Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor)

Oncogene volume 24, pages 1615–1624 (2005)Cite this article

Abstract

Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations, resulting in β-catenin-mediated transcriptional activation. We found that plasminogen activator inhibitor-1 (PAI-1) was upregulated fourfold in aggressive fibromatosis. We investigated the ability of β-catenin to regulate a PAI-1 reporter, and found that PAI-1 is an indirect target. To determine the role of PAI-1 in vivo, a mouse containing a targeted deletion in Pai-1 was crossed with a mouse that develops aggressive fibromatosis and gastrointestinal tumors (Apc/Apc1638N mouse). Pai-1 deficiency reduced the number of aggressive fibromatosis tumors formed, but not the number of gastrointestinal tumors. Deficiency of Pai-1 reduced tumor cell proliferation and motility rate. Although PAI-1 can alter cell motility by competing for a common binding site on vitronectin, blocking this site did not alter the motility rate. The number of cells moving through matrigel (invasion rate) did not change with Pai-1 deficiency, but because of the low motility rate the invasion index (invasion rate/motility) was increased in Pai-1-deficient cells. This suggests a proteolytic effect for PAI-1 regulating cell invasiveness. Our study found that, although PAI-1 has cellular effects that could inhibit or enhance tumor growth, on balance, it acts as a tumor enhancer in aggressive fibromatosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Abe M, Harpel JG, Metz CN, Nunes I, Loskutoff DJ and Rifkin DB . (1994). Anal. Biochem., 216, 276–284.

  • Alman BA, Li C, Pajerski ME, Diaz-Cano S and Wolfe HJ . (1997a). Am. J. Pathol., 151, 329–334.

  • Alman BA, Pajerski ME, Diaz-Cano S, Corboy K and Wolfe HJ . (1997b). Diag. Mol. Pathol., 6, 98–101.

  • Almholt K, Nielsen BS, Frandsen TL, Brunner N, Dano K and Johnsen M . (2003). Oncogene, 22, 4389–4397.

  • Andreasen PA, Kjoller L, Christensen L and Duffy MJ . (1997). Int. J. Cancer, 72, 1–22.

  • Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D and Foidart JM . (1998). Nat. Med., 4, 923–928.

  • Binder BR, Christ G, Gruber F, Grubic N, Hufnagl P, Krebs M, Mihaly J and Prager GW . (2002). Physiol. Sci., 17, 56–61.

  • Cajot JF, Bamat J, Bergonzelli GE, Kruithof EK, Medcalf RL, Testuz J and Sordat B . (1990). Proc. Natl. Acad. Sci. USA, 87, 6939–6943.

  • Carmeliet P, Kieckens L, Schoonjans L, Ream B, van Nuffelen A, Prendergast G, Cole M, Bronson R, Collen D and Mulligan RC . (1993a). J. Clin. Invest., 92, 2746–2755.

  • Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord JJ, De Mol M, Mulligan RC and Collen D . (1993b). J. Clin. Invest., 92, 2756–2760.

  • Cheon SS, Cheah AY, Turley S, Nadesan P, Poon R, Clevers H and Alman BA . (2002). Proc. Natl. Acad. Sci. USA, 99, 6973–6978.

  • Crandall DL, Busler DE, McHendry-Rinde B, Groeling TM and Kral JG . (2000). J. Clin. Endocrinol. Metab., 85, 2609–2614.

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier JM . (1998). EMBO J., 17, 3091–3100.

  • Descheemaeker KA, Wyns S, Nelles L, Auwerx J, Ny T and Collen D . (1992). J. Biol. Chem., 267, 15086–15091.

  • Dormans JP, Spiegel D, Meyer J, Asada N, Alman BA, Pill SG, Himelstein B and Womer R . (2001). Med. Pediatr. Oncol., 37, 126–131.

  • Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B, Breukel C, Alt E, Lipkin M and Khan PM . (1994). Proc. Natl. Acad. Sci. USA, 91, 8969–8973.

  • Grimaldi G, Di Fiore P, Locatelli EK, Falco J and Blasi F . (1986). EMBO J., 5, 855–861.

  • Grondahl-Hansen J, Christensen IJ, Briand P, Pappot H, Mouridsen HT, Blichert-Toft M, Dano K and Brunner N . (1997a). Clin. Cancer Res., 3, 233–239.

  • Grondahl-Hansen J, Christensen IJ, Rosenquist C, Brunner N, Mouridsen HT, Dano K and Blichert-Toft M . (1993). Cancer Res., 53, 2513–2521.

  • Grondahl-Hansen J, Hilsenbeck SG, Christensen IJ, Clark GM, Osborne CK and Brunner N . (1997b). Breast Cancer Res. Treat., 43, 153–163.

  • Grondahl-Hansen J, Peters HA, van Putten WL, Look MP, Pappot H, Ronne E, Dano K, Klijn JG, Brunner N and Foekens JA . (1995). Clin. Cancer Res., 1, 1079–1087.

  • Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA and Castellino FJ . (2000). Cancer Res., 60, 5839–5847.

  • Hjortland GO, Bjornland K, Pettersen S, Garman-Vik SS, Emilsen E, Nesland JM, Fodstad O and Engebraaten O . (2003). Clin. Exp. Metastasis, 20, 301–309.

  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P and McKechnie D . (1991). Science, 253, 661–665.

  • Kjoller L, Kanse SM, Kirkegaard T, Rodenburg KW, Ronne E, Goodman SL, Preissner KT, Ossowski L and Andreasen PA . (1997). Exp. Cell. Res., 232, 420–429.

  • Kong Y, Poon R, Nadesan P, Di Muccio T, Fodde R, Khokha R and Alman BA . (2004). Cancer Res., 64, 5795–5803.

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H . (1997). Science, 275, 1784–1787.

  • Kute TE, Grondahl-Hansen J, Shao SM, Long R, Russell G and Brunner N . (1998). Breast Cancer Res. Treat., 47, 9–16.

  • Kutz C, Pebler S, Otte J and von der Ahe D . (1995). Nucleic Acids Res., 23, 3710–3717.

  • Kwaan HC, Wang J, Svoboda K and Declerck PJ . (2000). Br. J. Cancer, 82, 1702–1708.

  • Li C, Nguyen Q, Cole WG and Alman BA . (2001). J. Ped. Orthop., 21, 372–377.

  • Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O’Higgins N, Eppenberger U, Janicke F, Schmitt M and Foekens JA . (2002). J. Natl. Cancer Inst., 94, 116–128.

  • Meng X, Poon R, Zhang X, Cheah A, Ding Q, Hui CC and Alman B . (2001). J. Biol. Chem., 276, 40113–40119.

  • Miller JR, Hocking AM, Brown JD and Moon RT . (1999). Oncogene, 18, 7860–7872.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW . (1997). Science, 275, 1787–1790.

  • Morita Y, Hayashi Y, Kanamaru T, Itoh T, Suzuki S, Yamamoto M, Kuroda Y and Itoh H . (1999). Jpn. J. Cancer Res., 90, 747–752.

  • Mulholland DJ, Cheng H, Reid K, Rennie PS and Nelson CC . (2002). J. Biol. Chem., 277, 17933–17943.

  • Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J and Blasi F . (1997). EMBO J., 16, 2610–2620.

  • Pawlowski JE, Ertel JR, Allen MP, Xu M, Butler C, Wilson EM and Wierman ME . (2002). J. Biol. Chem., 277, 20702–20710.

  • Poon R, Smits R, Li C, Jagmohan-Changur S, Kong M, Cheon S, Yu C, Fodde R and Alman BA . (2001). Oncogene, 20, 451–460.

  • Rakic JM, Maillard C, Jost M, Bajou K, Masson V, Devy L, Lambert V, Foidart JM and Noel A . (2003). Cell. Mol. Life Sci., 60, 463–473.

  • Roose J and Clevers H . (1999). Biochim. Biophys. Acta, 1424, M23–M37.

  • Ryan MP, Kutz SM and Higgins PJ . (1996). Biochem. J., 314, 1041–1046.

  • Schmitt M, Harbeck N, Thomssen C, Wilhjelm O, Magdolen V and Reuning U . (1997). Thromb. Haemostasis, 78, 285–296.

  • Scott RJ, Froggatt NJ, Trembath RC, Evans DG, Hodgson SV and Maher ER . (1996). Hum. Mol. Genet., 5, 1921–1924.

  • Smits R, van der Houven van Oordt W, Luz A, Zurcher C, Jagmohan-Changur S, Breukel C, Khan PM and Fodde R . (1998). Gastroenterology, 114, 275–283.

  • Steinmetzer T . (2003). IDrugs, 6, 138–146.

  • Sugiura Y, Ma L, Sun B, Shimada H, Laug WE, Seeger RC and DeClerck YA . (1999). Cancer Res., 59, 1237–1336.

  • Tejpar S, Li C, Yu C, Poon R, Denys H, Sciot R, Van Cutsem E, Cassiman JJ and Alman BA . (2001). Br. J. Cancer, 85, 98–101.

  • Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P, Van Cutsem E, Bapat B, van Roy F, Cassiman JJ and Alman BA . (1999). Oncogene, 18, 6615–6620.

  • Tischler AS, Ruzicka LA and Riseberg JC . (1992). J. Histochem. Cytochem., 40, 1043–1045.

  • Tolg C, Poon R, Fodde R, Turley EA and Alman BA . (2003). Oncogene, 22, 6873–6882.

  • van der Houven van Oordt CW, Smits R, Schouten TG, Houwing-Duistermaat JJ, Williamson SL, Luz A, Meera Khan P, van der Eb AJ, Breuer ML and Fodde R . (1999). Genes Chromosomes Cancer, 24, 191–198.

  • Waltz DA, Natkin LR, Fujita RM, Wei Y and Chapman HA . (1997). J. Clin. Invest., 100, 58–67.

  • Yang JL, Seetoo DQ, Wang Y, Ranson M, Berney CR, Ham JM, Russell PJ and Crowe PJ . (2000). Int. J. Cancer (Pred. Oncol.), 89, 431–439.

  • Zavizion B, White JH and Bramley AJ . (1998). Biochim. Biophys. Acta, 1403, 141–150.

Download references

Acknowledgements

PAI-1 promoter construct (P800-neo-luc) was a gift provided by Dr DB Rifkin, Department of Cell Biology, New York University Medical Center, New York. This study was funded by Grants from the National Cancer Institute of Canada to BAA and by the Danish Medical Research Foundation, grant number 9901192 to NB. BAA is supported by the Canadian Research Chairs Program. CFL is a recipient of Ontario Graduate Scholarship.

Author information

Authors and Affiliations

  1. Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8

    Catherine Fen Li, Christopher Kandel, Frank Baliko, Puviindran Nadesan & Benjamin A Alman

  2. Royal Veterinary and Agricultural University, 1870 Frederiksberg, Copenhagen, Denmark

    Nils Brünner

  3. The Department of Surgery, University of Toronto, USA

    Benjamin A Alman

Authors
  1. Catherine Fen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Kandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank Baliko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Puviindran Nadesan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nils Brünner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Benjamin A Alman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin A Alman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fen Li, C., Kandel, C., Baliko, F. et al. Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor). Oncogene 24, 1615–1624 (2005). https://doi.org/10.1038/sj.onc.1208193

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208193

Keywords

This article is cited by

Search

Advanced search

Quick links