Abstract
Angiogenesis, the expansion of preexisting blood vessels, is a complex process required for tumor growth and metastasis. Although current antiangiogenic strategies have shown promising results in several cancer types, identification of additional antiangiogenic targets is required to improve the therapeutic response. Herein, we show that the microtubule-binding protein CLIP-170 (cytoplasmic linker protein of 170 kDa) is highly expressed in breast tumor samples and correlates positively with blood vessel density. Depletion of CLIP-170 significantly impaired vascular endothelial tube formation and sprouting in vitro and inhibited breast tumor growth in mice by decreasing tumor vascularization. Our data further show that CLIP-170 is important for the migration but not the proliferation of vascular endothelial cells. In addition, CLIP-170 promotes the polarization of endothelial cells in response to the angiogenic stimulus. These findings thus demonstrate a critical role for CLIP-170 in tumor angiogenesis and suggest its potential as a novel antiangiogenic target.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Akhmanova, A., and Steinmetz, M.O. (2008). Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat Rev Mol Cell Biol 9, 309–322.
Bilbe, G., Delabie, J., Bruggen, J., Richener, H., Asselbergs, F.A., Cerletti, N., Sorg, C., Odink, K., Tarcsay, L., Wiesendanger, W., et al. (1992). Restin: a novel intermediate filament-associated protein highly expressed in the Reed-Sternberg cells of Hodgkin’s disease. EMBO J 11, 2103–2113.
Bornens, M. (2008). Organelle positioning and cell polarity. Nat Rev Mol Cell Biol 9, 874–886.
Bossung, V., and Harbeck, N. (2010). Angiogenesis inhibitors in the management of breast cancer. Curr Opin Obstet Gynecol 22, 79–86.
Carmeliet, P., and Jain, R.K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307.
Chae, S.S., Paik, J.H., Furneaux, H., and Hla, T. (2004). Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest 114, 1082–1089.
Delabie, J., Shipman, R., Bruggen, J., De Strooper, B., van Leuven, F., Tarcsay, L., Cerletti, N., Odink, K., Diehl, V., Bilbe, G., et al. (1992). Expression of the novel intermediate filament-associated protein restin in Hodgkin’s disease and anaplastic large-cell lymphoma. Blood 80, 2891–2896.
Dong, X., Liu, F., Sun, L., Liu, M., Li, D., Su, D., Zhu, Z., Dong, J.T., Fu, L., and Zhou, J. (2010). Oncogenic function of microtubule endbinding protein 1 in breast cancer. J Pathol 220, 361–369.
Folkman, J. (2007). Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6, 273–286.
Gao, J., Sun, L., Huo, L., Liu, M., Li, D., and Zhou, J. (2010). CYLD regulates angiogenesis by mediating vascular endothelial cell migration. Blood 115, 4130–4137.
Gouveia, S.M., and Akhmanova, A. (2010). Cell and molecular biology of microtubule plus end tracking proteins: end binding proteins and their partners. Int Rev Cell Mol Biol 285, 1–74.
Lamalice, L., Le Boeuf, F., and Huot, J. (2007). Endothelial cell migration during angiogenesis. Circ Res 100, 782–794.
Li, D., Xie, S., Ren, Y., Huo, L., Gao, J., Cui, D., Liu, M., and Zhou, J. (2011). Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner. Protein Cell 2, 150–160.
Li, J., Sun, X., Wang, Z., Chen, L., Li, D., Zhou, J., and Liu, M. (2012). Regulation of vascular endothelial cell polarization and migration by Hsp70/Hsp90-organizing protein. PLoS One 7, e36389.
Li, R., and Gundersen, G.G. (2008). Beyond polymer polarity: how the cytoskeleton builds a polarized cell. Nat Rev Mol Cell Biol 9, 860–873.
Liu, M., Wang, X., Yang, Y., Li, D., Ren, H., Zhu, Q., Chen, Q., Han, S., Hao, J., and Zhou, J. (2010). Ectopic expression of the microtubuledependent motor protein Eg5 promotes pancreatic tumourigenesis. J Pathol 221, 221–228.
Mackey, J.R., Kerbel, R.S., Gelmon, K.A., McLeod, D.M., Chia, S.K., Rayson, D., Verma, S., Collins, L.L., Paterson, A.H., Robidoux, A., et al. (2012). Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials. Cancer Treat Rev 38, 673–688.
Peng, G., Ren, Y., Sun, X., Zhou, J., and Li, D. (2012). Inhibition of farnesyltransferase reduces angiogenesis by interrupting endothe lial cell migration. Biochem Pharmacol 83, 1374–1382.
Rodriguez, O.C., Schaefer, A.W., Mandato, C.A., Forscher, P., Bement, W.M., and Waterman-Storer, C.M. (2003). Conserved microtubuleactin interactions in cell movement and morphogenesis. Nat Cell Biol 5, 599–609.
Shi, X., Liu, M., Li, D., Wang, J., Aneja, R., and Zhou, J. (2012). Cep70 contributes to angiogenesis by modulating microtubule rearrangement and stimulating cell polarization and migration. Cell Cycle 11, 1554–1563.
Sun, L., Gao, J., Dong, X., Liu, M., Li, D., Shi, X., Dong, J.T., Lu, X., Liu, C., and Zhou, J. (2008). EB1 promotes Aurora-B kinase activity through blocking its inactivation by protein phosphatase 2A. Proc Natl Acad Sci U S A 105, 7153–7158.
Sun, X., Li, D., Yang, Y., Ren, Y., Li, J., Wang, Z., Dong, B., Liu, M., and Zhou, J. (2012). Microtubule-binding protein CLIP-170 is a mediator of paclitaxel sensitivity. J Pathol 226, 666–673.
Suzuki, K., and Takahashi, K. (2008). Regulation of lamellipodia formation and cell invasion by CLIP-170 in invasive human breast cancer cells. Biochem Biophys Res Commun 368, 199–204.
Vicente-Manzanares, M., and Horwitz, A.R. (2011). Cell migration: an overview. Methods Mol Biol 769, 1–24.
Wang, H., Liu, B., Zhang, C., Peng, G., Liu, M., Li, D., Gu, F., Chen, Q., Dong, J.T., Fu, L., et al. (2009). Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule-dependent mechanism. J Pathol 218, 76–85.
Watanabe, T., Noritake, J., and Kaibuchi, K. (2005). Regulation of microtubules in cell migration. Trends Cell Biol 15, 76–83.
Weis, S.M., and Cheresh, D.A. (2011). Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17, 1359–1370.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Sun, X., Li, F., Dong, B. et al. Regulation of tumor angiogenesis by the microtubule-binding protein CLIP-170. Protein Cell 4, 266–276 (2013). https://doi.org/10.1007/s13238-013-3007-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13238-013-3007-z