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Micrornas: Lines of communication

Nature Reviews Cancer 12, 9 (01 September 2012) | doi:10.1038/nrc3348

Although pharmacological inhibitors of vascular endothelial growth factor (VEGF) signalling and angiogenesis are used in the treatment of many cancers, resistance often develops and therefore it would be desirable to find other non-VEGF pathways that might be exploited therapeutically. Guanglei Zhuang, Napoleone Ferrara and colleagues have identified a role for activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in endothelial cells by tumour cell-derived microRNAs (miRNAs).

Lara Crow/NPG

The authors began by taking a non-biased approach to identify miRNAs that were differentially expressed in endothelial cells following co-culture with tissue-matched tumour cells. They found significant upregulation of a group of miRNAs in five endothelial cell lines, and this effect was replicated using conditioned media from the tumour cells, indicating that soluble factors might be responsible. The authors attempted to biochemically characterize the miRNA-inducing activity and isolated it to a large molecular weight fraction. They also found that endothelial cells did not exhibit changes in primary or precursor miRNAs following stimulation with conditioned media, but knockdown of the miRNA-processing enzyme DROSHA in tumour cells blocked miRNA induction, indicating that the miRNAs might be produced in the tumour cells and secreted in large molecular weight complexes, possibly microvesicles. They then isolated the microvesicles present in the conditioned media and showed they could be taken up by human umbilical vein endothelial cells (HUVECs) and could induce HUVEC migration, a process that was blocked by DROSHA knockdown in the tumour cells.

microvesicles ... could induce HUVEC migration

Testing of a panel of miRNAs indicated that miR-9 had the greatest effect on HUVEC migration and angiogenic sprouting, and this was confirmed by miR-9 overexpressionin HUVECs or knockdown in tumour cell-derived microvesicles. Furthermore, miR-9 levels were increased in the plasma of mice implanted with colorectal or lung tumour cells, and a miR-9 antagomir could slow tumour growth and angiogenesis. How might miR-9 control angiogenesis? Examination of downstream signalling pathways showed increased activation of the JAK–STAT pathway. In addition, suppressor of cytokine signalling 5 (SOCS5), a negative regulator of this pathway, was downregulated. Interestingly, SOCS5 was also identified as a candidate target gene for miR-9 in silico, and miR-9 could suppress transcription of a SOCS5 reporter construct, indicating that SOCS5 may be directly downregulated by miR-9. Finally, pointing to the therapeutic potential of this pathway, a JAK inhibitor (GNE-372) blocked migration of HUVECs overexpressing miR-9 and inhibited tumour growth.

Tumour cell to endothelial cell communication and induction of endothelial cell migration via miRNAs from tumour cell-derived microvesicles has also recently been reported by Umezu et al., suggesting that this mode of signalling could be common.

Sarah Seton-Rogers

ORIGINAL RESEARCH PAPERS

  1. Zhuang, G. et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 6 Jul 2012 (doi:10.1038/emboj.2012.183) | Article |
  2. Umezu, T. et al. Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene 16 Jul 2012 (doi:10.1038/onc.2012.295) | Article |

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