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.

‘Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma’

Abstract

Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Here, we show that PEDF expression is high in melanocytes, but it is lost during malignant progression of human melanoma. Using a high-throughput analysis of the data from microarray studies of molecular profiling of human melanoma, we found that PEDF expression is lost in highly invasive melanomas. In paired cell lines established from the same lesion but representing the high and low extremes of malignant potential, abundant PEDF expression was restricted to the poorly aggressive counterparts. We used RNA interference to directly address the functional consequences of PEDF silencing. PEDF knockdown in poorly aggressive melanoma cell lines augmented migration, invasion and vasculogenic mimicry, which translated into an increased in vivo metastatic potential. PEDF interference also significantly enhanced the migratory and invasive capability of normal melanocytes and moderately increased their proliferative potential. Our results show that loss of PEDF enables melanoma cells to acquire an invasive phenotype and, therefore, modulation of this multifunctional factor could be critical for the malignant progression of human melanoma.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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

References

  • Abramson LP, Stellmach V, Doll JA, Cornwell M, Arensman RM, Crawford SE . (2003). Wilms' tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model. J Pediatr Surg 38: 336–342.

    Article  Google Scholar 

  • Alberdi E, Aymerich MS, Becerra SP . (1999). Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons. Evidence for a PEDF receptor. J Biol Chem 274: 31605–31612.

    Article  CAS  Google Scholar 

  • Aymerich MS, Alberdi EM, Martinez A, Becerra SP . (2001). Evidence for pigment epithelium-derived factor receptors in the neural retina. Invest Ophthalmol Vis Sci 42: 3287–3293.

    CAS  PubMed  Google Scholar 

  • Becerra SP . (1997). Structure-function studies on PEDF A noninhibitory serpin with neurotrophic activity. Adv Exp Med Biol 425: 223–237.

    Article  CAS  Google Scholar 

  • Beitzinger M, Hofmann L, Oswald C, Beinoraviciute-Kellner R, Sauer M, Griesmann H et al. (2008). p73 poses a barrier to malignant transformation by limiting anchorage-independent growth. EMBO J 27: 792–803.

    Article  CAS  Google Scholar 

  • Bilak MM, Becerra SP, Vincent AM, Moss BH, Aymerich MS, Kuncl RW . (2002). Identification of the neuroprotective molecular region of pigment epithelium-derived factor and its binding sites on motor neurons. J Neurosci 22: 9378–9386.

    Article  CAS  Google Scholar 

  • Bilak MM, Corse AM, Bilak SR, Lehar M, Tombran-Tink J, Kuncl RW . (1999). Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J Neuropathol Exp Neurol 58: 719–728.

    Article  CAS  Google Scholar 

  • Bouck N . (1990). Tumor angiogenesis: the role of oncogenes and tumor suppressor genes. Cancer Cells 2: 179–185.

    CAS  PubMed  Google Scholar 

  • Bouck N . (2002). PEDF: anti-angiogenic guardian of ocular function. Trends Mol Med 8: 330–334.

    Article  CAS  Google Scholar 

  • Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek KS et al. (2006). Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev 20: 3426–3439.

    Article  CAS  Google Scholar 

  • Chin L . (2003). The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer 3: 559–570.

    Article  CAS  Google Scholar 

  • Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W et al. (1999). Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285: 245–248.

    Article  CAS  Google Scholar 

  • Diaz R, Pena C, Silva J, Lorenzo Y, Garcia V, Garcia JM et al. (2008). p73 Isoforms affect VEGF, VEGF165b and PEDF expression in human colorectal tumors: VEGF165b downregulation as a marker of poor prognosis. Int J Cancer 123: 1060–1067.

    Article  CAS  Google Scholar 

  • Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP et al. (2003). Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas. Nat Med 9: 774–780.

    Article  CAS  Google Scholar 

  • Ek ET, Dass CR, Choong PF . (2006a). PEDF: a potential molecular therapeutic target with multiple anti-cancer activities. Trends Mol Med 12: 497–502.

    Article  CAS  Google Scholar 

  • Ek ET, Dass CR, Choong PF . (2006b). Pigment epithelium-derived factor: a multimodal tumor inhibitor. Mol Cancer Ther 5: 1641–1646.

    Article  CAS  Google Scholar 

  • Fernandez-Garcia NI, Palmer HG, Garcia M, Gonzalez-Martin A, del Rio M, Barettino D et al. (2005). 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. Oncogene 24: 6533–6544.

    Article  CAS  Google Scholar 

  • Fernandez-Garcia NI, Volpert OV, Jimenez B . (2007). Pigment epithelium-derived factor as a multifunctional antitumor factor. J Mol Med 85: 15–22.

    Article  CAS  Google Scholar 

  • Filleur S, Volz K, Nelius T, Mirochnik Y, Huang H, Zaichuk TA et al. (2005). Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. Cancer Res 65: 5144–5152.

    Article  CAS  Google Scholar 

  • Garcia M, Fernandez-Garcia NI, Rivas V, Carretero M, Escamez MJ, Gonzalez-Martin A et al. (2004). Inhibition of xenografted human melanoma growth and prevention of metastasis development by dual antiangiogenic/antitumor activities of pigment epithelium-derived factor. Cancer Res 64: 5632–5642.

    Article  CAS  Google Scholar 

  • Gray-Schopfer V, Wellbrock C, Marais R . (2007). Melanoma biology and new targeted therapy. Nature 445: 851–857.

    Article  CAS  Google Scholar 

  • Guan M, Yam HF, Su B, Chan KP, Pang CP, Liu WW et al. (2003). Loss of pigment epithelium derived factor expression in glioma progression. J Clin Pathol 56: 277–282.

    Article  CAS  Google Scholar 

  • Halin S, Wikstrom P, Rudolfsson SH, Stattin P, Doll JA, Crawford SE et al. (2004). Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors. Cancer Res 64: 5664–5671.

    Article  CAS  Google Scholar 

  • Hendrix MJ, Seftor EA, Hess AR, Seftor RE . (2003). Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3: 411–421.

    Article  CAS  Google Scholar 

  • Hendrix MJ, Seftor EA, Seftor RE, Kasemeier-Kulesa J, Kulesa PM, Postovit LM . (2007). Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7: 246–255.

    Article  CAS  Google Scholar 

  • Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP . (2007). PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res 76: 213–223.

    Article  CAS  Google Scholar 

  • Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N, Schaerer L et al. (2008). In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res 68: 650–656.

    Article  CAS  Google Scholar 

  • Hoek KS, Schlegel NC, Brafford P, Sucker A, Ugurel S, Kumar R et al. (2006). Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Res 19: 290–302.

    Article  CAS  Google Scholar 

  • Li G, Satyamoorthy K, Herlyn M . (2001a). N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 61: 3819–3825.

    CAS  PubMed  Google Scholar 

  • Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M . (2001b). Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 20: 8125–8135.

    Article  CAS  Google Scholar 

  • Matsumoto K, Ishikawa H, Nishimura D, Hamasaki K, Nakao K, Eguchi K . (2004). Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma. Hepatology 40: 252–259.

    Article  CAS  Google Scholar 

  • Miller AJ, Mihm Jr MC . (2006). Melanoma. N Engl J Med 355: 51–65.

    Article  CAS  Google Scholar 

  • Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C et al. (2006). Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem 281: 38022–38037.

    Article  CAS  Google Scholar 

  • Notari L, Miller A, Martinez A, Amaral J, Ju M, Robinson G et al. (2005). Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia. Invest Ophthalmol Vis Sci 46: 2736–2747.

    Article  Google Scholar 

  • Punzon I, Criado LM, Serrano A, Serrano F, Bernad A . (2004). Highly efficient lentiviral-mediated human cytokine transgenesis on the NOD/scid background. Blood 103: 580–582.

    Article  CAS  Google Scholar 

  • Quan GM, Ojaimi J, Li Y, Kartsogiannis V, Zhou H, Choong PF . (2005). Localization of pigment epithelium-derived factor in growing mouse bone. Calcif Tissue Int 76: 146–153.

    Article  CAS  Google Scholar 

  • Sasaki Y, Naishiro Y, Oshima Y, Imai K, Nakamura Y, Tokino T . (2005). Identification of pigment epithelium-derived factor as a direct target of the p53 family member genes. Oncogene 24: 5131–5136.

    Article  CAS  Google Scholar 

  • Sato S, Yamamoto H . (2001). Development of pigment cells in the brain of ascidian tadpole larvae: insights into the origins of vertebrate pigment cells. Pigment Cell Res 14: 428–436.

    Article  CAS  Google Scholar 

  • Sawant S, Aparicio S, Tink AR, Lara N, Barnstable CJ, Tombran-Tink J . (2004). Regulation of factors controlling angiogenesis in liver development: a role for PEDF in the formation and maintenance of normal vasculature. Biochem Biophys Res Commun 325: 408–413.

    Article  CAS  Google Scholar 

  • Seftor EA, Brown KM, Chin L, Kirschmann DA, Wheaton WW, Protopopov A et al. (2005). Epigenetic transdifferentiation of normal melanocytes by a metastatic melanoma microenvironment. Cancer Res 65: 10164–10169.

    Article  CAS  Google Scholar 

  • Seigel GM, Tombran-Tink J, Becerra SP, Chader GJ, Diloreto Jr DA, del Cerro C et al. (1994). Differentiation of Y79 retinoblastoma cells with pigment epithelial-derived factor and interphotoreceptor matrix wash: effects on tumorigenicity. Growth Factors 10: 289–297.

    Article  CAS  Google Scholar 

  • Steele FR, Chader GJ, Johnson LV, Tombran-Tink J . (1993). Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci USA 90: 1526–1530.

    Article  CAS  Google Scholar 

  • Tombran-Tink J, Barnstable CJ . (2003). PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 4: 628–636.

    Article  CAS  Google Scholar 

  • Uehara H, Miyamoto M, Kato K, Ebihara Y, Kaneko H, Hashimoto H et al. (2004). Expression of pigment epithelium-derived factor decreases liver metastasis and correlates with favorable prognosis for patients with ductal pancreatic adenocarcinoma. Cancer Res 64: 3533–3537.

    Article  CAS  Google Scholar 

  • van der Schaft DW, Seftor RE, Seftor EA, Hess AR, Gruman LM, Kirschmann DA et al. (2004). Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst 96: 1473–1477.

    Article  CAS  Google Scholar 

  • Yabe T, Wilson D, Schwartz JP . (2001). NFkappaB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons. J Biol Chem 276: 43313–43319.

    Article  CAS  Google Scholar 

  • Yamagishi S, Inagaki Y, Nakamura K, Abe R, Shimizu T, Yoshimura A et al. (2004). Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. J Mol Cell Cardiol 37: 497–506.

    Article  CAS  Google Scholar 

  • Zaichuk TA, Shroff EH, Emmanuel R, Filleur S, Nelius T, Volpert OV . (2004). Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J Exp Med 199: 1513–1522.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge with gratitude all researchers that contributed with cell lines: M Herlyn, PF Peñas, F Vidal-Vanaclocha, GN Van Muijen, AM Valverde, M Garcia and M del Rio. We also thank P Fernández for her technical assistance in lentivirus production. Supported by grants: Ministerio de Educación y Ciencia grant SAF2007-62292 (BJ), Comunidad de Madrid SAL-0311-2006 (BJ), NIH grant RO1 HL68033 (OV), NIH merit grant CA59702 (MJCH). JL Orgaz has been supported by a Ministerio de Educación y Ciencia fellowship, O Ladhani by an NIH/NCI training grant T32CA009560 and A Fernández-Barral by a Consejo Superior de Investigaciones Científicas fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B Jiménez.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Orgaz, J., Ladhani, O., Hoek, K. et al. ‘Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma’. Oncogene 28, 4147–4161 (2009). https://doi.org/10.1038/onc.2009.284

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.284

Keywords

  • PEDF
  • melanoma progression
  • vasculogenic mimicry
  • anti-angiogenic factors

This article is cited by

Search

Quick links