Defining the Rules of Breast Cancer Cell Traffic Through Bone

摘要 乳腺癌的主要死因是转移性复发，最常发生在 骨头。对早期乳腺癌妇女进行的骨髓活组织检查显示， 临床上看不出来的微小“微转移”实际上在许多患者确诊时就已经存在。 这些微转移瘤可以在辅助化疗的情况下存活，并潜伏多年。 它们变得增殖，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不断加深的了解向我们揭示了宿主的重要性 组织在为转移创造易于接受和保护的环境中发挥作用。来自我们实验室的初步数据使用 小鼠异种移植模型显示乳腺癌细胞(BCC)转移到唯一的 血管周围造血祖细胞和干细胞(HSPC)的壁龛。这些区域的血管是 区别于它们的正弦形态和它们高基础表达的黏附分子E- 选择素和细胞因子SDF-1。使用高度特异的E-选择素和CXCR4抑制剂，我们已经确定 E-选择素和SDF-1在BCC贩运中扮演相反的角色。虽然E-选择素的相互作用对 允许BCC进入BM，SDF-1/CXCR4将BCC锚定到微环境及其抑制诱导 动员潜伏的微转移瘤进入循环。此外，我们的免疫组织化学研究 对骨髓微转移患者进行的活组织检查显示存在潜伏性转移。 邻近SDF-1+血管构筑。根据这些数据，我们假设休眠的国库银行藏匿在 独特的窦周血管BM龛，它们能够从那里动态地来回传递到 外周循环以及骨骼内替代的、促进增殖的微环境。我们也 假设CXCR4和E-选择素抑制等干预措施可以将休眠的BCC从 保护性的正弦利基，使它们容易受到细胞毒性或激素治疗的影响。为了测试这些 假设，我们将使用单细胞分辨率、视频速率在活体显微镜下对小鼠异种移植模型进行追踪 通过黑石实时迁移BCC。结合体外分子和细胞生物学方法， 我们将1)研究关键调控BCC骨转移进入的信号；2)研究分子 BCC从骨转移灶出口到外周循环的调节机制及对其的影响 对基底细胞癌信号和生存能力的动员；以及3)了解与窦周骨髓的串扰 血管壁龛调节基底细胞休眠和对化疗和激素治疗的敏感性。获得的知识 通过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音的治疗方法 癌症。

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.