Endostatin specifically targets both tumor blood vessels and lymphatic vessels

Abstract

Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, was first identified as a potent angiogenic inhibitor. The anti-angiogenic function of endostatin has been well documented during the past decade. Recently, several studies demonstrated that endostatin also inhibits tumor lymphangiogenesis and lymphatic metastasis. However, the exact mechanism that endostatin executes its anti-angiogenic and anti-lymphangiogenic functions remains elusive. In the current mini-review, we briefly summarize recent novel findings, including the functions of endostatin targeting not only angiogenesis but also lymphangiogenesis, and the underlying mechanism by which endostatin internalization regulates its biological functions.

Keywords

endostatin / angiogenesis / lymphangiogenesis / nystatin / internalization / tumor

References

[1] O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88(2): 277–285

[2] Folkman J. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 2006; 312(5): 594–607

[3] Fu Y, Chen Y, Luo X, Liang Y, Shi H, Gao L, Zhan S, Zhou D, Luo Y. The heparin binding motif of endostatin mediates its interaction with receptor nucleolin. Biochemistry 2009; 48(49): 11655–11663

[4] Fu Y, Luo Y. The N-terminal integrity is critical for the stability and biological functions of endostatin. Biochemistry 2010; 49(30): 6420–6429

[5] Fu Y, Tang H, Huang Y, Song N, Luo Y. Unraveling the mysteries of endostatin. IUBMB Life 2009; 61(6): 613–626

[6] Fukumoto S, Morifuji M, Katakura Y, Ohishi M, Nakamura S. Endostatin inhibits lymph node metastasis by a down-regulation of the vascular endothelial growth factor C expression in tumor cells. Clin Exp Metastasis 2005; 22(1): 31–38

[7] Brideau G, Mäkinen MJ, Elamaa H, Tu H, Nilsson G, Alitalo K, Pihlajaniemi T, Heljasvaara R. Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Res 2007; 67(24): 11528–11535

[8] Zhuo W, Luo C, Wang X, Song X, Fu Y, Luo Y. Endostatin inhibits tumour lymphangiogenesis and lymphatic metastasis via cell surface nucleolin on lymphangiogenic endothelial cells. J Pathol 2010; 222(3): 249–260

[9] Ou J, Li J, Pan F, Xie G, Zhou Q, Huang H, Liang H. Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin α9. J Cell Biochem 2011; 112(8): 2106–2114

[10] Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 2005; 7(2): 121–127

[11] Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 2005; 438(7070): 946–953

[12] Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 2008; 3(1): 367–397

[13] Cao R, Björndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004; 6(4): 333–345

[14] Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 2005; 24(16): 2885–2895

[15] Björndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 2005; 102(43): 15593–15598

[16] Chang LK, Garcia-Cardeña G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 2004; 101(32): 11658–11663

[17] Shi H, Huang Y, Zhou H, Song X, Yuan S, Fu Y, Luo Y. Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin. Blood 2007; 110(8): 2899–2906

[18] Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engström A, Timpl R, Welsh M, Claesson-Welsh L. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 2000; 95(11): 3403–3411

[19] MacDonald NJ, Shivers WY, Narum DL, Plum SM, Wingard JN, Fuhrmann SR, Liang H, Holland-Linn J, Chen DH, Sim BK. Endostatin binds tropomyosin: a potential modulator of the antitumor activity of endostatin. J Biol Chem 2001; 276(27): 25190–25196

[20] Zhou H, Wang W, Luo Y. Contributions of disulfide bonds in a nested pattern to the structure, stability, and biological functions of endostatin. J Biol Chem 2005; 280(12): 11303–11312

[21] Le Roy C, Wrana JL. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol 2005; 6(2): 112–126

[22] Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol 2007; 8(3): 185–194

[23] Pellinen T, Tuomi S, Arjonen A, Wolf M, Edgren H, Meyer H, Grosse R, Kitzing T, Rantala JK, Kallioniemi O, Fässler R, Kallio M, Ivaska J. Integrin trafficking regulated by Rab21 is necessary for cytokinesis. Dev Cell 2008; 15(3): 371–385

[24] Shi F, Sottile J. Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnover. J Cell Sci 2008; 121(14): 2360–2371

[25] Caswell PT, Vadrevu S, Norman JC. Integrins: masters and slaves of endocytic transport. Nat Rev Mol Cell Biol 2009; 10(12): 843–853

[26] Chen Y, Wang S, Lu X, Zhang H, Fu Y, Luo Y. Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways. Blood 2011; 117(23): 6392–6403

[27] Abdollahi A, Hahnfeldt P, Maercker C, Gröne HJ, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE. Endostatin’s antiangiogenic signaling network. Mol Cell 2004; 13(5): 649–663

[28] Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, Adams R, Muro AF, Sheppard D, Makinen T. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 2009; 17(2): 175–186

[29] Christian S, Pilch J, Akerman ME, Porkka K, Laakkonen P, Ruoslahti E. Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels. J Cell Biol 2003; 163(4): 871–878

[30] Huang Y, Shi H, Zhou H, Song X, Yuan S, Luo Y. The angiogenic function of nucleolin is mediated by vascular endothelial growth factor and nonmuscle myosin. Blood 2006; 107(9): 3564–3571

[31] Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997; 390(6658): 404–407

[32] Herbst RS, Hess KR, Tran HT, Tseng JE, Mullani NA, Charnsangavej C, Madden T, Davis DW, McConkey DJ, O’Reilly MS, Ellis LM, Pluda J, Hong WK, Abbruzzese JL. Phase I study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2002; 20(18): 3792–3803

[33] Dong X, Zhao X, Xiao T, Tian H, Yun C. Endostar, a recombined humanized endostatin, inhibits lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma xenograft in mice. Thorac Cardiovasc Surg 2011; 59(3): 133–136

[34] Jia Y, Liu M, Huang W, Wang Z, He Y, Wu J, Ren S, Ju Y, Geng R, Li Z.Recombinant human endostatin endostar inhibits tumor growth and metastasis in a mouse xenograft model of colon cancer. Pathol Oncol Res 2011Sep 22. [Epub ahead of print]

[35] Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 2009; 15(9): 1023–1030

[36] Rehn M, Veikkola T, Kukk-Valdre E, Nakamura H, Ilmonen M, Lombardo C, Pihlajaniemi T, Alitalo K, Vuori K. Interaction of endostatin with integrins implicated in angiogenesis. Proc Natl Acad Sci USA 2001; 98(3): 1024–1029

[37] Karumanchi SA, Jha V, Ramchandran R, Karihaloo A, Tsiokas L, Chan B, Dhanabal M, Hanai JI, Venkataraman G, Shriver Z, Keiser N, Kalluri R, Zeng H, Mukhopadhyay D, Chen RL, Lander AD, Hagihara K, Yamaguchi Y, Sasisekharan R, Cantley L, Sukhatme VP. Cell surface glypicans are low-affinity endostatin receptors. Mol Cell 2001; 7(4): 811–822

[38] Sasaki T, Fukai N, Mann K, Göhring W, Olsen BR, Timpl R. Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. EMBO J 1998; 17(15): 4249–4256

[39] Kim YM, Jang JW, Lee OH, Yeon J, Choi EY, Kim KW, Lee ST, Kwon YG. Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res 2000; 60(19): 5410–5413

[40] Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci USA 2003; 100(8): 4766–4771

[41] Wickström SA, Alitalo K, Keski-Oja J. Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res 2002; 62(19): 5580–5589

[42] Wickström SA, Alitalo K, Keski-Oja J. Endostatin associates with lipid rafts and induces reorganization of the actin cytoskeleton via down-regulation of RhoA activity. J Biol Chem 2003; 278(39): 37895–37901

[43] Anderson RG. The caveolae membrane system. Annu Rev Biochem 1998; 67(1): 199–225

[44] Zhang AY, Yi F, Zhang G, Gulbins E, Li PL. Lipid raft clustering and redox signaling platform formation in coronary arterial endothelial cells. Hypertension 2006; 47(1): 74–80

[45] Jin S, Zhang Y, Yi F, Li PL. Critical role of lipid raft redox signaling platforms in endostatin-induced coronary endothelial dysfunction. Arterioscler Thromb Vasc Biol 2008; 28(3): 485–490

[46] Said EA, Krust B, Nisole S, Svab J, Briand JP, Hovanessian AG. The anti-HIV cytokine midkine binds the cell surface-expressed nucleolin as a low affinity receptor. J Biol Chem 2002; 277(40): 37492–37502

[47] Legrand D, Vigié K, Said EA, Elass E, Masson M, Slomianny MC, Carpentier M, Briand JP, Mazurier J, Hovanessian AG. Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells. Eur J Biochem 2004; 271(2): 303–317

Acknowledgements

This work was supported in part by the General Programs of the National Natural Science Foundation of China (Grant No. 30771083), the National High Technology Research and Development Program of China (No. 2007AA02Z155 and No. 2008AA02Z136), and the National Science and Technology Major Project (No. 2009ZX09103-703 and No. 2009ZX09306-002). The authors declare no competing financial interests.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg