Skip to main content
Springer Nature Link
Log in

Lack of evidence for PlGF mediating the tumor resistance after anti-angiogenic therapy in malignant gliomas

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Placenta growth factor (PlGF) is a member of vascular endothelial growth factor family which can promote cancer growth by various mechanisms. Placenta growth factor is upregulated in many neoplastic diseases and serum levels of PlGF are increased in cancer patients following anti-angiogenic therapy. However, its role in glioma growth is yet not fully elucidated. In this study we analyzed the expression of PlGF mRNA using real time PCR in human gliomas of different WHO grades. Placenta growth factor mRNA levels were highly variable and did not correlate with WHO grades, arguing against a significant role in glioma progression. The highest PlGF expression was observed in anaplastic astrocytomas whereas grade II astrocytomas and glioblastomas displayed lower levels of expression. Immunohistochemical analysis showed that PlGF was expressed by inflammatory and endothelial cells in addition to tumor cells. Placenta growth factor mRNA expression in 12 matched glioblastoma samples before and after therapy, including bevacizumab and cilengitide treatment was largely unaffected by the aforementioned treatment modalities. In vitro, the exposure of VEGFR-1 expressing glioma cells to bevacizumab did not increase the expression levels of PlGF mRNA. In summary, our results do not support the hypothesis that PlGF plays a major role in the resistance of gliomas after anti-angiogenic therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, VandenDriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    Article  CAS  PubMed  Google Scholar 

  2. DiSalvo J, Bayne ML, Conn G, Kwok PW, Trivedi PG, Soderman DD, Palisi TM, Sullivan KA, Thomas KA (1995) Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer. J Biol Chem 270:7717–7723

    Article  CAS  PubMed  Google Scholar 

  3. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M (2002) Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain. J Biol Chem 277:24818–24825

    Article  CAS  PubMed  Google Scholar 

  4. Green CJ, Lichtlen P, Huynh NT, Yanovsky M, Laderoute KR, Schaffner W, Murphy BJ (2001) Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1. Cancer Res 61:2696–2703

    CAS  PubMed  Google Scholar 

  5. De Falco S (2012) The discovery of placenta growth factor and its biological activity. Exp Mol Med 44:1–9

    Article  PubMed Central  PubMed  Google Scholar 

  6. Cao Y (2009) Positive and negative modulation of angiogenesis by VEGFR1 ligands. Sci Signal 2:re1

    PubMed  Google Scholar 

  7. Autiero M, Luttun A, Tjwa M, Carmeliet P (2003) Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 1:1356–1370

    Article  CAS  PubMed  Google Scholar 

  8. Parr C, Watkins G, Boulton M, Cai J, Jiang WG (2005) Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer 41:2819–2827

    Article  CAS  PubMed  Google Scholar 

  9. Wei SC, Tsao PN, Yu SC, Shun CT, Tsai-Wu JJ, Wu CH, Su YN, Hsieh FJ, Wong JM (2005) Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 54:666–672

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Escudero-Esparza A, Martin TA, Douglas-Jones A, Mansel RE, Jiang WG (2010) PGF isoforms, PLGF-1 and PGF-2 and the PGF receptor, neuropilin, in human breast cancer: prognostic significance. Oncol Rep 23:537–544

    CAS  PubMed  Google Scholar 

  11. Chen CN, Chang CC, Su TE, Hsu WM, Jeng YM, Ho MC, Hsieh FJ, Lee PH, Kuo ML, Lee H, Chang KJ (2009) Identification of calreticulin as a prognosis marker and angiogenic regulator in human gastric cancer. Ann Surg Oncol 16:524–533

    Article  CAS  PubMed  Google Scholar 

  12. Xu L, Jain RK (2007) Down-regulation of placenta growth factor by promoter hypermethylation in human lung and colon carcinoma. Mol Cancer Res 5:873–880

    Article  CAS  PubMed  Google Scholar 

  13. Snuderl M, Batista A, Kirkpatrick ND, de Ruiz A, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065–1076

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Ikai T, Miwa H, Shikami M, Hiramatsu A, Tajima E, Yamamoto H, Imai N, Hattori A, Nishii K, Miura K, Satoh A, Itoh M, Imamura A, Mihara H, Katoh Y, Nitta M (2005) Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathways. Eur J Haematol 75:273–279

    Article  CAS  PubMed  Google Scholar 

  15. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475

    Article  CAS  PubMed  Google Scholar 

  16. Taylor AP, Rodriguez M, Adams K, Goldenberg DM, Blumenthal RD (2003) Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence. Int J Cancer 105:158–164

    Article  CAS  PubMed  Google Scholar 

  17. Lieu CH, Tran H, Jiang ZQ, Mao M, Overman MJ, Lin E, Eng C, Morris J, Ellis L, Heymach JV, Kopetz S (2013) The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PLoS One 8:e77117

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Loges S, Schmidt T, Carmeliet P (2009) “Antimyeloangiogenic” therapy for cancer by inhibiting PlGF. Clin Cancer Res 15:3648–3653

    Article  CAS  PubMed  Google Scholar 

  19. Nomura M, Yamagishi S, Harada S, Yamashima T, Yamashita J, Yamamoto H (1998) Placenta growth factor (PlGF) mRNA expression in brain tumors. J Neurooncol 40:123–130

    Article  CAS  PubMed  Google Scholar 

  20. de Groot JF, Piao Y, Tran H, Gilbert M, Wu HK, Liu J, Bekele BN, Cloughesy T, Mehta M, Robins HI, Lassman A, DeAngelis L, Camphausen K, Chen A, Yung WK, Prados M, Wen PY, Heymach JV (2011) Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res 17:4872–4881

    Article  PubMed Central  PubMed  Google Scholar 

  21. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed Central  PubMed  Google Scholar 

  23. Coenegrachts L, Maes C, Torrekens S, Van Looveren R, Mazzone M, Guise TA, Bouillon R, Stassen JM, Carmeliet P, Carmeliet G (2010) Anti-placental growth factor reduces bone metastasis by blocking tumor cell engraftment and osteoclast differentiation. Cancer Res 70:6537–6547

    Article  CAS  PubMed  Google Scholar 

  24. Plate KH, Scholz A, Dumont DJ (2012) Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol 124:763–775

    Article  PubMed Central  PubMed  Google Scholar 

  25. Quick A, Patel D, Hadziahmetovic M, Chakravarti A, Mehta M (2010) Current therapeutic paradigms in glioblastoma. Rev Recent Clin Trials 5:14–27

    Article  CAS  PubMed  Google Scholar 

  26. Gerstner ER, Eichler AF, Plotkin SR, Drappatz J, Doyle CL, Xu L, Duda DG, Wen PY, Jain RK, Batchelor TT (2011) Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide. J Neurooncol 103:325–332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ (2008) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26:3743–3748

    Article  CAS  PubMed  Google Scholar 

  28. Bagley RG, Ren Y, Weber W, Yao M, Kurtzberg L, Pinckney J, Bangari D, Nguyen C, Brondyk W, Kaplan J, Teicher BA (2011) Placental growth factor upregulation is a host response to antiangiogenic therapy. Clin Cancer Res 17:976–988

    Article  CAS  PubMed  Google Scholar 

  29. Bagley RG, Kurtzberg L, Weber W, Nguyen TH, Roth S, Krumbholz R, Yao M, Richards B, Zhang M, Pechan P, Schmid S, Scaria A, Kaplan J, Teicher BA (2011) sFLT01: a novel fusion protein with antiangiogenic activity. Mol Cancer Ther 10:404–415

    Article  CAS  PubMed  Google Scholar 

  30. Bais C, Wu X, Yao J, Yang S, Crawford Y, McCutcheon K, Tan C, Kolumam G, Vernes JM, Eastham-Anderson J, Haughney P, Kowanetz M, Hagenbeek T, Kasman I, Reslan HB, Ross J, Van Bruggen N, Carano RA, Meng YJ, Hongo JA, Stephan JP, Shibuya M, Ferrara N (2010) PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141:166–177

    Article  CAS  PubMed  Google Scholar 

  31. Ning Q, Liu C, Hou L, Meng M, Zhang X, Luo M, Shao S, Zuo X, Zhao X (2013) Vascular endothelial growth factor receptor-1 activation promotes migration and invasion of breast cancer cells through epithelial-mesenchymal transition. PLoS One 8:e65217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77:998–1002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Yao J, Wu X, Zhuang G, Kasman IM, Vogt T, Phan V, Shibuya M, Ferrara N, Bais C (2011) Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. Proc Natl Acad Sci U S A 108:11590–11595

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J, Saab KR, Osherov V, Widlund HR, Gasser M, Waaga-Gasser AM, Kupper TS, Murphy GF, Frank MH (2011) VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res 71:1474–1485

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Wey JS, Fan F, Gray MJ, Bauer TW, McCarty MF, Somcio R, Liu W, Evans DB, Wu Y, Hicklin DJ, Ellis LM (2005) Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104:427–438

    Article  CAS  PubMed  Google Scholar 

  36. Fan F, Samuel S, Gaur P, Lu J, Dallas NA, Xia L, Bose D, Ramachandran V, Ellis LM (2011) Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration. Br J Cancer 104:1270–1277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Our work was supported by grants from the Deutsche Krebshilfe (Project Number 109410). We thank Dr. Carro and Dr. Osterberg, Department of Neurosurgery, University Medical Center Freiburg for providing the glioma cells, Prof. Shibuya (University of Tokio) for providing the monoclonal anti-VEGFR-1 antibody, S. Reiser for screening of the glioma cells, Ms. Eva Bug for processing the tumor tissue samples and C. El Gaz, K. Strasser and V. Sverdlick for help with the immunohistochemistry analysis.

Conflict of interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University Medical Center Freiburg, Breisacher Straβe 64, 79106, Freiburg, Germany

    Kristin Schneider, Astrid Weyerbrock & Marcia Regina Machein

  2. Department of Neuropathology, Edinger Institute, University of Frankfurt Medical School, Frankfurt, Germany

    Karl Plate

  3. Department of Neuropathology, University Medical Center Freiburg, Freiburg, Germany

    Soroush Doostkam

Authors
  1. Kristin Schneider
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Astrid Weyerbrock
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Soroush Doostkam
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Karl Plate
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Marcia Regina Machein
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Marcia Regina Machein.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schneider, K., Weyerbrock, A., Doostkam, S. et al. Lack of evidence for PlGF mediating the tumor resistance after anti-angiogenic therapy in malignant gliomas. J Neurooncol 121, 269–278 (2015). https://doi.org/10.1007/s11060-014-1647-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1647-3

Keywords