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:

Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor)

Oncogene volume 22, pages 6873–6882 (2003)Cite this article

Abstract

Aggressive fibromatosis (desmoid tumor) is a locally invasive soft tissue neoplasm associated with mutations resulting in β-catenin-mediated transcriptional activation. This tumor is composed of cells with histological and molecular characteristics common to proliferating mesenchymal cells of dermal wounds. Using immunohistochemistry and RT–PCR, we show that Rhamm, a protein with an important role in wound healing and neoplastic progression, is also expressed at high levels in aggressive fibromatosis. A mouse harboring a targeted deletion in Rhamm was generated, resulting in viable Rhamm−/− animals. Rhamm−/− mice were crossed with Apc/Apc1638N mice, which harbor a targeted mutation in the Apc gene predisposing animals to gastrointestinal and aggressive fibromatosis tumors. Rhamm deficiency significantly decreased the number of aggressive fibromatosis tumors formed, but did not alter the number of gastrointestinal polyps. Cell culture studies show that Rhamm regulates cell proliferation in both fibroblasts and fibromatosis cells under conditions of low density, but not high density. These results suggest that Rhamm regulates proliferation of cells with sparse cell–cell contacts, such as occurs in aggressive fibromatosis; provides the first genetic evidence implicating Rhamm in tumor pathology; and suggest Rhamm blockade as a potential therapeutic target for this otherwise difficult-to-treat neoplasm.

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

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

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

  • Assmann V, Jenkinson D, Marshall JF, Hart IR . (1999). J. Cell. Sci., 112, 3943–3954.

  • Assmann V, Gillett CE, Poulsom R, Ryder K, Hart IR and Hanby AM . (2001). J. Pathol., 195, 191–196.

  • Bissell MJ and Radisky D . (2001). Nat. Rev. Cancer, 1, 46–54.

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

  • Cheung WF, Cruz TF and Turley EA . (1999). Biochem. Soc. Trans., 27, 135–142.

  • Crainie M, Belch AR, Mant MJ and Pilarski LM . (1999). Blood, 93, 1684–1696.

  • Duval A, Rolland S, Compoint A, Tubacher E, Iacopetta B, Thomas G and Hamelin R . (2001). Hum. Mol. Genet., 10, 513–518.

  • 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.

  • Gares SL and Pilarski LM . (2000). Dev. Immunol., 7, 209–225.

  • Gerdin B and Hallgren R . (1997). J. Intern. Med., 242, 49–55.

  • Gutierrez-Ruiz MC, Robles-Diaz G and Kershenobich D . (2002). Arch. Med. Res., 33, 595–599.

  • Hall CL, Lange LA, Prober DA, Zhang S and Turley EA . (1996). Oncogene, 13, 2213–2224.

  • Hall CL, Yang B, Yang X, Zhang S, Turley M, Samuel S, Lange LA, Wang C, Curpen GD, Savani RC, Greenberg AH and Turley EA . (1995). Cell, 82, 19–26.

  • Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D, Cripps V, Austen L, Nance DM and Turley EA . (1992). J. Cell. Biol., 117, 1343–1350.

  • Hopyan S, Gokgoz N, Bell RS, Andrulis IL, Alman BA and Wunder JS . (1999). J. Orthop. Res., 17, 633–638.

  • Kong QY, Liu J, Chen XY, Wang XW, Sun Y and Li H . (2003). Oncol. Rep., 10, 51–55.

  • Li C, Bapat B and Alman BA . (1998). Am. J. Pathol., 153, 709–714.

  • Li H, Guo L, Li JW, Liu N, Qi R and Liu J . (2000). Int. J. Oncol., 17, 927–932.

  • Line A, Slucka Z, Stengrevics A, Silina K, Li G and Rees RC . (2002). Cancer Immunol. Immunother., 51, 574–582.

  • Lokeshwar VB and Selzer MG . (2000). J. Biol. Chem., 275, 27641–27649.

  • Lovvorn III HN, Cass DL, Sylvester KG, Yang EY, Crombleholme TM, Adzick NS and Savani RC . (1998). J. Pediatr. Surg., 33, 1062–1069.

  • Lynn BD, Li X, Cattini PA, Turley EA and Nagy JI . (2001). J. Comp. Neurol., 439, 315–330.

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

  • Mohapatra S, Yang X, Wright JA, Turley EA and Greenberg AH . (1996). J. Exp. Med., 183, 1663–1668.

  • Naor D, Sionov RV, Zahalka M, Rochman M, Holzmann B and Ish-Shalom D . (1998). Curr. Top. Microbiol. Immunol., 231, 143–166.

  • Pear W, Nolan GP, Scott M and Baltimore D . (1993). Proc. Natl. Acad. Sci. USA, 90, 8392–8396.

  • Pilarski LM, Masellis-Smith A, Belch AR, Yang B, Savani RC and Turley EA . (1994). Leuk. Lymphoma, 14, 363–374.

  • Ponta H, Sherman L and Herrlich PA . (2003). Nat. Rev. Mol. Cell. Biol., 4, 33–45.

  • 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.

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

  • Savanger P . (2001). BioEssays, 23, 912–923.

  • Savani RC, Cao G, Pooler PM, Zaman A, Zhou Z and DeLisser HM . (2001). J. Biol. Chem., 276, 36770–36778.

  • Savani RC, Wang C, Yang B, Zhang S, Kinsella MG, Wight TN, Stern R, Nance DM and Turley EA . (1995). J. Clin. Invest., 95, 58–68.

  • Sivaraman VS, Wang H, Nuovo GJ and Malbon CC . (1997). J. Clin. Invest., 99, 1478–1483.

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

  • Spicer AP, Roller ML, Camper SA, McPherson JD, Wasmuth JJ, Hakim S, Wang C, Turley EA and McDonald JA . (1995). Genomics, 30, 115–117.

  • Tammi MI, Day AJ and Turley EA . (2002). J. Biol. Chem., 277, 4581–4584.

  • 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.

  • Toole BP . (2002). Glycobiology, 12, 37R–42R.

  • Turley EA . (1982). Biochem. Biophys. Res. Commun., 188, 1016–1024.

  • Turley E and Auersperg N . (1989). Exp. Cell. Res., 182, 340–348.

  • Turley EA, Austen L, Vandeligt K and Clary C . (1991). J. Cell. Biol., 112, 1041–1047.

  • Turley EA, Bowman P and Kytryk MA . (1985). J. Cell. Sci., 78, 133–145.

  • Turley EA, Brassel P and Moore D . (1990). Exp. Cell Res., 187, 243–249.

  • Turley EA, Noble PW and Bourguignon LY . (2002). J. Biol. Chem., 277, 4589–4592.

  • 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 Chromosom. Cancer, 24, 191–198.

  • van der Lugt N, Maandag ER, te Riele H, Laird PW and Berns A . (1991). Gene, 105, 263–267.

  • Wang C, Thor AD, Moore II DH, Zhao Y, Kerschmann R, Stern R, Watson PH and Turley EA . (1998). Clin. Cancer Res., 4, 567–576.

  • Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers H and Pals ST . (1999). Am. J. Pathol., 154, 515–523.

  • Wong NA and Pignatelli M . (2002). Am. J. Pathol., 160, 389–401.

  • Yang B, Yang BL, Savani RC and Turley EA . (1994). EMBO J., 13, 286–296.

  • Zhang S, Chang MC, Zylka D, Turley S, Harison R and Turley EA . (1998). J. Biol. Chem., 273, 11342–11348.

  • Zhou R, Wu X and Skalli O . (2002). J. Neurooncol., 59, 15–26.

Download references

Acknowledgements

This work is funded by Grants from the National Cancer Institute of Canada (BAA) and Canadian Institutes of Health Research (EAT). ET is supported by the Pamela GreenawayKohlmeier Translation Breast Cancer Unit Salary Award and BAA is supported by the Canadian Research Chairs Program.

Author information

Authors and Affiliations

  1. Departments of Oncology and Biochemistry, The University of Western Ontario, Canada

    Cornelia Tolg & Eva Ann Turley

  2. London Regional Cancer Centre, 790 Commissioner's Road East, London, N6A 4L6, Ontario, Canada

    Cornelia Tolg & Eva Ann Turley

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

    Raymoond Poon & Benjamin Aaron Alman

  4. MGC-Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, Leiden, 2333AL, The Netherlands

    Riccardo Fodde

  5. Department of Surgery and Division of Orthopaedic Surgery, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Benjamin Aaron Alman

Authors
  1. Cornelia Tolg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raymoond Poon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Riccardo Fodde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Ann Turley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin Aaron Alman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin Aaron Alman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tolg, C., Poon, R., Fodde, R. et al. Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor). Oncogene 22, 6873–6882 (2003). https://doi.org/10.1038/sj.onc.1206811

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206811

Keywords

This article is cited by

Search

Advanced search

Quick links