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

基本信息

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
项目类别：
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

项目摘要

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复发，最常首先发生在对患有早期乳腺癌的女性进行的骨髓 (BM) 活检表明，许多患者在诊断时实际上已经存在临床上不明显的小“微转移”。这些微转移可以在辅助化疗中存活，并在化疗前休眠数年。它们会增殖，导致明显的转移性疾病，在这个阶段，疾病变得无法治愈。我们对乳腺癌生物学的日益了解揭示了宿主的重要性我们实验室使用的初步数据为转移创造了一个接受和保护的环境。小鼠异种移植模型显示乳腺癌细胞 (BCC) 转移并休眠于独特的环境中。这些区域的血管是血管周围造血祖细胞和干细胞（HSPC）生态位。其特征在于其正弦形态和粘附分子 E-的高基础表达选择素和细胞因子 SDF-1 使用高度特异性的 E-选择素和 CXCR4 抑制剂，我们发现 E-选择素和 SDF-1 在 BCC 运输中协调竞争角色，而 E-选择素相互作用对于 BCC 运输至关重要。 SDF-1/CXCR4 允许 BCC 进入 BM，将 BCC 锚定到微环境，并且其抑制诱导此外，我们的免疫组织化学研究将休眠的微转移转移到循环中。对患有微转移性骨髓侵犯的患者进行的活检显示，存在休眠转移根据这些数据，我们捕获了与 SDF-1+ 脉管系统相邻的休眠 BCC 的庇护所。独特的窦周血管 BM 生态位，它们能够动态地来回转移到我们还研究外周循环以及骨内的替代性促增殖微环境。 CXCR4 和 E-选择素抑制等干预措施可以清除休眠的 BCC 保护性正弦微环境，使它们容易受到细胞毒性或激素疗法的影响。假设，我们将在小鼠异种移植模型中使用单细胞分辨率、视频速率体内显微镜来跟踪通过 BM 实时迁移 BCC 并结合体外分子和细胞生物学方法，我们将 1) 研究关键调节 BCC 转移进入骨的信号 2) 研究分子；调节 BCC 从骨转移部位进入外周循环的机制以及 BCC 信号传导和活力的动员；以及 3) 了解如何与正弦曲线周围 BM 进行交互血管生态位介导基底细胞癌休眠和对化疗和激素疗法的敏感性。这项工作将确定控制微转移动态运动的基本机制 BCC 并将建议针对 BM 和休眠乳房之间的支持性串扰的治疗方法癌症。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

休眠的乳腺癌微转移存在于特定的骨髓生态位中，这些生态位调节它们进出骨骼的转运。

DOI：
发表时间：
2016
期刊：
影响因子：
17.1
作者：
Price, Trevor T;Burness, Monika L;Sivan, Ayelet;Warner, Matthew J;Cheng, Renee;Lee, Clara H;Olivere, Lindsey;Comatas, Karrie;Magnani, John;Kim Lyerly, H;Cheng, Qing;McCall, Chad M;Sipkins, Dorothy A
通讯作者：
Sipkins, Dorothy A