Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.
Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.
复制标题
DOI：
10.1126/scitranslmed.aad4059
复制
发表时间：
2016-05-25
影响因子：
17.1
通讯作者：
Sipkins DA
中科院分区：
文献类型：
--
作者：
Price TT;Burness ML;Sivan A;Warner MJ;Cheng R;Lee CH;Olivere L;Comatas K;Magnani J;Kim Lyerly H;Cheng Q;McCall CM;Sipkins DA
乳腺癌转移性复发可在治疗后数年发生，表明播散性乳腺癌细胞（BCC）在增殖之前具有延长的休眠期。疾病传播和复发的主要部位是骨，尽管对允许循环BCC识别骨微血管、进入组织并与微环境结合的关键信号知之甚少。在乳腺癌异种移植模型中使用骨髓（BM）的实时体内显微镜检查，我们发现休眠和增殖的BCC占据不同的区域，休眠的BCC主要存在于E-选择素和基质细胞衍生因子1（SDF-1）丰富的窦周血管区域。我们使用E-选择素和C-X-C趋化因子受体4型（CXCR 4）（SDF-1受体）的高度特异性抑制剂来证明E-选择素和SDF-1在BCC运输中协调相反的作用。尽管E-选择素相互作用对于允许BCC进入BM至关重要，但SDF-1/CXCR 4相互作用将BCC锚定到微环境，并且其抑制诱导休眠微转移进入循环的动员。原发性基底细胞癌的归巢研究也表明，E-选择素调节它们通过窦状隙进入骨，患者BM的免疫组织化学染色显示与SDF-1+血管相邻的休眠微转移性疾病。这些发现揭示了BCC如何在宿主内运输，并表明同时阻断患者中的CXCR 4和E-选择素可以从保护性BM环境中分子切除休眠的微转移，防止其作为复发性疾病出现。
Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin– and stromal cell–derived factor 1 (SDF-1)–rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1+ vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.
登录
查看更多内容
影响因子：
158.5
作者：
Cristofanilli, M;Budd, GT;Hayes, DF
通讯作者：
Hayes, DF
影响因子：
11.2
作者：
Barkan D;Kleinman H;Simmons JL;Asmussen H;Kamaraju AK;Hoenorhoff MJ;Liu ZY;Costes SV;Cho EH;Lockett S;Khanna C;Chambers AF;Green JE
通讯作者：
Green JE
影响因子：
7.4
作者：
Fehm, Tanja;Becker, Sven;Becker-Pergola, Graziella;Sotlar, Karl;Gebauer, Gerhard;Duerr-Stoerzer, Silke;Neubauer, Hans;Wallwiener, Diethelm;Solomayer, Erich-Franz
通讯作者：
Solomayer, Erich-Franz
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
3.8
作者：
Chase, S. D.;Magnani, J. L.;Simon, S. I.
通讯作者：
Simon, S. I.