; Equilibrium; Etiology; Excision; Exhibits; Fostering; Fracture; Freezing; Frequencies; Gap Junctions; Goals; Homeostasis; Injury; Lead; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mesenchymal Cell Neoplasm; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Micrometastasis; Microscopic; Molecular; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Pathologic; Patients; Physiological; Pliability; Process; Publishing; Recurrence; Research; Rest; Risk; Role; Signal Transduction; Site; Stretching; Structure; Testing; Therapeutic; Tissues; bisphosphonate; bone; bone repair; bone turnover; cancer cell; cell motility; cell type; cofilin; design; insight; malignant breast neoplasm; migration; mouse model; neoplastic cell; osteogenic; recruit; trait

Project Summary Overt metastases are often diagnosed years after the removal of primary breast tumors, indicating the existence of systemically disseminated tumor cells or microscopic metastases. Adjuvant therapies have been designed to eliminate these cells. Although significant advances were made, a substantial proportion of patients still develop overt metastases, accounting for over 90% of breast cancer-related deaths. How micrometastases resume aggressive outgrowth and become incurable overt metastases remains poorly understood. Our long-term goals are to elucidate the biology underlying the survival and progression of microscopic metastases and to design therapeutic strategies against these latent tumor cells. The overall objective of this project is to investigate how tissue homeostasis of the bone, the organ most frequently affected by metastatic breast cancer, dictates the fate of bone micrometastases (BMM). Bone and bone marrow comprise of several highly distinctive microenvironment niches. Dormant disseminated tumor cells (DTCs) may reside in the perivascular niche, whereas proliferative BMM were found in the osteogenic niche that exhibit features of active osteogenesis (the bone-making process). It remains elusive how cancer cells are relocated from one niche to another, and switch their fates from dormancy to outgrowth. In search for such mechanism, we observed an interesting “migration- by-tethering” phenomenon: cancer cells can adhere to osteogenic cells such as mesenchymal stem cells (MSCs) through a dendritic spine-like structure (DSLS) that is highly pliable and elastic. Like dormant DTCs, resting MSCs also localize in perivascular niches. Turnover of bone tissues releases signals to mobilize and chemo- attracted MSCs to sites needing osteogenesis, thereby providing a possible vehicle for cancer cells to “ride” and relocate from the perivascular niche to the osteogenic niche. The subsequent differentiation of MSCs will then fuel the development of the osteogenic niche, and directly promoting metastasis progression. These findings lead us to hypothesize that the bone turnover process may recruit both osteogenic cells and DTCs via a “migration-by-tethering” mechanism, and foster the development of osteogenic niche to pro-mote bone colonization. We will test these hypotheses by pursuing the following specific aims. Aim 1. To molecularly dissect the “migration-by-tethering” mechanism and determine its role in the development of the osteogenic niche and early-stage bone colonization of DTCs. Aim 2. To determine the impact of perturbations of bone turnover on bone metastasis, and assess how this impact is mediated by the “migration-by-tethering” mechanism that recruits DTCs to the osteogenic niche. The proposed research will have impact at multiple levels. At a cellular level, it will elucidate how cell migration can occur with assistance of microenvironment cells but without acquisition of cancer-intrinsic migratory traits. At a physiological and pathological level, it will establish connections between bone homeostasis and bone metastasis, reveal etiology of late-onset bone recurrences, and provide therapeutic insights.

项目摘要 切除原发性乳腺肿瘤几年后通常被诊断出明显的转移量，表明存在 全身传播的肿瘤细胞或微观转移。调整疗法已设计为 消除这些细胞。尽管取得了重大进展，但仍有很大一部分患者发展 公开转移量，占乳腺癌相关的90％以上的死亡。微型转移如何恢复 积极的生长和成为无法治愈的明显转移量仍然知之甚少。我们的长期目标 阐明了微观转移的生存和进展的生物学，并设计 针对这些潜在肿瘤细胞的治疗策略。该项目的总体目的是调查如何 骨骼的组织体内平衡，最常见受转移性乳腺癌影响的器官决定了命运 骨微晶（BMM）的。几个高度独特的骨头和骨髓 微环境利基市场。休眠的散布肿瘤细胞（DTC）可能位于血管周期壁基中， 而在成骨的生态裂市场中发现了增殖的BMM，该小众发现了活性成骨的特征（该特征 造骨过程）。它仍然难以捉摸如何将癌细胞从一个小众转移到另一个利基市场，然后切换 他们的命运从休眠到产物。在寻找这种机制时，我们观察到了一个有趣的“迁移 - 通过诱导”现象：癌细胞可以粘附于成骨细胞，例如间充质干细胞（MSC） 通过高度柔韧和弹性的树突状脊柱状结构（DSL）。像休眠的DTC一样休息 MSC还本地化于血管周期壁ches。骨组织的营业额释放信号以动员和化学 吸引MSC到需要成骨的地点，从而为癌细胞“骑”和 从血管生殖位迁移到成骨壁ri。然后，MSC的随后分化将 助长成骨的发展，并直接促进转移进展。这些发现 导致我们假设骨转换过程可以通过A募集成骨细胞和DTC “逐个迁移”机制，并促进了成骨的生态裂骨的发展 殖民化。我们将通过追求以下特定目标来检验这些假设。目标1。分子剖析 “逐个迁移”机制，并确定其在成骨的发展中的作用 DTC的早期骨定殖。目的2。确定骨骼更新的扰动的影响 骨转移，并评估这种影响是如何通过招募的“逐个迁移”机制介导的 DTC到成骨的生态位。拟议的研究将在多个层面上产生影响。在细胞水平上 会在微环境细胞的帮助下阐明细胞迁移如何发生，但没有获得 癌症迁移特征。在物理和病理层面，它将建立 骨体内平衡和骨转移，揭示了晚期骨骼的病因，并提供治疗 见解。