Abstract：
Tumor dormancy refers to a critical stage in cancer development in which tumor cells remain occult for a prolonged period of time until they eventually progress and become clinically apparent. We previously showed that the switch of dormant tumors to fast-growth is angiogenesis dependent and requires a stable transcriptional reprogramming in tumor cells. Considering microRNAs (miRs) as master regulators of transcriptome, we sought to investigate their role in the control of tumor dormancy. We report here the identification of a consensus set of 19 miRs that govern the phenotypic switch of human dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors to fast-growth. Loss of expression of dormancy-associated miRs (DmiRs, 16/19) was the prevailing regulation pattern correlating with the switch of dormant tumors to fast-growth. The expression pattern of two DmiRs (miR-580 and 190) was confirmed to correlate with disease stage in human glioma specimens. Reconstitution of a single DmiR (miR-580, 588 or 190) led to phenotypic reversal of fast-growing angiogenic tumors towards prolonged tumor dormancy. Of note, 60% of angiogenic glioblastoma and 100% of angiogenic osteosarcoma over-expressing miR190 remained dormant during the entire observation period of ∼ 120 days. Next, the ability of DmiRs to regulate angiogenesis and dormancy-associated genes was evaluated. Transcriptional reprogramming of tumors via DmiR-580, 588 or 190 over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF and TGFalpha. In addition, a G-CSF independent downregulation of Bv8 was found as a common target of all three DmiRs and correlated with decreased tumor recruitment of bone marrow-derived CD11b+ Gr-1+ myeloid cells. In contrast, antiangiogenic and dormancy promoting pathways such as EphA5 and Angiomotin were upregulated in DmiR over-expressing tumors. This work suggests novel means to reverse the malignant tumor phenotype into an asymptomatic dormant state and may provide promising targets for early detection or prevention of cancer.
摘要：
肿瘤休眠是指癌症发展的关键阶段，其中肿瘤细胞长时间保持隐匿，直到它们最终发展并变得临床明显。我们先前表明，休眠肿瘤向快速生长的转变是血管生成依赖性的，并且需要肿瘤细胞中稳定的转录重编程。考虑到microRNAs（miRs）作为转录组的主要调节因子，我们试图研究它们在控制肿瘤休眠中的作用。我们在这里报告了一组19miRs的共有识别，它们控制着人类休眠乳腺癌的表型转换，胶质母细胞瘤,骨肉瘤,和脂肪肉瘤肿瘤快速生长。休眠相关miRs（DMIRs，16/19）是与休眠肿瘤向快速生长的转变相关的普遍调节模式。证实了两个DmiR(miR-580和190)的表达模式与人神经胶质瘤标本中的疾病阶段相关。单个DmiR（miR-580、588或190）的重建导致快速生长的血管生成肿瘤向延长的肿瘤休眠的表型逆转。值得注意的是，60%的血管生成胶质母细胞瘤和100%的过表达miR190的血管生成骨肉瘤在~120天的整个观察期间保持休眠状态。接下来,评估了DMIR调节血管生成和休眠相关基因的能力。经由DmiR-580、588或190过表达的肿瘤的转录重编程导致促血管生成因子如TIMP-3、bFGF和TGFα的下调。此外,发现不依赖G-CSF的Bv8下调是所有3种DMiR的共同靶标,并且与骨髓来源的CD11b+Gr-1+骨髓细胞的肿瘤募集减少相关.相比之下,抗血管生成和休眠促进途径如EphA5和血管生成素在DmiR过表达的肿瘤中上调。这项工作提出了将恶性肿瘤表型逆转为无症状休眠状态的新方法，并可能为早期检测或预防癌症提供有希望的目标。
