Abstract
Tumor-associated macrophages (TAMs) mostly exhibit M2-like (alternatively activated) properties and play positive roles in angiogenesis and tumorigenesis. Vascular endothelial growth factor (VEGF) is a key angiogenic factor. During tumor development, TAMs secrete VEGF and other factors to promote angiogenesis; thus, anti-treatment against TAMs and VEGF can repress cancer development, which has been demonstrated in clinical trials and on an experimental level. In the present work, we show that miR-150 is an oncomir because of its promotional effect on VEGF. MiR-150 targets TAMs to up-regulate their secretion of VEGF in vitro. With the utilization of cell-derived vesicles, named microvesicles (MVs), we transferred antisense RNA targeted to miR-150 into mice and found that the neutralization of miR-150 down-regulates miR-150 and VEGF levels in vivo and attenuates angiogenesis. Therefore, we proposed the therapeutic potential of neutralizing miR-150 to treat cancer and demonstrated a novel, natural, microvesicle-based method for the transfer of nucleic acids.
Article PDF
Similar content being viewed by others
References
Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., and Wood, M.J. (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341–345.
Baek, J.H., Mahon, P.C., Oh, J., Kelly, B., Krishnamachary, B., Pearson, M., Chan, D.A., Giaccia, A.J., and Semenza, G.L. (2005). OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol Cell 17, 503–512.
Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.
Bingle, L., Brown, N.J., and Lewis, C.E. (2002). The role of tumourassociated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196, 254–265.
Bolat, F., Kayaselcuk, F., Nursal, T.Z., Yagmurdur, M.C., Bal, N., and Demirhan, B. (2006). Microvessel density, VEGF expression, and tumor-associated macrophages in breast tumors: correlations with prognostic parameters. J Exp Clin Cancer Res 25, 365–372.
Brahimi-Horn, C., and Pouyssegur, J. (2006). The role of the hypoxiainducible factor in tumor metabolism growth and invasion. Bulletin du cancer 93, E73–80.
Chen, X., Liang, H., Zhang, J., Zen, K., and Zhang, C.Y. (2012). Secreted microRNAs: a new form of i ntercellular communication. Trends Cell Biol 22, 125–132.
Coffelt, S.B., Hughes, R., and Lewis, C.E. (2009). Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796, 11–18.
Colla, S., Tagliaferri, S., Morandi, F., Lunghi, P., Donofrio, G., Martorana, D., Mancini, C., Lazzaretti, M., Mazzera, L., Ravanetti, L., et al. (2007). The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesis. Blood 110, 4464–4475.
Cristofanilli, M., Charnsangavej, C., and Hortobagyi, G.N. (2002). Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov 1, 415–426.
Esquela-Kerscher, A., and Slack, F.J. (2006). Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer 6, 259–269.
Ferrara, N. (2010). Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev 21, 21–26.
Ferrara, N., Gerber, H.P., and LeCouter, J. (2003). The biology of VEGF and its receptors. Nat Med 9, 669–676.
Folkman, J. (2007). Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6, 273–286.
Fukuda, K., Kobayashi, A., and Watabe, K. (2012). The role of tumorassociated macrophage in tumor progression. Front Biosci (Schol Ed) 4, 787–798.
Goga, A., and Benz, C. (2007). Anti-oncomir suppression of tumor phenotypes. Mol Interv 7, 199–202, 180.
Hanahan, D., and Coussens, L.M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322.
Kim, K.J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H.S., and Ferrara, N. (1993). Inhibition of vascular endothelial growth factorinduced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844.
Kota, J., Chivukula, R.R., O’Donnell, K.A., Wentzel, E.A., Montgomery, C.L., Hwang, H.W., Chang, T.C., Vivekanandan, P., Torbenson, M., Clark, K.R., et al. (2009). Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137, 1005–1017.
Lewis, C.E., Leek, R., Harris, A., and McGee, J.O. (1995). Cytokine regulation of angiogenesis in breast cancer: the role of tumorassociated macrophages. J Leukoc Biol 57, 747–751.
Lewis, C.E., and Pollard, J.W. (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Res 66, 605–612.
Lin, E.Y., Nguyen, A.V., Russell, R.G., and Pollard, J.W. (2001). Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193, 727–740.
Lin, E.Y., and Pollard, J.W. (2007). Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res 67, 5064–5066.
Luo, Y., Zhou, H., Krueger, J., Kaplan, C., Lee, S.H., Dolman, C., Markowitz, D., Wu, W., Liu, C., Reisfeld, R.A., et al. (2006). Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116, 2132–2141.
McDonnell, C.O., Bouchier-Hayes, D.J., Toomey, D., Foley, D., Kay, E.W., Leen, E., and Walsh, T.N. (2003). Effect of neoadjuvant chemoradiotherapy on angiogenesis in oesophageal cancer. Br J Surg 90, 1373–1378.
Millan Nunez-Cortes, J. (1991). Angiogenesis: a crucial element in tumor development. An Med Interna 8, 369–371.
Murdoch, C., Muthana, M., Coffelt, S.B., and Lewis, C.E. (2008). The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8, 618–631.
Ozer, A., Wu, L.C., and Bruick, R.K. (2005). The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A 102, 7481–7486.
Presta, L.G., Chen, H., O’Connor, S.J., Chisholm, V., Meng, Y.G., Krummen, L., Winkler, M., and Ferrara, N. (1997). Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57, 4593–4599.
Qian, B.Z., and Pollard, J.W. (2010). Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51.
Rolny, C., Mazzone, M., Tugues, S., Laoui, D., Johansson, I., Coulon, C., Squadrito, M.L., Segura, I., Li, X., Knevels, E., et al. (2011). HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44.
Stockmann, C., Doedens, A., Weidemann, A., Zhang, N., Takeda, N., Greenberg, J.I., Cheresh, D.A., and Johnson, R.S. (2008). Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818.
Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J.J., and Lotvall, J.O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9, 654–659.
van den Boorn, J.G., Schlee, M., Coch, C., and Hartmann, G. (2011). SiRNA delivery with exosome nanoparticles. Nat Biotechnol 29, 325–326.
Warren, R.S., Yuan, H., Matli, M.R., Gillett, N.A., and Ferrara, N. (1995). Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95, 1789–1797.
Zhang, Y., Liu, D., Chen, X., Li, J., Li, L., Bian, Z., Sun, F., Lu, J., Yin, Y., Cai, X., et al. (2010). Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39, 133–144.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Liu, Y., Zhao, L., Li, D. et al. Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development. Protein Cell 4, 932–941 (2013). https://doi.org/10.1007/s13238-013-3092-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13238-013-3092-z