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

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.

项目概要 明显的转移通常在原发性乳腺肿瘤切除数年后才被诊断出来，这表明存在 全身播散的肿瘤细胞或显微转移。辅助疗法的目的是 消除这些细胞。尽管取得了重大进展，但仍有相当一部分患者仍患有 明显的转移，占乳腺癌相关死亡的 90% 以上。微转移如何恢复 侵袭性生长并成为无法治愈的明显转移仍然知之甚少。我们的长期目标 旨在阐明微观转移存活和进展的生物学原理，并设计 针对这些潜在肿瘤细胞的治疗策略。该项目的总体目标是研究如何 骨骼的组织稳态决定了命运，骨骼是最常受转移性乳腺癌影响的器官 骨微转移（BMM）。骨骼和骨髓由几种高度独特的成分组成 微环境利基。休眠播散性肿瘤细胞（DTC）可能驻留在血管周围微环境中， 而增殖性 BMM 在成骨生态位中发现，表现出活跃成骨的特征（ 制骨过程）。癌细胞如何从一个生态位转移到另一个生态位并进行切换仍然难以捉摸。 它们的命运从休眠到生长。在寻找这种机制的过程中，我们观察到了一个有趣的“迁移- 通过“束缚”现象：癌细胞可以粘附到成骨细胞，例如间充质干细胞（MSC） 通过高度柔韧和弹性的树突棘状结构（DSLS）。与休眠 DTC 一样，休息 间充质干细胞也定位于血管周围微环境。骨组织的更新释放信号以动员和化疗 将间充质干细胞吸引到需要成骨的部位，从而为癌细胞“骑行”和提供可能的载体 从血管周围微环境迁移到成骨微环境。 MSCs的后续分化将 促进成骨生态位的发展，并直接促进转移进展。这些发现 使我们假设骨转换过程可能通过以下方式招募成骨细胞和 DTC： “束缚迁移”机制，促进成骨生态位的发展，促进骨生长 殖民化。我们将通过追求以下具体目标来检验这些假设。目标 1. 分子解剖 “束缚迁移”机制并确定其在成骨生态位发展中的作用 DTC 的早期骨定植。目标 2. 确定骨转换扰动对骨转换的影响 骨转移，并评估这种影响是如何通过招募的“束缚迁移”机制介导的 DTC 到成骨利基。拟议的研究将在多个层面产生影响。在细胞水平上，它 将阐明细胞迁移如何在微环境细胞的帮助下发生，但无需获得 癌症固有的迁移特征。在生理和病理层面上，它将在之间建立联系 骨稳态和骨转移，揭示迟发性骨复发的病因，并提供治疗 见解。