The major route of tumor spread is through the bloodstream. Once in circulation, the tumor cells aggregate in clumps with platelets, which enhances the tumor cell survival. The tumor emboli will then adhere to the endothelium and by the release of proteases extravasation of the cells will occur. One of the platelet-secreted proteins is thrombospondin-1. In this article, thrombospondin-1 will be described as a modulator of angiogenesis through its role in regulating endothelial cell apoptosis, protease expression, and vascular endothelial growth factor expression. We hope to convey the idea that activity of thrombospondin-1 in tumor progression is dependent upon its interaction with several host- and tumor-associated proteins.
KEYWORDS
Thrombospondin-1 - metastasis - angiogenesis - proteases - vascular endothelial growth factor
REFERENCES
-
1 Recamier J C. L'Histoire de la Même Maladie. Vol 2 Paris; Gabon 1829: 731-737
-
2
Paget S.
The distribution of secondary growths in cancer of the breast.
Lancet.
1889;
1
571-573
-
3 Billroth T. Lectures on Surgical Pathology and Therapeutics: A Handbook for Students and Practitioners. London; New Syndenham Society 1878: 355
-
4 Trousseau A. Clinique Médicale de L'Hôtel de Paris. Vol 3 Paris; Balliere 1865: 654-656
-
5
Bick R L.
Coagulation abnormalities in malignancy: a review.
Semin Thromb Hemost.
1992;
18
353-372
-
6
Falanga A, Gordon S G.
Isolation and characterization of cancer procoagulant: a cysteine proteinase from malignant tissue.
Biochemistry.
1985;
24
5558-5567
-
7
Tohgo A, Tanaka N, Ashida S, Ogawa H.
Platelet-aggregating activities of metastasizing tumor cells. II. Variety of the aggregation mechanisms.
Invasion Metastasis.
1984;
4
134-145
-
8
Gasic G J, Gasic T B, Stewart C C.
Antimetastatic effects associated with platelet reduction.
Proc Natl Acad Sci USA.
1968;
61
46-52
-
9
Karpatkin S, Pearlstein E, Ambrogio C, Coller B S.
Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo.
J Clin Invest.
1988;
81
1012-1019
-
10
Honn K V, Tang D G, Chen Y Q.
Platelets and cancer metastasis: more than an epiphenomenon.
Semin Thromb Hemost.
1992;
18
392-415
-
11
Honn K V, Cicone B, Skoff A.
Prostacyclin: a potent antimetastatic agent.
Science.
1981;
212
1270-1272
-
12
Marnett L J.
Aspirin and the potential role of prostaglandins in colon cancer.
Cancer Res.
1992;
52
5575-5589
-
13
Tuszynski G P, Gasic T B, Rothman V L, Knudsen K A, Gasic G J.
Thrombospondin, a potentiator of tumor cell metastasis.
Cancer Res.
1987;
47
4130-4133
-
14
Tuszynski G P, Rothman V L, Murphy A, Siegler K, Knudsen K A.
Thrombospondin promotes platelet aggregation.
Blood.
1988;
72
109-115
-
15
Hogg P J, Stenflo J, Mosher D F.
Thrombospondin is a slow tight-binding inhibitor of plasmin.
Biochemistry.
1992;
31
265-269
-
16
Lawler J.
Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth.
J Cell Mol Med.
2002;
6
1-12
-
17
Baenziger N L, Brodie G N, Majerus P W.
A thrombin-sensitive protein of human platelet membranes.
Proc Natl Acad Sci USA.
1971;
68
240-243
-
18
DiPietro L A, Polverini P J.
Angiogenic macrophages produce the angiogenic inhibitor thrombospondin 1.
Am J Pathol.
1993;
143
678-684
-
19
Reed M J, Puolakkainen P, Lane T F, Dickerson D, Bornstein P, Sage E H.
Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization.
J Histochem Cytochem.
1993;
41
1467-1477
-
20
Adolph K W.
A thrombospondin homologue in Drosophila melanogaster: cDNA and protein structure.
Gene.
2001;
269
177-184
-
21
Tolsma S S, Volpert O V, Good D J, Frazier W A, Polverini P J, Bouck N.
Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity.
J Cell Biol.
1993;
122
497-511
-
22
Dawson D W, Volpert O V, Pearce S F et al..
Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat.
Mol Pharmacol.
1999;
55
332-338
-
23
Reiher F K, Volpert O V, Jimenez B et al..
Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics.
Int J Cancer.
2002;
98
682-689
-
24
Iruela-Arispe M L, Lombardo M, Krutzsch H C, Lawler J, Roberts D D.
Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats.
Circulation.
1999;
100
1423-1431
-
25
Kanda S, Shono T, Tomasini-Johansson B, Klint P, Saito Y.
Role of thrombospondin-1-derived peptide, 4N1K, in FGF-2-induced angiogenesis.
Exp Cell Res.
1999;
252
262-272
-
26
Taraboletti G, Morbidelli L, Donnini S et al..
The heparin binding 25 kDa fragment of thrombospondin-1 promotes angiogenesis and modulates gelatinase and TIMP-2 production in endothelial cells.
FASEB J.
2000;
14
1674-1676
-
27
Ferrari do Outeiro-Bernstein M A, Nunes S S, Andrade A C, Alves T R, Legrand C, Morandi V.
A recombinant NH(2)-terminal heparin-binding domain of the adhesive glycoprotein, thrombospondin-1, promotes endothelial tube formation and cell survival: a possible role for syndecan-4 proteoglycan.
Matrix Biol.
2002;
21
311-324
-
28
Guo N, Krutzsch H C, Inman J K, Roberts D D.
Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells.
Cancer Res.
1997;
57
1735-1742
-
29
Dawson D W, Pearce S F, Zhong R, Silverstein R L, Frazier W A, Bouck N P.
CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells.
J Cell Biol.
1997;
138
707-717
-
30
Jimenez B, Volpert O V, Crawford S E, Febbraio M, Silverstein R L, Bouck N.
Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.
Nat Med.
2000;
6
41-48
-
31
Jimenez B, Volpert O V, Reiher F et al..
c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1.
Oncogene.
2001;
20
3443-3448
-
32
Volpert O V, Zaichuk T, Zhou W et al..
Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.
Nat Med.
2002;
8
349-357
-
33
Freyberg M A, Kaiser D, Graf R, Vischer P, Friedl P.
Integrin-associated protein and thrombospondin-1 as endothelial mechanosensitive death mediators.
Biochem Biophys Res Commun.
2000;
271
584-588
-
34
Freyberg M A, Kaiser D, Graf R, Buttenbender J, Friedl P.
Proatherogenic flow conditions initiate endothelial apoptosis via thrombospondin-1 and the integrin-associated protein.
Biochem Biophys Res Commun.
2001;
286
141-149
-
35
Stromblad S, Becker J C, Yebra M, Brooks P C, Cheresh D A.
Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis.
J Clin Invest.
1996;
98
426-433
-
36
Hogg P J.
Thrombospondin 1 as an enzyme inhibitor.
Thromb Haemost.
1994;
72
787-792
-
37
Albo D, Arnoletti J P, Castiglioni A et al..
Thrombospondin (TSP) and transforming growth factor beta 1 (TGF-beta) promote human A549 lung carcinoma cell plasminogen activator inhibitor type 1 (PAI-1) production and stimulate tumor cell attachment in vitro.
Biochem Biophys Res Commun.
1994;
203
857-865
-
38
Arnoletti J P, Albo D, Granick M S et al..
Thrombospondin and transforming growth factor-beta 1 increase expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in human MDA-MB-231 breast cancer cells.
Cancer.
1995;
76
998-1005
-
39
Blasi F.
Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness.
Bioessays.
1993;
15
105-111
-
40
Albo D, Berger D H, Wang T N, Hu X, Rothman V, Tuszynski G P.
Thrombospondin-1 and transforming growth factor-beta l promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system.
Surgery.
1997;
122
493-449
, discussion
499-500
-
41
Albo D, Berger D H, Tuszynski G P.
The effect of thrombospondin-1 and TGF-beta 1 on pancreatic cancer cell invasion.
J Surg Res.
1998;
76
86-90
-
42
Albo D, Rothman V L, Roberts D D, Tuszynski G P.
Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor.
Br J Cancer.
2000;
83
298-306
-
43
John A, Tuszynski G.
The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis.
Pathol Oncol Res.
2001;
7
14-23
-
44
Qian X, Wang T N, Rothman V L, Nicosia R F, Tuszynski G P.
Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells.
Exp Cell Res.
1997;
235
403-412
-
45
Bein K, Simons M.
Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity.
J Biol Chem.
2000;
275
32167-32173
-
46
Rodriguez-Manzaneque J C, Lane T F, Ortega M A, Hynes R O, Lawler J, Iruela-Arispe M L.
Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.
Proc Natl Acad Sci USA.
2001;
98
12485-12490
-
47
Dvorak H F, Brown L F, Detmar M, Dvorak A M.
Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.
Am J Pathol.
1995;
146
1029-1039
-
48
Kawahara N, Ono M, Taguchi K et al..
Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma.
Hepatology.
1998;
28
1512-1517
-
49
de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz E M, Feige J J.
Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations.
J Clin Endocrinol Metab.
2000;
85
4734-4741
-
50
Kang D H, Anderson S, Kim Y G et al..
Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease.
Am J Kidney Dis.
2001;
37
601-611
-
51
Kang D H, Joly A H, Oh S W et al..
Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1.
J Am Soc Nephrol.
2001;
12
1434-1447
-
52
Tanaka K, Sonoo H, Kurebayashi J et al..
Inhibition of infiltration and angiogenesis by thrombospondin-1 in papillary thyroid carcinoma.
Clin Cancer Res.
2002;
8
1125-1131
-
53
Tan X J, Lang J H, Liu D Y, Shen K, Leng J H, Zhu L.
Expression of vascular endothelial growth factor and thrombospondin-1 mRNA in patients with endometriosis.
Fertil Steril.
2002;
78
148-153
-
54
Dameron K M, Volpert O V, Tainsky M A, Bouck N.
Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1.
Science.
1994;
265
1582-1584
-
55
Kieser A, Weich H A, Brandner G, Marme D, Kolch W.
Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression.
Oncogene.
1994;
9
963-969
-
56
Mukhopadhyay D, Tsiokas L, Sukhatme V P.
Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression.
Cancer Res.
1995;
55
6161-6165
-
57
Grossfeld G D, Ginsberg D A, Stein J P et al..
Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression.
J Natl Cancer Inst.
1997;
89
219-227
-
58
Fontanini G, Boldrini L, Calcinai A et al..
Thrombospondins I and II messenger RNA expression in lung carcinoma: relationship with p53 alterations, angiogenic growth factors, and vascular density.
Clin Cancer Res.
1999;
5
155-161
-
59
Kwak C, Jin R J, Lee C, Park M S, Lee S E.
Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia.
BJU Int.
2002;
89
303-309
-
60
Chen H, Herndon M E, Lawler J.
The cell biology of thrombospondin-1.
Matrix Biol.
2000;
19
597-614
-
61
Dumont N, Arteaga C L.
Transforming growth factor-beta and breast cancer: tumor promoting effects of transforming growth factor-beta.
Breast Cancer Res.
2000;
2
125-132
-
62
Murphy-Ullrich J E, Schultz-Cherry S, Hook M.
Transforming growth factor-beta complexes with thrombospondin.
Mol Biol Cell.
1992;
3
181-188
-
63
Taraboletti G, Belotti D, Borsotti P et al..
The 140-kilodalton antiangiogenic fragment of thrombospondin-1 binds to basic fibroblast growth factor.
Cell Growth Differ.
1997;
8
471-479
-
64
Majack R A, Goodman L V, Dixit V M.
Cell surface thrombospondin is functionally essential for vascular smooth muscle cell proliferation.
J Cell Biol.
1988;
106
415-422
-
65
Hogg P J, Hotchkiss K A, Jimenez B M, Stathakis P, Chesterman C N.
Interaction of platelet-derived growth factor with thrombospondin 1.
Biochem J.
1997;
326(pt 3)
709-716
-
66
Krishnaswami S, Ly Q P, Rothman V L, Tuszynski G P.
Thrombospondin-1 promotes proliferative healing through stabilization of PDGF.
J Surg Res.
2002;
107
124-130
-
67
Ichii T, Koyama H, Tanaka S et al..
Thrombospondin-1 mediates smooth muscle cell proliferation induced by interaction with human platelets.
Arterioscler Thromb Vasc Biol.
2002;
22
1286-1292
-
68
Lamszus K, Joseph A, Jin L et al..
Scatter factor binds to thrombospondin and other extracellular matrix components.
Am J Pathol.
1996;
149
805-819
-
69
Goicoechea S, Orr A W, Pallero M A, Eggleton P, Murphy-Ullrich J E.
Thrombospondin mediates focal adhesion disassembly through interactions with cell surface calreticulin.
J Biol Chem.
2000;
275
36358-36368
-
70
Goicoechea S, Pallero M A, Eggleton P, Michalak M, Murphy-Ullrich J E.
The anti-adhesive activity of thrombospondin is mediated by the N-terminal domain of cell surface calreticulin.
J Biol Chem.
2002;
277
37219-37228
-
71
Wong S Y, Purdie A T, Han P.
Thrombospondin and other possible related matrix proteins in malignant and benign breast disease. An immunohistochemical study.
Am J Pathol.
1992;
140
1473-1482
-
72
Wakiyama T, Shinohara T, Shirakusa T, John A S, Tuszynski G P.
The localization of thrombospondin-1 (TSP-1), cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) TSP receptor, and matrix metalloproteinase-9 (MMP-9) in colorectal cancer.
Histol Histopathol.
2001;
16
345-351
-
73
Rice A J, Steward M A, Quinn C M.
Thrombospondin 1 protein expression relates to good prognostic indices in ductal carcinoma in situ of the breast.
J Clin Pathol.
2002;
55
921-925
-
74
Alvarez A A, Axelrod J R, Whitaker R S et al..
Thrombospondin-1 expression in epithelial ovarian carcinoma: association with p53 status, tumor angiogenesis, and survival in platinum-treated patients.
Gynecol Oncol.
2001;
82
273-278
-
75
Tuszynski G P, Rothman V L, Deutch A H, Hamilton B K, Eyal J.
Biological activities of peptides and peptide analogues derived from common sequences present in thrombospondin, properdin, and malarial proteins.
J Cell Biol.
1992;
116
209-217
-
76
Tuszynski G P, Rothman V L, Papale M, Hamilton B K, Eyal J.
Identification and characterization of a tumor cell receptor for CSVTCG, a thrombospondin adhesive domain.
J Cell Biol.
1993;
120
513-521
-
77
Bogdanov Jr A, Marecos E, Cheng H C et al..
Treatment of experimental brain tumors with trombospondin-1 derived peptides: an in vivo imaging study.
Neoplasia.
1999;
1
438-445
George P TuszynskiPh.D.
Center for Neurovirology and Cancer Biology, Temple University
1900 North 12th Street, Philadelphia, PA 19122
Email: gpt@temple.edu
