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Inhibition of Neuroblastoma Progression by Targeting Lymphangiogenesis: Role of an Endogenous Soluble Splice-Variant of VEGFR-2

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Tumors of the Central Nervous System, Volume 12

Part of the book series: Tumors of the Central Nervous System ((TCNS,volume 12))

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Abstract

The endogenous-soluble-vascular-endothelial-growth-factor-receptor-2 (esVEGFR-2) is a novel member of the VEGFR-family. It is generated from the VEGFR-2 gene by alternative splicing and was shown to bind VEGF-C with high affinity, therefore acting as an endogenous inhibitor of lymphangiogenesis. Still little is known about its functions in development and disease. We explored the distribution patterns of esVEGFR-2 in human embryonic tissues and found it expressed in many organs and structures throughout the developing organism. Most interestingly, sympathetic ganglia and the adrenal medulla were positive for the inhibitor, too. Neuroblastoma is an embryonic tumor, developing from sympathetic progenitor cells of the neural crest, which in normal development form the sympathetic nervous system as well as the adrenal medulla. Immunohistology revealed that in neuroblastoma with a differentiating type of histopathology and in differentiated tumors of the ganglioneuroblastoma type, esVEGFR-2 was expressed regularly, whereas in highly malignant neuroblastoma with an undifferentiated phenotype it could be rarely detected. All-trans-retinoic acid (ATRA) is known as crucial compound in embryonic differentiation processes. It has also been shown to induce differentiation of neuroblastoma in vitro, and is a part of clinical regimen for neuroblastoma treatment. Neuroblastoma cells treated with ATRA showed increased expression of esVEGFR-2, suggesting that high expression of esVEGFR-2 may indicate differentiated neuroblastoma and vice versa. Real-time RT-PCR analyses revealed that INSS stage 1 and 2 neuroblastomas express higher amounts of esVEGFR-2 transcripts than stage 3 and 4 tumors. Intriguingly, the down-regulation of the transcripts inversely correlates with lymph-node involvement and metastasis formation.

Together, esVEGFR-2 may indicate differentiation in neuroblastoma and provide new insights into cancer progression mechanisms where not only expression of pro-angiogenic molecules may facilitate tumor progression, but also the down regulation of anti-(lymphangiogenic)-molecules could drive malignancy.

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References

  • Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8(6):464–478

    Article  CAS  PubMed  Google Scholar 

  • Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J (2009) Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 15(9):1023–1030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, Albuquerque RJ, Richter E, Sakurai E, Newcomb MT, Kleinman ME, Caldwell RB, Lin Q, Ogura Y, Orecchia A, Samuelson DA, Agnew DW, St Leger J, Green WR, Mahasreshti PJ, Curiel DT, Kwan D, Marsh H, Ikeda S, Leiper LJ, Collinson JM, Bogdanovich S, Khurana TS, Shibuya M, Baldwin ME, Ferrara N, Gerber HP, De Falco S, Witta J, Baffi JZ, Raisler BJ, Ambati J (2006) Corneal avascularity is due to soluble VEGF receptor-1. Nature 443(7114):993–997

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Becker J, Pavlakovic H, Ludewig F, Wilting F, Weich HA, Albuquerque R, Ambati J, Wilting J (2010) Neuroblastoma progression correlates with downregulation of the lymphangiogenesis inhibitor sVEGFR-2. Clin Cancer Res 16(5):1431–1441

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Becker J, Frohlich J, Hansen J, Zelent C, Perske C, Wilting J (2012) The lymphangiogenesis inhibitor esVEGFR-2 in human embryos: expression in sympatho-adrenal tissues and differentiation-induced up-regulation in neuroblastoma. Histol Histopathol 27(6):721–733

    CAS  PubMed  Google Scholar 

  • Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Varney ML, Backora MW, Cowan K, Solheim JC, Talmadge JE, Singh RK (2005) Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Res 65(19):9004–9011

    Article  CAS  PubMed  Google Scholar 

  • Eggert A, Ikegaki N, Kwiatkowski J, Zhao H, Brodeur GM, Himelstein BP (2000) High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin Cancer Res 6(5):1900–1908

    CAS  PubMed  Google Scholar 

  • Kang J, Rychahou PG, Ishola TA, Mourot JM, Evers BM, Chung DH (2008) N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. Oncogene 27(28):3999–4007

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61(5):1786–1790

    CAS  PubMed  Google Scholar 

  • Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437(2):169–183

    Article  CAS  PubMed  Google Scholar 

  • Lagodny J, Juttner E, Kayser G, Niemeyer CM, Rossler J (2007) Lymphangiogenesis and its regulation in human neuroblastoma. Biochem Biophys Res Commun 352(2):571–577

    Article  CAS  PubMed  Google Scholar 

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    Article  CAS  PubMed  Google Scholar 

  • Masetti R, Biagi C, Zama D, Vendemini F, Martoni A, Morello W, Gasperini P, Pession A (2012) Retinoids in pediatric onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma. Adv Ther 29(9):747–762

    Article  CAS  PubMed  Google Scholar 

  • Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD (2009) The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27(2):298–303

    Article  PubMed Central  PubMed  Google Scholar 

  • Papoutsi M, Siemeister G, Weindel K, Tomarev SI, Kurz H, Schachtele C, Martiny-Baron G, Christ B, Marme D, Wilting J (2000) Active interaction of human A375 melanoma cells with the lymphatics in vivo. Histochem Cell Biol 114(5):373–385

    CAS  PubMed  Google Scholar 

  • Pepper MS, Tille JC, Nisato R, Skobe M (2003) Lymphangiogenesis and tumor metastasis. Cell Tissue Res 314(1):167–177

    Article  CAS  PubMed  Google Scholar 

  • Reynolds CP, Schindler PF, Jones DM, Gentile JL, Proffitt RT, Einhorn PA (1994) Comparison of 13-cis-retinoic acid to trans-retinoic acid using human neuroblastoma cell lines. Prog Clin Biol Res 385:237–244

    CAS  PubMed  Google Scholar 

  • Reynolds CP, Matthay KK, Villablanca JG, Maurer BJ (2003) Retinoid therapy of high-risk neuroblastoma. Cancer Lett 197(1–2):185–192

    Article  CAS  PubMed  Google Scholar 

  • Shibata MA, Ambati J, Shibata E, Albuquerque RJ, Morimoto J, Ito Y, Otsuki Y (2010) The endogenous soluble VEGF receptor-2 isoform suppresses lymph node metastasis in a mouse immunocompetent mammary cancer model. BMC Med 8:69

    Article  PubMed Central  PubMed  Google Scholar 

  • Sidell N (1982) Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J Natl Cancer Inst 68(4):589–596

    CAS  PubMed  Google Scholar 

  • Silva SR, Bowen KA, Rychahou PG, Jackson LN, Weiss HL, Lee EY, Townsend CM Jr, Evers BM (2011) VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Int J Cancer 128(5):1045–1056

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sitohy B, Nagy JA, Dvorak HF (2012) Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 72(8):1909–1914

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7(2):192–198

    Article  CAS  PubMed  Google Scholar 

  • Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7(2):186–191

    Article  CAS  PubMed  Google Scholar 

  • Uehara H, Cho Y, Simonis J, Cahoon J, Archer B, Luo L, Das SK, Singh N, Ambati J, Ambati BK (2013) Dual suppression of hemangiogenesis and lymphangiogenesis by splice-shifting morpholinos targeting vascular endothelial growth factor receptor 2 (KDR). FASEB J 27(1):76–85. doi:10.1096/fj.12-213835. Epub 2012 Sep 20. Source: Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA

    Google Scholar 

  • Vorlova S, Rocco G, Lefave CV, Jodelka FM, Hess K, Hastings ML, Henke E, Cartegni L (2011) Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation. Mol Cell 43(6):927–939

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Westermann F, Schwab M (2002) Genetic parameters of neuroblastomas. Cancer Lett 184(2):127–147

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University Medicine Goettingen, 37075, Goettingen, Germany

    Jürgen Becker

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  1. Jürgen Becker
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Correspondence to Jürgen Becker .

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  1. Department of Biological Sciences, Kean University, Room 213, Library Building, Union, New Jersey, USA

    M.A. Hayat

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Becker, J. (2014). Inhibition of Neuroblastoma Progression by Targeting Lymphangiogenesis: Role of an Endogenous Soluble Splice-Variant of VEGFR-2. In: Hayat, M. (eds) Tumors of the Central Nervous System, Volume 12. Tumors of the Central Nervous System, vol 12. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7217-5_6

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  • DOI: https://doi.org/10.1007/978-94-007-7217-5_6

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