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 Article
  • Published:

Autocrine activation of PDGFRα promotes the progression of ovarian cancer

Abstract

Platelet-derived growth factor receptor (PDGFR)α expression was found in ovarian cancer cells and tumors by microarray hybridization. This led us to test whether ovarian cancers also produce ligands for this receptor, as this would demonstrate that such malignancies support their own growth and spread through autocrine activation. We assayed the expression of ligands for the PDGFR in ovarian tumors, cell lines and peritoneal fluid using RT–PCR, immunohistochemistry (IHC) and ELISA. We detected strong mRNA expression for the PDGFRα ligands in most ovarian tumors. Receptor and ligand expressions (PDGFRα and PDGF AB) were also detected by IHC in, respectively, 34 and 32 of 47 ovarian tumors. The stainings for PDGFRα and PDGF AB were strongly correlated (P-value=0.014), suggesting that an autocrine loop is functional in ovarian cancer. PDGF AA and BB were quantified in peritoneal fluid by ELISA. Both ligands are secreted at higher levels in ovarian cancer ascites specimens (n=54) than in fluid from nonmalignant disorders (n=8). PDGF was detected in media conditioned by ovarian cancer cells. Such conditioned media induced activation of the PDGFR, Akt and MAPK and stimulated cell proliferation. A neutralizing PDGF antibody blocked these effects. Specific PDGFR inhibition by siRNA or a neutralizing antibody to the receptor inhibited PDGF-stimulated receptor activation and cell proliferation, suggesting that receptor targeting has a role in ovarian cancer treatment.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Aase K, Abramsson A, Karlsson L, Betsholtz C, Eriksson U . (2002). Mech Dev 110: 187–191.

  • Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR . (2003). J Clin Oncol 21: 283–290.

  • Dong J, Grunstein J, Tejada M, Peale F, Frantz G, Liang WC et al. (2004). EMBO J 23: 2800–2810.

  • Eriksson A, Siegbahn A, Westermark B, Heldin CH, Claesson-Welsh L . (1992). EMBO J 11: 543–550.

  • Franklin WA, Christison WH, Colley M, Montag AG, Stephens JK, Hart CE . (1990). Cancer Res 50: 6344–6348.

  • Gillan L, Matei D, Fishman DA, Gerbin CS, Karlan BY, Chang DD . (2002). Cancer Res 62: 5358–5364.

  • Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ . (2001). J Clin Oncol 19: 3312–3322.

  • Greenhalgh DG, Sprugel KH, Murray MJ, Ross R . (1990). Am J Pathol 136: 1235–1246.

  • Greenlee RT, Murray T, Bolden S, Wingo PA . (2000). CA Cancer J Clin 50: 7–33.

  • Hart CE, Forstrom JW, Kelly JD, Seifert RA, Smith RA, Ross R et al. (1988). Science 240: 1529–1531.

  • Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N et al. (2003). Science 299: 708–710.

  • Heldin CH, Ostman A, Ronnstrand L . (1998). Biochim Biophys Acta 1378: F79–F113.

  • Henriksen R, Funa K, Wilander E, Backstrom T, Ridderheim M, Oberg K . (1993). Cancer Res 53: 4550–4554.

  • Hu Y, Bock G, Wick G, Xu Q . (1998). FASEB J 12: 1135–1142.

  • Huang JS, Huang SS, Deuel TF . (1984). Cell 39: 79–87.

  • Ikeda K, Sakai K, Yamamoto R, Hareyama H, Tsumura N, Watari H et al. (2003). Int J Gynecol Cancer 13: 776–784.

  • Ismail RS, Baldwin RL, Fang J, Browning D, Karlan BY, Gasson JC et al. (2000). Cancer Res 60: 6744–6749.

  • Jensen RA, Beeler JF, Heidaran MA, LaRochelle WJ . (1992). Biochemistry 31: 10887–10892.

  • Karlan BY, Baldwin RL, Cirisano FD, Mamula PW, Jones J, Lagasse LD . (1995). Gynecol Oncol 59: 67–74.

  • LaRochelle WJ, Jeffers M, McDonald WF, Chillakuru RA, Giese NA, Lokker NA et al. (2001). Nat Cell Biol 3: 517–521.

  • Lassus H, Sihto H, Leminen A, Nordling S, Joensuu H, Nupponen NN et al. (2004). Br J Cancer 91: 2048–2055.

  • Li X, Ponten A, Aase K, Karlsson L, Abramsson A, Uutela M et al. (2000). Nat Cell Biol 2: 302–309.

  • Loizos N, Xu Y, Huber J, Liu M, Lu D, Finnerty B et al. (2005). Mol Cancer Ther 4: 369–379.

  • Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA . (2002). Cancer Res 62: 3729–3735.

  • Matei D, Chang DD, Jeng MH . (2004). Clin Cancer Res 10: 681–690.

  • Matei D, Graeber TG, Baldwin RL, Karlan BY, Rao J, Chang DD . (2002). Oncogene 21: 6289–6298.

  • Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M et al. (1989). Science 243: 800–804.

  • Ozols R . (1997). In: DeVita VT, HSaRS (eds). Cancer Principles and Practice of Oncology, vol. 1. Lippincott-Raven: Philadelphia, NY, pp 1502–1540.

    Google Scholar 

  • Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH et al. (2002). Cancer Res 62: 5476–5484.

  • Schmandt RE, Broaddus R, Lu KH, Shvartsman H, Thornton A, Malpica A et al. (2003). Cancer 98: 758–764.

  • Sihto H, Sarlomo-Rikala M, Tynninen O, Tanner M, Andersson LC, Franssila K et al. (2005). J Clin Oncol 23: 49–57.

  • Spentzos D, Levine DA, Ramoni MF, Joseph M, Gu X, Boyd J et al. (2004). J Clin Oncol 22: 4700–4710.

  • Uren A, Yu JC, Gholami NS, Pierce JH, Heidaran MA . (1994). Biochem Biophys Res Commun 204: 628–634.

  • Valius M, Kazlauskas A . (1993). Cell 73: 321–334.

  • Versnel MA, Haarbrink M, Langerak AW, de Laat PA, Hagemeijer A, van der Kwast TH et al. (1994). Cancer Genet Cytogenet 73: 60–64.

  • Wilczynski SP, Chen YY, Chen W, Howell SB, Shively JE, Alberts DS . (2005). Hum Pathol 36: 242–249.

  • Yao R, Cooper GM . (1995). Science 267: 2003–2006.

  • Yu J, Moon A, Kim HR . (2001). Biochem Biophys Res Commun 282: 697–700.

  • Yu JC, Mahadevan D, LaRochelle WJ, Pierce JH, Heidaran MA . (1994). J Biol Chem 269: 10668–10674.

  • Zwerner JP, May WA . (2001). Oncogene 20: 626–633.

Download references

Acknowledgements

We thank Dr Nick Loizos for supplying the 3G3 neutralizing antibody to PDGFRα. This work was supported by a Career Development Award from the Amgen Oncology Institute, a Clarian Value Fund Award and a Mentored Research Scholar Grant from the American Cancer Society (MRSG#107613) to DM.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D Matei.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matei, D., Emerson, R., Lai, YC. et al. Autocrine activation of PDGFRα promotes the progression of ovarian cancer. Oncogene 25, 2060–2069 (2006). https://doi.org/10.1038/sj.onc.1209232

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209232

Keywords

This article is cited by

Search

Quick links