Thrombospondin-1 Suppresses Spontaneous Tumor Growth and Inhibits Activation of Matrix Metalloproteinase-9 and Mobilization of Vascular Endothelial Growth Factor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2001 Oct 19

PMID 11606713

Citations 168

Authors

T F Lane

M A Ortega

R O Hynes

J Lawler

M L Iruela-Arispe

Affiliations

Soon will be listed here.

Abstract

Growth of tumors and metastasis are processes known to require neovascularization. To ascertain the participation of the endogenous angiogenic inhibitor thrombospondin-1 (TSP1) in tumor progression, we generated mammary tumor-prone mice that either lack, or specifically overexpress, TSP1 in the mammary gland. Tumor burden and vasculature were significantly increased in TSP1-deficient animals, and capillaries within the tumor appeared distended and sinusoidal. In contrast, TSP1 overexpressors showed delayed tumor growth or lacked frank tumor development (20% of animals); tumor capillaries showed reduced diameter and were less frequent. Interestingly, absence of TSP1 resulted in increased association of vascular endothelial growth factor (VEGF) with its receptor VEGFR2 and higher levels of active matrix metalloproteinase-9 (MMP9), a molecule previously shown to facilitate both angiogenesis and tumor invasion. In vitro, enzymatic activation of proMMP9 was suppressed by TSP1. Together these results argue for a protective role of endogenous inhibitors of angiogenesis in tumor growth and implicate TSP1 in the in vivo regulation of metalloproteinase-9 activation and VEGF signaling.

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References

Bashkin P, Doctrow S, Klagsbrun M, Svahn C, Folkman J, Vlodavsky I . Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. Biochemistry. 1989; 28(4):1737-43. DOI: 10.1021/bi00430a047. View

Muller W, Sinn E, Pattengale P, Wallace R, Leder P . Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988; 54(1):105-15. DOI: 10.1016/0092-8674(88)90184-5. View

Talhouk R, Chin J, Unemori E, Werb Z, Bissell M . Proteinases of the mammary gland: developmental regulation in vivo and vectorial secretion in culture. Development. 1991; 112(2):439-49. PMC: 2975574. DOI: 10.1242/dev.112.2.439. View

Tolsma S, Volpert O, Good D, Frazier W, Polverini P, BOUCK N . Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J Cell Biol. 1993; 122(2):497-511. PMC: 2119646. DOI: 10.1083/jcb.122.2.497. View

Iruela-Arispe M, Liska D, Sage E, Bornstein P . Differential expression of thrombospondin 1, 2, and 3 during murine development. Dev Dyn. 1993; 197(1):40-56. DOI: 10.1002/aja.1001970105. View

Vogel T, Guo N, Krutzsch H, Blake D, Hartman J, Mendelovitz S . Modulation of endothelial cell proliferation, adhesion, and motility by recombinant heparin-binding domain and synthetic peptides from the type I repeats of thrombospondin. J Cell Biochem. 1993; 53(1):74-84. DOI: 10.1002/jcb.240530109. View

Zabrenetzky V, Harris C, Steeg P, Roberts D . Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma, lung and breast carcinoma cell lines. Int J Cancer. 1994; 59(2):191-5. DOI: 10.1002/ijc.2910590209. View

Zabrenetzky V, Vanhoutte K, Frazier W, Roberts D, Steeg P . Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res. 1994; 54(24):6504-11. View

Naldini L, Vigna E, Bardelli A, Follenzi A, Galimi F, Comoglio P . Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. J Biol Chem. 1995; 270(2):603-11. DOI: 10.1074/jbc.270.2.603. View

10.

Hogg P . Thrombospondin 1 as an enzyme inhibitor. Thromb Haemost. 1994; 72(6):787-92. View

11.

Sheibani N, Frazier W . Thrombospondin 1 expression in transformed endothelial cells restores a normal phenotype and suppresses their tumorigenesis. Proc Natl Acad Sci U S A. 1995; 92(15):6788-92. PMC: 41414. DOI: 10.1073/pnas.92.15.6788. View

12.

Ogata Y, Itoh Y, Nagase H . Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases. J Biol Chem. 1995; 270(31):18506-11. DOI: 10.1074/jbc.270.31.18506. View

13.

Reed M, OBrien E, Truong T, LaBell T, Bornstein P, Sage E . Expression of thrombospondins by endothelial cells. Injury is correlated with TSP-1. Am J Pathol. 1995; 147(4):1068-80. PMC: 1870996. View

14.

Iruela-Arispe M, Porter P, Bornstein P, Sage E . Thrombospondin-1, an inhibitor of angiogenesis, is regulated by progesterone in the human endometrium. J Clin Invest. 1996; 97(2):403-12. PMC: 507031. DOI: 10.1172/JCI118429. View

15.

Whitelock J, Murdoch A, Iozzo R, Underwood P . The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem. 1996; 271(17):10079-86. DOI: 10.1074/jbc.271.17.10079. View

16.

Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996; 86(3):353-64. DOI: 10.1016/s0092-8674(00)80108-7. View

17.

Guo N, Krutzsch H, INMAN J, Roberts D . Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res. 1997; 57(9):1735-42. View

18.

Guo N, Krutzsch H, INMAN J, Shannon C, Roberts D . Antiproliferative and antitumor activities of D-reverse peptides derived from the second type-1 repeat of thrombospondin-1. J Pept Res. 1997; 50(3):210-21. DOI: 10.1111/j.1399-3011.1997.tb01187.x. View

19.

Qian X, Wang T, Rothman V, Nicosia R, Tuszynski G . Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells. Exp Cell Res. 1997; 235(2):403-12. DOI: 10.1006/excr.1997.3681. View

20.

Lawler J, Sunday M, Thibert V, Duquette M, George E, Rayburn H . Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest. 1998; 101(5):982-92. PMC: 508649. DOI: 10.1172/JCI1684. View