Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
Nature. 2011 Dec 14;481(7380):190-4. doi: 10.1038/nature10661.
Metastatic progression of cancer is a complex and clinically daunting process. We previously identified a set of human microRNAs (miRNAs) that robustly suppress breast cancer metastasis to lung and bone and which display expression levels that predict human metastasis. Although these findings revealed miRNAs as suppressors of cell-autonomous metastatic phenotypes, the roles of non-coding RNAs in non-cell-autonomous cancer progression processes remain unknown. Here we reveal that endogenous miR-126, an miRNA silenced in a variety of common human cancers, non-cell-autonomously regulates endothelial cell recruitment to metastatic breast cancer cells, in vitro and in vivo. It suppresses metastatic endothelial recruitment, metastatic angiogenesis and metastatic colonization through coordinate targeting of IGFBP2, PITPNC1 and MERTK--novel pro-angiogenic genes and biomarkers of human metastasis. Insulin-like growth factor binding protein 2 (IGFBP2) secreted by metastatic cells recruits endothelia by modulating IGF1-mediated activation of the IGF type-I receptor on endothelial cells; whereas c-Mer tyrosine kinase (MERTK) receptor cleaved from metastatic cells promotes endothelial recruitment by competitively antagonizing the binding of its ligand GAS6 to endothelial MERTK receptors. Co-injection of endothelial cells with breast cancer cells non-cell-autonomously rescues their miR-126-induced metastatic defect, revealing a novel and important role for endothelial interactions in metastatic initiation. Through loss-of-function and epistasis experiments, we delineate an miRNA regulatory network's individual components as novel and cell-extrinsic regulators of endothelial recruitment, angiogenesis and metastatic colonization. We also identify the IGFBP2/IGF1/IGF1R and GAS6/MERTK signalling pathways as regulators of cancer-mediated endothelial recruitment. Our work further reveals endothelial recruitment and endothelial interactions in the tumour microenvironment to be critical features of metastatic breast cancer.
癌症的转移进展是一个复杂且临床上令人畏惧的过程。我们之前确定了一组人类 microRNAs(miRNAs),它们能强烈抑制乳腺癌向肺和骨转移,并且其表达水平可预测人类的转移。尽管这些发现揭示了 miRNAs 作为细胞自主转移性表型的抑制因子,但非编码 RNA 在非细胞自主的癌症进展过程中的作用仍然未知。在这里,我们揭示了内源性 miR-126,一种在多种常见人类癌症中沉默的 miRNA,通过非细胞自主方式调节内皮细胞向转移性乳腺癌细胞的募集,在体外和体内都是如此。它通过协调靶向 IGFBP2、PITPNC1 和 MERTK——新型促血管生成基因和人类转移的生物标志物,抑制转移性内皮细胞募集、转移性血管生成和转移性定植。转移性细胞分泌的胰岛素样生长因子结合蛋白 2(IGFBP2)通过调节 IGF1 对内皮细胞上 IGF 型-I 受体的激活,招募内皮细胞;而从转移性细胞中切割下来的 c-Mer 酪氨酸激酶(MERTK)受体通过竞争性拮抗其配体 GAS6 与内皮 MERTK 受体的结合,促进内皮细胞的募集。将内皮细胞与乳腺癌细胞非细胞自主共注射可挽救其 miR-126 诱导的转移缺陷,揭示了内皮相互作用在转移起始中的新的重要作用。通过功能丧失和上位性实验,我们描绘了 miRNA 调控网络的单个成分作为内皮细胞募集、血管生成和转移性定植的新的、细胞外调节因子。我们还确定了 IGFBP2/IGF1/IGF1R 和 GAS6/MERTK 信号通路作为癌症介导的内皮细胞募集的调节因子。我们的工作进一步揭示了肿瘤微环境中的内皮细胞募集和内皮细胞相互作用是乳腺癌转移的关键特征。