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
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
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.
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
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206811
Keywords
This article is cited by
-
RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling
Breast Cancer Research (2023)
-
Biology and biotechnology of hyaluronan
Glycoconjugate Journal (2015)
-
Overexpression of receptor for hyaluronan-mediated motility (RHAMM) in MC3T3-E1 cells induces proliferation and differentiation through phosphorylation of ERK1/2
Journal of Bone and Mineral Metabolism (2012)
-
An investigation of hormesis of trichloroethylene in L-02 liver cells by differential proteomic analysis
Molecular Biology Reports (2009)
-
Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse
BMC Genomics (2007)