Editors' ChoiceCancer

miRly Interfering with Junctions

Sci. Signal.  22 Apr 2014:
Vol. 7, Issue 322, pp. ec106
DOI: 10.1126/scisignal.2005394

Exosomes are vesicles released from cells and contain proteins and RNAs. Exosomes modify the behavior of the cells that internalize them, which can be either near to or far from the releasing cell. Exosomes derived from cancer cells may contain factors that influence the local tumor microenvironment or spread to distant sites to influence cells at potential sites of metastasis. Zhou et al. report that both metastatic breast cancer cell lines and noncancerous mammary epithelial cell lines released exosomes that could be taken up by primary human microvascular endothelial cells (HMVECs), but only exosomes released by the metastatic cells or RNAs isolated from these exosomes induced the HMVECs to migrate. The microRNA miR-105 was present in greater abundance in exosomes derived from three different metastatic breast cancer cell lines compared with those released from noncancerous or nonmetastatic cells and was transferred to recipient HMVEC cells through exosomes. Ectopically expressing miR-105 in HMVECs or adding exosomes from the metastatic breast cancer cell lines reduced the abundance of ZO-1, a known target of this miRNA and a component of tight junctions. Transfecting HMVECs with an inhibitor of miR-105 before incubation with the exosomes prevented ZO-1 down-regulation. Exosomes from the metastatic breast cancer cell lines also increased the permeability of HMVEC monolayers, allowing both fluorescently labeled dextran and cancer cells to pass through in transwell assays. Injection of exosomes from the metastatic breast cancer cell lines into mice also increased miR-105 abundance, reduced ZO-1 abundance in endothelial cells, and increased vascular permeability in lung and brain. Ectopic expression of miR-105 in a breast cancer cell line that exhibits only moderate metastatic potential increased the ability of these cells to invade the lung and brain when xenografted into mice. In mice with tumors established by metastatic breast cancer cell lines with high miR-105 expression, treating the animals with an inhibitor of miR-105 reduced the size of the primary tumor, decreased the number of lung and brain metastases from the primary tumor, reduced vascular permeability, and increased ZO-1 abundance in vascular endothelial cells compared to xenografted mice not treated with the inhibitor. Exosomes containing miR-105 were present in blood samples from breast cancer patients, and the abundance of circulating miR-105 positively correlated with metastatic disease, whereas the abundance of ZO-1 in tumors and vascular endothelial cells negatively correlated with metastatic disease. Thus, miR-105 might be both a target for treating metastatic breast cancer and a biomarker of metastatic potential.

W. Zhou, M. Y. Fong, Y. Min, G. Somlo, L. Liu, M. R. Palomares, Y. Yu, A. Chow, S. T. F. O’Connor, A. R. Chin, Y. Yen, Y. Wang, E. G. Marcusson, P. Chu, J. Wu, X. Wu, A. X. Li, Z. Li, H. Gao, X. Ren, M. P. Boldin, P. C. Lin, S. E. Wang, Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515 (2014). [PubMed]