Defining the Rules of Breast Cancer Cell Traffic Through Bone

定义乳腺癌细胞通过骨运输的规则

• 批准号: 10368923
• 负责人: Dorothy A Sipkins
• 金额: $ 15.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-09 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368923
• 关键词: Adjuvant Chemotherapy; Adjuvant Therapy; Apoptotic; Area; Back; Biopsy; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Involvement; Bone marrow biopsy; Breast Cancer Cell; Breast Cancer Patient; CXCR4 gene; Cancer Biology; Cancer Etiology; Cause of Death; Cell Adhesion Molecules; Cell Cycle; Cell Survival; Cell surface; Cells; Cessation of life; Chemosensitization; Clinical; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Diagnosis; Disease; E-Selectin; Environment; Estrogen receptor positive; Flushing; Hematopoietic stem cells; Homing; Hormonal; In Vitro; Individual; Integrins; Intervention; Knowledge; Laboratories; Ligands; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Methods; Micrometastasis; Microscopy; Molecular; Molecular and Cellular Biology; Morphology; Movement; Mus; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Peripheral; Phenotype; Proliferating; Recurrent disease; Relapse; Resistance; Resolution; Role; Selectins; Shelter facility; Signal Transduction; Site; Source; Stains; Stromal Cell-Derived Factor 1; Testing; Therapeutic; Time; Tissues; Tropism; Woman; Work; Xenograft Model; base; bone; cancer cell; cell motility; cytokine; design; hormone therapy; in vivo; in vivo imaging; inhibitor; malignant breast neoplasm; mortality; new therapeutic target; prevent; protective effect; stem cells; trafficking; Adjuvant Chemotherapy; Adjuvant Therapy; Apoptotic; Area; Back; Biopsy; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Involvement; Bone marrow biopsy; Breast Cancer Cell; Breast Cancer Patient; CXCR4 gene; Cancer Biology; Cancer Etiology; Cause of Death; Cell Adhesion Molecules; Cell Cycle; Cell Survival; Cell surface; Cells; Cessation of life; Chemosensitization; Clinical; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Diagnosis; Disease; E-Selectin; Environment; Estrogen receptor positive; Flushing; Hematopoietic stem cells; Homing; Hormonal; In Vitro; Individual; Integrins; Intervention; Knowledge; Laboratories; Ligands; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Methods; Micrometastasis; Microscopy; Molecular; Molecular and Cellular Biology; Morphology; Movement; Mus; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Peripheral; Phenotype; Proliferating; Recurrent disease; Relapse; Resistance; Resolution; Role; Selectins; Shelter facility; Signal Transduction; Site; Source; Stains; Stromal Cell-Derived Factor 1; Testing; Therapeutic; Time; Tissues; Tropism; Woman; Work; Xenograft Model; base; bone; cancer cell; cell motility; cytokine; design; hormone therapy; in vivo; in vivo imaging; inhibitor; malignant breast neoplasm; mortality; new therapeutic target; prevent; protective effect; stem cells; trafficking

ABSTRACT The major cause of death from breast cancer is metastatic relapse, which most commonly occurs first in the bone. Bone marrow (BM) biopsies performed on women with early stage breast cancer have shown that small, clinically unapparent “micrometastases” are actually present at the time of diagnosis in many patients. These micrometastases can survive in the face of adjuvant chemotherapy and lay dormant for years before they become proliferative, causing overt metastatic disease. At this stage, disease becomes incurable. Our increasing understanding of breast cancer biology has revealed to us the importance of the host tissue in creating a receptive and protective environment for metastases. Preliminary data from our lab using mouse xenograft models show that breast cancer cells (BCCs) metastasize to and lay dormant in unique perivascular hematopoietic progenitor and stem cell (HSPC) niches. The blood vessels in these regions are distinguished by their sinusoidal morphology and their high basal expression of the adhesion molecule E- selectin, and the cytokine SDF-1. Using highly specific E-selectin and CXCR4 inhibitors, we have identified that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. While E-selectin interactions are critical for allowing BCC entry in BM, SDF-1/CXCR4 anchors BCCs to the microenvironment and its inhibition induces mobilization of dormant micrometastases into circulation. Moreover, our immunohistochemical studies of biopsies performed on patients with micrometastatic BM involvement show that dormant metastases reside adjacent to SDF-1+ vasculature. Based on these data, we hypothesize that dormant BCCs shelter within unique peri-sinusoidal vascular BM niches from which they are able to dynamically transit back-and-forth to the peripheral circulation as well as to alternative, pro-proliferative microenvironments within the bone. We also hypothesize that interventions such as CXCR4 and E-selectin inhibition can flush dormant BCCs from the protective sinusoidal niche, making them susceptible to cytotoxic or hormonal therapies. To test these hypotheses, we will use single cell resolution, video rate in vivo microscopy in mouse xenograft models to track BCC migration through BM in real time. In combination with in vitro molecular and cellular biology approaches, we will 1) Investigate the signals that critically regulate BCC metastatic entry in bone; 2) Study the molecular mechanisms that regulate BCC exit from bone metastatic sites into peripheral circulation and the impact of mobilization on BCC signaling and viability; and 3) Understand how cross talk with the peri-sinusoidal BM vascular niche mediates BCC dormancy and sensitivity to chemo- and hormonal therapies. Knowledge gained from this work will identify fundamental mechanisms governing the dynamic movement of micrometastatic BCCs and will suggest therapeutic methods to target supportive crosstalk between BM and dormant breast cancer.

抽象的 乳腺癌死亡的主要原因是转移性继电器，最常见的是首先发生 骨头。对早期乳腺癌女性进行的骨髓（BM）活检表明 在许多患者的诊断时，实际上存在临床上临床上的较小的“微转移”。 这些微型转移可以在调整化学疗法的情况下生存，并在休眠状态下多年 它们成为增生剂，引起明显的转移性疾病。在此阶段，疾病变得无法治愈。 我们对乳腺癌生物学的越来越了解向我们揭示了宿主的重要性 组织为转移创造一种接受和受保护的环境。我们实验室的初步数据使用 小鼠异种移植模型表明，乳腺癌细胞（BCC）转移到处于独特的状态 血管周围造血祖细胞和干细胞（HSPC）壁ni。这些地区的血管是 以它们的正弦形态和粘合分子e-的高基本表达为由 选择素和细胞因子SDF-1。使用高度特异的E-选择蛋白和CXCR4抑制剂，我们已经确定 电子选择素和SDF-1在BCC贩运中策划了相反的角色。虽然电子选择蛋白相互作用对于 允许BCC进入BM，SDF-1/CXCR4将BCC锚定在微环境及其抑制作用诱导 使休眠的微转移酶动员到循环中。此外，我们的免疫组织化学研究 对微转移BM受累的患者进行的活检表明休眠转移酶休息 与SDF-1+脉管系统相邻。基于这些数据，我们假设处于休眠的BCC庇护 独特的螺旋性血管BM壁ni 周围循环以及骨骼内的替代性，促销的微环境。我们也是 假设诸如CXCR4和E-选择蛋白抑制之类的干预措施可以从休眠的BCC中冲洗 保护性正弦生位，使它们容易受到细胞毒性或激素疗法的影响。测试这些 假设，我们将使用单细胞分辨率，鼠标Xenographotic模型中的视频速率在体内显微镜进行跟踪 BCC实时通过BM迁移。结合体外分子和细胞生物学方法， 我们将1）调查严重调节骨骼中BCC转移性进入的信号； 2）研究分子 调节BCC从骨转移部位退出到外围循环的机制以及 动员BCC信号传导和生存能力； 3）了解如何与螺旋体BM交谈 血管壁基介导BCC的休眠和对化学和激素疗法的敏感性。知识获得了 从这项工作中，将确定管理微观运动动态运动的基本机制 BCC并将建议使用治疗方法来靶向BM和休眠乳房之间的支持的串扰 癌症。