New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
Cancer Res. 2011 Mar 1;71(5):1550-60. doi: 10.1158/0008-5472.CAN-10-2372. Epub 2011 Feb 22.
Bone marrow (BM) metastasis of breast cancer (BC) can recur even decades after initial diagnosis and treatment, implying the long-term survival of disseminated cancer cells in a dormant state. Here we investigated the role of microRNAs (miRNA) transmitted from BM stroma to BC cells via gap junctions and exosomes in tumor cell quiescence. MDA-MB-231 and T47D BC cells arrest in G(0) phase of the cell cycle when cocultured with BM stroma. Analyses of miRNA expression profiles identified numerous miRNAs implicated in cell proliferation including miR-127, -197, -222, and -223 targeting CXCL12. Subsequently, we showed that these CXCL12-specific miRNAs are transported from BM stroma to BC cells via gap junctions, leading to reduced CXCL12 levels and decreased proliferation. Stroma-derived exosomes containing miRNAs also contributed to BC cell quiescence, although to a lesser degree than miRNAs transmitted via gap junctions. This study shows that the transfer of miRNAs from BM stroma to BC cells might play a role in the dormancy of BM metastases.
骨髓（BM）转移的乳腺癌（BC）甚至可以在初始诊断和治疗后几十年内复发，这意味着播散的癌细胞以休眠状态长期存活。在这里，我们研究了通过缝隙连接和外泌体从 BM 基质传递到 BC 细胞的 microRNAs（miRNA）在肿瘤细胞静止中的作用。当与 BM 基质共培养时，MDA-MB-231 和 T47D BC 细胞在细胞周期的 G(0)期停滞。对 miRNA 表达谱的分析鉴定了许多与细胞增殖相关的 miRNA，包括靶向 CXCL12 的 miR-127、-197、-222 和 -223。随后，我们表明这些 CXCL12 特异性 miRNA 通过缝隙连接从 BM 基质传递到 BC 细胞，导致 CXCL12 水平降低和增殖减少。尽管程度不如通过缝隙连接传递的 miRNA，但来自基质的含有 miRNA 的外泌体也促成了 BC 细胞的静止。这项研究表明，从 BM 基质到 BC 细胞的 miRNA 转移可能在 BM 转移的休眠中发挥作用。
