Abstract
The progressive growth of most neoplasms is dependent upon the establishment of new blood vessels, a process regulated by tumor-secreted factors and matrix proteins. We examined the in vitro and in vivo angiogenic ability of conditioned media obtained from fibrosarcoma, carcinoma, and osteosarcoma cells and their decorin-transfected counterparts. Human endothelial cells were investigated in vitro by evaluating three essential steps of angiogenesis: migration, attachment, and differentiation. On the whole, wild-type tumor cell-secretions enhanced endothelial cell attachment, migration, and differentiation, whereas their decorin-expressing forms inhibited these processes. Similarly, decorin-containing media suppressed endothelial cell sprouting in an ex vivo aortic ring assay. Since angiogenesis is an important component of tumor expansion, the growth rate of these cells as tumor xenografts was examined by implantation in nude mice. In vivo, the decorin-expressing tumor xenografts grew at markedly lower rates and showed a significant suppression of neovascularization. Immunohistochemical, Northern and Western blot analyses indicated that the decorin-expressing cells produced vascular endothelial growth factor (VEGF) at markedly reduced rates vis-á-vis their wild-type counterparts. Specificity of this process was confirmed by experiments where addition of recombinant decorin to the wild-type tumor cells caused 80–95% suppression of VEGF mRNA and protein. These results provide a novel mechanism of action for decorin, and indicate that decorin could adversely affect in vivo tumor growth by suppressing the endogenous tumor cell production of a powerful angiogenic stimulus.
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Abbreviations
- VEGF:
-
vascular endothelial growth factors
- FGF2:
-
fibroblast growth factor 2 also known as basic FGF
- EGFR:
-
epidermal growth factor receptor
- HUVEC:
-
human umbilical vein endothelial cells
- SFM:
-
serum-free medium
- SDS–PAGE:
-
Na dodecylsulfate polyacrylamide gel electrophoresis
- DPBS:
-
Dulbecco's phosphate buffered saline
References
Abe T, Okamura K, Ono M, Kohno K, Mori T, Hori S, Kuwano M . 1993 J. Clin. Invest. 92: 54–61
Adany R, Heimer R, Caterson B, Sorrell JM, Iozzo RV . 1990 J. Biol. Chem. 265: 11389–11396
Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, McEwan RN . 1987 Cancer Res. 47: 3239–3245
Aviezer D, Hecht D, Safran M, Eisinger M, David G, Yayon A . 1994 Cell 79: 1005–1013
Balsari A, Maier JAM, Golnaghi MI, Ménard S . 1999 Lab. Invest. 79: 897–902
Bianco P, Riminucci M, Fisher LW . 1993 Dermatan Sulphate Proteoglycans Scott JE (ed) London: Portland Press. pp. 193–205
Bidanset D, LeBaron R, Rosenberg L, Murphy-Ullrich JE, Höök M . 1992 J. Cell. Biol. 118: 1523–1531
Cheng S-Y, Huang H-JS, Nagane M, Ji X-D, Wang D, Shih CC-Y, Arap W, Huang C-M, Cavenee WK . 1996 Proc. Natl. Acad. Sci. USA 93: 8502–8507
Coppock DL, Kopman C, Scandalis S, Gilleran S . 1993 Cell Growth Differ. 4: 483–493
Csordás G, Santra M, Reed CC, Eichstetter I, McQuillan D, Gross D, Nugent MA, Hajnóczky G, Iozzo RV . 2000 J. Biol. Chem. 275: 32879–32887
Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV . 1997 J. Cell. Biol. 136: 729–743
de Lange Davies C, Melder RJ, Munn LL, Mouta-Carreira C, Jain RK, Boucher Y . 2001 Microvasc. Res. 62: 26–42
De Luca A, Santra M, Baldi A, Giordano A, Iozzo RV . 1996 J. Biol. Chem. 271: 18961–18965
Esko JD, Rostand KS, Weinke JL . 1988 Science 241: 1092–1096
Filmus J, Selleck SB . 2001 J. Clin. Invest. 108: 497–501
Fisher LW, Stubbs III JT, Young MF . 1995 Acta Orthop. Scand. 66: 61–65
Folkman J, D'Amore PA . 1996 Cell 87: 1153–1155
Folkman J, Haudenschild CC, Zetter BR . 1979 Proc. Natl. Acad. Sci. USA 76: 5217–5221
Garrido T, Riese HH, Aracil M, Pérez-Aranda A . 1995 Br. J. Cancer 71: 770–775
Ghiselli G, Eichstetter I, Iozzo RV . 2001 Biochem. J. 359: 153–163
Grant DS, Tashiro K-I, Segui-Real B, Yamada Y, Martin GR, Kleinman HK . 1989 Cell 58: 933–943
Hanahan D, Folkman J . 1996 Cell 86: 353–364
Iozzo RV . 1998 Annu. Rev. Biochem. 67: 609–652
Iozzo RV . 1999 J. Biol. Chem. 274: 18843–18846
Iozzo RV . 2001 J. Clin. Invest. 108: 165–167
Iozzo RV, Moscatello D, McQuillan DJ, Eichstetter I . 1999 J. Biol. Chem. 274: 4489–4492
Iozzo RV, San Antonio JD . 2001 J. Clin. Invest. 108: 349–355
Järveläinen HT, Iruela-Arispe ML, Kinsella MG, Sandell LJ, Sange EH, Wight TN . 1992 Exp. Cell Res. 203: 395–401
Järveläinen HT, Kinsella MG, Wight TN, Sandell LJ . 1991 J. Biol. Chem. 266: 23274–23281
Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D . 1991 Cell 66: 1095–1104
Kinsella MG, Fischer JW, Mason DP, Wight TN . 2000 J. Biol. Chem. 275: 13924–13932
Kleinman HK, McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW, Martin GR . 1986 Biochemistry 25: 312–318
Kleinman HK, McGarvey ML, Liotta LA, Robey PG, Tryggvason K, Martin GR . 1982 Biochemistry 24: 6188–6193
Klezovitch O, Edelstein C, Zhu L, Scanu AM . 1998 J. Biol. Chem. 273: 23856–23865
Kobe B, Deisenhofer J . 1993 Nature 366: 751–756
Kresse H, Schönherr E . 2001 J. Cell. Physiol. 189: 266–274
Mann DM, Yamaguchi Y, Bourdon MA, Ruoslahti E . 1990 J. Biol. Chem. 265: 5317–5323
Mauviel A, Santra M, Chen YQ, Uitto J, Iozzo RV . 1995 J. Biol. Chem. 270: 11692–11700
Mongiat M, Taylor K, Otto J, Aho S, Uitto J, Whitelock J, Iozzo RV . 2000 J. Biol. Chem. 275: 7095–7100
Moscatello D, Santra M, Mann DM, McQuillan D, Wong AJ, Iozzo RV . 1998 J Clin Invest 101: 406–412
Nelimarkka L, Salminen H, Kuopio T, Nikkari S, Ekfors T, Laine J, Pelliniemi L, Järveläinen H . 2001 Am. J. Pathol. 158: 345–353
Nicosia RF, Madri JA . 1987 Am. J. Pathol. 128: 78–90
Nicosia RF, Ottinetti A . 1990 Lab. Invest. 63: 115–122
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J . 1997 Cell 88: 277–285
Petit AMV, Rak J, Hung M-C, Rockwell P, Goldstein N, Fendly B, Kerbel RS . 1997 Am. J. Pathol. 151: 1523–1530
Polakowski IJ, Lewis MK, Muthukkaruppan VR, Erdman B, Kubai L, Auerbach R . 1993 Am. J. Pathol. 143: 507–517
Reed CC, Gauldie J, Iozzo RV . 2002 Oncogene 21: 3688–3695
Risau W . 1995 FASEB J. 9: 926–933
Risau W . 1997 Nature 386: 671–674
Sage EH . 1997 Trends Cell Biol. 7: 182–186
Saksela O, Moscatelli D, Sommer A, Rifkin DB . 1988 J. Cell. Biol. 107: 743–751
Saksela O, Rifkin DB . 1990 J. Cell. Biol. 110: 767–775
Santra M, Eichstetter I, Iozzo RV . 2000 J. Biol. Chem. 275: 35153–35161
Santra M, Mann DM, Mercer EW, Skorski T, Calabretta B, Iozzo RV . 1997 J. Clin. Invest. 100: 149–157
Santra M, Skorski T, Calabretta B, Lattime EC, Iozzo RV . 1995 Proc. Natl. Acad. Sci. USA 92: 7016–7020
Schmidt G, Robenek H, Harrach B, Glössl J, Nolte V, Hörmann H, Richter H, Kresse H . 1987 J. Cell. Biol. 104: 1683–1691
Scholzen T, Solursh M, Suzuki S, Reiter R, Morgan JL, Buchberg AM, Siracusa LD, Iozzo RV . 1994 J. Biol. Chem. 269: 28270–28281
Schönherr E, Levkau B, Schaefer L, Kresse H, Walsh K . 2001 J. Biol. Chem. 276: 40687–40692
Schönherr E, O'Connell BC, Schittny J, Robenek H, Fastermann D, Fisher LW, Plenz G, Vischer P, Young MF, Kresse H . 1999 Eur. J. Cell Biol. 78: 44–55
Vogel KG, Paulsson M, Heinegård D . 1984 Biochem. J. 223: 587–597
Weber IT, Harrison RW, Iozzo RV . 1996 J. Biol. Chem. 271: 31767–31770
Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J . 1994 Am. J. Pathol. 143: 401–409
Weidner N, Semple JP, Welch WR, Folkman J . 1991 New Engl. J. Med. 324: 1–8
Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA . 1996 J. Biol. Chem. 271: 10079–10086
Yang VWC, LaBrenz SR, Rosenberg LC, McQuillan D, Höök M . 1999 J. Biol. Chem. 274: 12454–12460
Acknowledgements
We thank J Pope for help with the quantization of the vessels in the mouse tumors, and J Caro, L Fisher and D Mann for providing valuable reagents. This work was supported by grants from the Landenberger Research Foundation and Merck Pharmaceuticals, Rahway N.J. (DS Grant) and from the National Institutes of Health grants RO1 CA39481 and RO1 CA47282, and grants from the Department of the Army, DAMD17-00-1-0663 and DAMD17-00-1-0425 (RV Iozzo), and from the Turkish Scientific Technical and Research Council (TÜBITAK) (C Yenisey).
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Grant, D., Yenisey, C., Rose, R. et al. Decorin suppresses tumor cell-mediated angiogenesis. Oncogene 21, 4765–4777 (2002). https://doi.org/10.1038/sj.onc.1205595
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DOI: https://doi.org/10.1038/sj.onc.1205595
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