Small noncoding RNAs (microRNAs) have been implicated in endothelial cell migration and angiogenesis. Acting within cancer cells, microRNAs, such as miR-126, can reduce the ability of cancer cells to recruit endothelial cells, thus acting as tumor suppressors (see Halberg et al.), but Zhuang et al. reported tumor-promoting activity for other tumor-derived microRNAs. Microarrays and quantitative PCR revealed increased abundance of many microRNAs, including miR-9, in microvascular endothelial cells from normal tissue cultured in the presence, but not absence, of several tumor cell lines. The authors detected microRNAs in tumor-conditioned media and hypothesized that they were carried by microvescicles (MVs). MVs isolated from tumor cell lines increased the abundance of microRNAs in endothelial cells, and endothelial cells internalized fluorescently labeled MVs added to the culture medium. Treatment of endothelial cells with tumor cell–conditioned media or overexpression of miR-9 in endothelial cells promoted migration and morphological changes. Interference with miR-9 in the endothelial cells with an antagonistic oligonucleotide inhibited the ability of MVs from the tumor cells to induce endothelial cell migration or increase sprouting angiogenesis in vitro. The authors detected miR-9 in the plasma of tumor-bearing mice, and intratumor injection of antagonistic oligonucleotides to miR-9 delayed tumor growth and decreased tumor-associated angiogenesis. Antibody array analysis revealed increased abundance of phosphorylated signal transducer and activator of transcription (STAT) 1 and 3 and Janus kinase (JAK) 1 and 2 in endothelial cells overexpressing miR-9 but not in cells overexpressing a control microRNA. Overexpression of miR-9 in endothelial cells or treatment of the cells with conditioned media or MVs isolated from tumor cells decreased the abundance of SOCS5, a negative regulator of the JAK-STAT pathway. Pharmacological inhibition of JAK2 reduced migration of endothelial cells overexpressing miR-9. Cancer cells can thus take advantage of microRNAs to recruit endothelial cells by releasing MVs containing microRNAs that influence signaling pathways that promote migration and angiogenesis.
G. Zhuang, X. Wu, Z. Jiang, I. Kasman, J. Yao, Y. Guan, J. Oeh, Z. Modrusan, C. Bais, D. Sampath, N. Ferrara, Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO. J. 31, 3513–3523 (2012). [PubMed]
N. Halberg, C. Alarcón, S. F. Tavazoie, microRNA regulation of cancer–endothelial interactions: Vesicular microRNAs on the move…. EMBO J. 31, 3509–3510 (2012). [PubMed]