Abstract
Angiogenesis is a process of capillary formation from pre-existing blood vessels. It is tightly controlled by the balance between positive and negative environmental signals – inducers and inhibitors of angiogenesis in such a way that predominance of inducers results in angiogenesis and predominance of inhibitors – in vascular quiescence. Here we discuss the ability of the angiogenic stimuli to promote survival and the pathways they may utilize. We also summarize information available on the signaling events elicited in the endothelial cells by a naturally occurring inhibitor of angiogenesis Thrombospondin-1 (TSP-1), that result in the endothelial cell apoptosis and inhibition of angiogenesis in vivo. This ability to cause programmed cell death in vascular endothelium is not unique to TSP-1. A substantial number of known angiogenesis inhibitors can also trigger apoptosis in the activated endothelial cells. This fact argues for the possibility of apoptosis to be a common denominator for a major fraction of anti-angiogenic molecules. If this is the case, it is equally possible that the ratio between environmental factors that control angiogenesis is interpreted within individual endothelial cell as a balance between pro-apoptotic and survival signals. Thus the relative strength of the death and survival signal or signals determines the fate of endothelial cell and therefore the fate of remodeling vessel.
Similar content being viewed by others
References
Bouck N, Stellmach V, Hsu S: How tumors become angiogenic. In:Vande Woude J, Klein G (eds) Advances in Cancer Research, 1995, pp 135-174
Folkman J: Is tissue mass regulated by vascular endothelial cells? Prostate as the first evidence. Endocrinology 139: 441-442, 1998
Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353-364, 1996
Folkman J, D'Amore PA: Blood vessel formation: what is its molecular basis? Cell 87: 1153-1155, 1996
Kerbel RS, Viloria-Petit A, Okada F, Rak J: Establishing a link between oncogenes and tumor angiogenesis. Molec Medi 4: 286-295, 1998
Volpert OV, Dameron KM, Bouck N: Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. Oncogene 14: 1495-1502, 1997
Pal S, Claffey KP, Dvorak HF, Mukhopadhyay D: The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. J Biol Chem 272: 27 509-27 512, 1997
Dameron KM, Volpert OV, Tainsky MA, Bouck N: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265: 1582-1584, 1994
Richard DR, Berra E, Pouyssegur J: Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Commun 266: 718-722, 1999
Blagosklonny MV, An WG, Romanova LY, Trepel J, Fojo T, Neckers L: p53 inhibits hypoxia-inducible factor-stimulated transcription. J Biol Chem 273: 11 995-11 998, 1998
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ: The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271-275, 1999
Holash J, Wiegand SJ, Yancopoulos GD: New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins andVEGF. Oncogene 18: 5356-5562, 1999
Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP: A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87: 6624-6628, 1990
Dawson D, Bouck N: Thrombospondin as an inhibitor of angiogenesis. In: Teicher BA (ed) Antiangiogenic Agents in Cancer Therapy. Human Press Inc, Totowa NJ, 1998, pp 185-203
Zabrenetzky V, Harris CC, Steeg PS, Roberts DD: Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma, lung and breast carcinoma cell lines. Intl J Cancer 59: 191-195, 1994
Slack JL, Bornstein P: Transformation by v-src causes transient induction followed by repression of mouse thrombospondin-1. Cell Growth Dif 5: 1373-1380, 1994
Tikhonenko AT, Black DJ, Linial ML: Viral Myc oncoproteins in infected fibroblasts down-modulate thrombospondin-1, a possible tumor suppressor gene. J Biol Chem 271: 30 741-30 747, 1996
Bein K, Ware JA, Simons M: Myb-dependent regulation of thrombospondin 2 expression. Role of mRNA stability. J Biol Chem 273: 21 423-21 429, 1998
Dejong V, Degeorges A, Filleur S, Ait-Si-Ali S, Mettouchi A, Bornstein P, Binetruy B, Cabon F: The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun. Oncogene 18: 3143-3151, 1999
Tolsma SS, Stack MS, Bouck N: Lumen formation and other angiogenic activities of cultured capillary endothelial cells are inhibited by thrombospondin-1. Microvascular Res 54: 13-26, 1997
DiPietro LA: Thrombospondin as a regulator of angiogenesis. EXS 79: 295-314, 1997
Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP: CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 138(3): 707-717, 1997
Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N: Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature Medicine 6: 41-48, 2000
Ozaki I, Tani E, Ikemoto H, Kitagawa H, Fujikawa H: Activation of stress-activated protein kinase/c-Jun NH2-terminal kinase and p38 kinase in calphostin C-induced apoptosis requires caspase-3-like proteases but is dispensable for cell death. J Biol Chem 274: 5310-5317, 1999
Guo N, Krutzsch HC, Inman JK, Roberts DD: Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res 57: 1735-1742, 1997
Boehm T, Folkman J, Browder T, O'Reilly MS: Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390: 404-407, 1997
Chen DH, Guo K, Yang JH, Frazier WA, Isner JM, Andres V: Vascular smooth muscle cell growth arrest on blockade of thrombospondin-1 requires p21(Cip1/WAF1). Amer J Physiol-Heart and Circul Physiol 46: H1100-H1106, 1999
Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N, Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93: 1159-1170, 1998
Stellmach V, Volpert OV, Crawford SE, Lawler J, Hynes RO, Bouck N: Tumour suppressor genes and angiogenesis: the role of TP53 in fibroblasts. Eur J Cancer 32A: 2394-2400, 1996
Yue TL, Wang X, Louden CS, Gupta S, Pillarisetti K, Gu JL, Hart TK, Lysko PG, Feuerstein GZ: 2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and Fas expression. Mol Pharmacol 51: 951-962, 1997
Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota SJ, Borlat F, Sim BK, Wu Z, Grau GE, Shing Y, Soff GA, Bouck N, Pepper MS: Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 92: 4730-4741, 1998
Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP: Endostatin induces endothelial cell apoptosis. J Biol Chem 274: 11 721-11 726, 1999
Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R: Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth (Article). J Biol Chem 275: 1209-1215, 2000
Bishop-Bailey D, Hla T: Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). J Biol Chem 274: 17 042-17 048, 1999
Sata M, Walsh K: Oxidized LDL activates fas-mediated endothelial cell apoptosis. J Clin Invest 102(9): 1682-1689, 1998
Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV: Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 96: 2811-2816, 1999
Chang Z, Choon A, Friedl A: Endostatin binds to blood vessels in situ independent of heparan sulfate and does not compete for fibroblast growth factor-2 binding. Amer J Pathol 155: 71-76, 1999
Meeson AP, Argilla M, Ko K, Witte L, Lang RA: VEGF deprivation-induced apoptosis is a component of programmed capillary regression. Development 126: 1407-1415, 1999
Harnett ME, Garcia CM, D'Amore PA: Release of bFGF, an endothelial cell survival factor, by osmotic shock. Invest Ophthal Visual Sci 40: 2945-2951, 1999
Fujikawa K, Scherpenseel ID, Jain SK, Presman E, Varticovski L: Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells. Exp Cell Res 253: 663-672, 1999
Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oostuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenberger-de Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E: Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98: 147-157, 1999
Babic AM, Chen CC, Lau LF: Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin aVb3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19: 2958-2966, 1999
Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM: NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 141: 1083-1093, 1998
Nunez G, del Peso L: Linking extracellular survival signals and the apoptotic machinery. Current Opin Neurobiol 8: 613-618, 1998
Nor JE, Christensen J, Mooney DJ, Polverini PJ: Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Amer J Pathol 154: 375-384, 1999
Tran J, Rak J, Sheehan C, Saibil SD, LaCasse E, Korneluk RG, Kerbel RS: Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Com 264: 781-788, 1999
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Volpert, O. Modulation of Endothelial Cell Survival by an Inhibitor of Angiogenesis Thrombospondin-1: a Dynamic Balance. Cancer Metastasis Rev 19, 87–92 (2000). https://doi.org/10.1023/A:1026560618302
Issue Date:
DOI: https://doi.org/10.1023/A:1026560618302