Skip to main content
Top
Published in: Tumor Biology 2/2016

01-02-2016 | Original Article

An orally administered DNA vaccine targeting vascular endothelial growth factor receptor-3 inhibits lung carcinoma growth

Authors: Yan Chen, Xin Liu, Cong Guo Jin, Yong Chun Zhou, Roya Navab, Kristine Raaby Jakobsen, Xiao Qun Chen, Jia Li, Ting Ting Li, Lu Luo, Xi Cai Wang

Published in: Tumor Biology | Issue 2/2016

Login to get access

Abstract

Lung cancer is the leading cause of mortality and 5-year survival rate is very low worldwide. Recent studies show that vascular endothelial growth factor receptor-3 (VEGFR-3) signaling pathway contributes to lung cancer progression. So we hypothesize that an oral DNA vaccine that targets VEGFR-3 carried by attenuated Salmonella enterica serovar typhimurium strain SL3261 has impacts on lung cancer progression. In this study, the oral VEGFR-3-based vaccine-immunized mice showed appreciable inhibition of tumor growth and tumor lymphatic microvessels in lung cancer mice model. Moreover, the oral VEGFR-3-based vaccine-immunized mice showed remarkable increases in both VEGFR-3-specific antibody levels and cytotoxic activity. Furthermore, the oral VEGFR-3-based vaccine-immunized mice showed a significant increase in the levels of T helper type 1 (Th1) cell intracellular cytokine expression (IL-2, IFN-γ, and TNF-α). After inoculation with murine Lewis lung carcinoma (LLC) cells, CD4+ or CD8+ T cell numbers obviously declined in control groups whereas high levels were maintained in the oral VEGFR-3-based vaccine group. These results demonstrated that the oral VEGFR-3-based vaccine could induce specific humoral and cellular immune responses and then significantly inhibit lung carcinoma growth via suppressing lymphangiogenesis.
Appendix
Available only for authorised users
Literature
3.
go back to reference Zuo SG, Chen Y, Wu ZP, Liu X, Liu C, Zhou YC, et al. Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. Biol Pharm Bull. 2010;33(2):174–82.CrossRefPubMed Zuo SG, Chen Y, Wu ZP, Liu X, Liu C, Zhou YC, et al. Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. Biol Pharm Bull. 2010;33(2):174–82.CrossRefPubMed
4.
go back to reference Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 2012;484(7392):110–4. doi:10.1038/nature10908.CrossRefPubMed Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 2012;484(7392):110–4. doi:10.​1038/​nature10908.CrossRefPubMed
7.
go back to reference Khromova N, Kopnin P, Rybko V, Kopnin BP. Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms. Oncogene. 2012;31(11):1389–97. doi:10.1038/onc.2011.330.CrossRefPubMed Khromova N, Kopnin P, Rybko V, Kopnin BP. Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms. Oncogene. 2012;31(11):1389–97. doi:10.​1038/​onc.​2011.​330.CrossRefPubMed
8.
go back to reference Varney ML, Singh RK. VEGF-C-VEGFR3/Flt4 axis regulates mammary tumor growth and metastasis in an autocrine manner. Am J Cancer Res. 2015;5(2):616–28.PubMedPubMedCentral Varney ML, Singh RK. VEGF-C-VEGFR3/Flt4 axis regulates mammary tumor growth and metastasis in an autocrine manner. Am J Cancer Res. 2015;5(2):616–28.PubMedPubMedCentral
9.
go back to reference Zhang L, Zhou F, Han W, Shen B, Luo J, Shibuya M, et al. VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Res. 2010;20(12):1319–31. doi:10.1038/cr.2010.116.CrossRefPubMed Zhang L, Zhou F, Han W, Shen B, Luo J, Shibuya M, et al. VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Res. 2010;20(12):1319–31. doi:10.​1038/​cr.​2010.​116.CrossRefPubMed
10.
go back to reference Chen F, Takenaka K, Ogawa E, Yanagihara K, Otake Y, Wada H, et al. Flt-4-positive endothelial cell density and its clinical significance in non-small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(24):8548–53. doi:10.1158/1078-0432.CCR-04-0950.CrossRef Chen F, Takenaka K, Ogawa E, Yanagihara K, Otake Y, Wada H, et al. Flt-4-positive endothelial cell density and its clinical significance in non-small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(24):8548–53. doi:10.​1158/​1078-0432.​CCR-04-0950.CrossRef
11.
go back to reference Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer. 2005;104(8):1668–77. doi:10.1002/cncr.21366.CrossRefPubMed Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer. 2005;104(8):1668–77. doi:10.​1002/​cncr.​21366.CrossRefPubMed
12.
go back to reference Li J, Yi H, Liu Z, Zhang H, Zhang D, Yue W, et al. Association between VEGFR-3 expression and lymph node metastasis in non-small-cell lung cancer. Exp Ther Med. 2015;9(2):389–94. doi:10.3892/etm.2014.2091.PubMed Li J, Yi H, Liu Z, Zhang H, Zhang D, Yue W, et al. Association between VEGFR-3 expression and lymph node metastasis in non-small-cell lung cancer. Exp Ther Med. 2015;9(2):389–94. doi:10.​3892/​etm.​2014.​2091.PubMed
15.
go back to reference Hu J, Cheng Y, Li Y, Jin Z, Pan Y, Liu G, et al. MicroRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C. Eur J Cancer. 2014;50(13):2336–50. doi:10.1016/j.ejca.2014.06.005.CrossRefPubMed Hu J, Cheng Y, Li Y, Jin Z, Pan Y, Liu G, et al. MicroRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C. Eur J Cancer. 2014;50(13):2336–50. doi:10.​1016/​j.​ejca.​2014.​06.​005.CrossRefPubMed
16.
go back to reference Chang YW, Su CM, Su YH, Ho YS, Lai HH, Chen HA, et al. Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects. Oncotarget. 2014;5(11):3823–35.CrossRefPubMedPubMedCentral Chang YW, Su CM, Su YH, Ho YS, Lai HH, Chen HA, et al. Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects. Oncotarget. 2014;5(11):3823–35.CrossRefPubMedPubMedCentral
17.
go back to reference Tiriveedhi V, Tucker N, Herndon J, Li L, Sturmoski M, Ellis M, et al. Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(23):5964–75. doi:10.1158/1078-0432.CCR-14-0059.CrossRef Tiriveedhi V, Tucker N, Herndon J, Li L, Sturmoski M, Ellis M, et al. Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(23):5964–75. doi:10.​1158/​1078-0432.​CCR-14-0059.CrossRef
21.
go back to reference Grille S, Moreno M, Bascuas T, Marques JM, Munoz N, Lens D, et al. Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect. Immunology. 2014;143(3):428–37. doi:10.1111/imm.12320.CrossRefPubMedPubMedCentral Grille S, Moreno M, Bascuas T, Marques JM, Munoz N, Lens D, et al. Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect. Immunology. 2014;143(3):428–37. doi:10.​1111/​imm.​12320.CrossRefPubMedPubMedCentral
22.
go back to reference Garmory HS, Griffin KF, Brown KA, Titball RW. Oral immunisation with live aroA attenuated Salmonella enterica serovar Typhimurium expressing the Yersinia pestis V antigen protects mice against plague. Vaccine. 2003;21(21–22):3051–7.CrossRefPubMed Garmory HS, Griffin KF, Brown KA, Titball RW. Oral immunisation with live aroA attenuated Salmonella enterica serovar Typhimurium expressing the Yersinia pestis V antigen protects mice against plague. Vaccine. 2003;21(21–22):3051–7.CrossRefPubMed
23.
go back to reference Liu XF, Hu JL, Quan QZ, Sun ZQ, Wang YJ, Qi F. Systemic immune responses to oral administration of recombinant attenuated Salmonella typhimurium expressing Helicobacter pylori urease in mice. World J Gastroenterol WJG. 2005;11(14):2154–6.CrossRefPubMed Liu XF, Hu JL, Quan QZ, Sun ZQ, Wang YJ, Qi F. Systemic immune responses to oral administration of recombinant attenuated Salmonella typhimurium expressing Helicobacter pylori urease in mice. World J Gastroenterol WJG. 2005;11(14):2154–6.CrossRefPubMed
25.
go back to reference Xiong G, Husseiny MI, Song L, Erdreich-Epstein A, Shackleford GM, Seeger RC, et al. Novel cancer vaccine based on genes of Salmonella pathogenicity island 2. Int J Cancer J Int Cancer. 2010;126(11):2622–34. doi:10.1002/ijc.24957. Xiong G, Husseiny MI, Song L, Erdreich-Epstein A, Shackleford GM, Seeger RC, et al. Novel cancer vaccine based on genes of Salmonella pathogenicity island 2. Int J Cancer J Int Cancer. 2010;126(11):2622–34. doi:10.​1002/​ijc.​24957.
26.
go back to reference Dong J, Yang J, Chen MQ, Wang XC, Wu ZP, Chen Y, et al. A comparative study of gene vaccines encoding different extracellular domains of the vascular endothelial growth factor receptor 2 in the mouse model of colon adenocarcinoma CT-26. Cancer Biol Ther. 2008;7(4):502–9.CrossRefPubMed Dong J, Yang J, Chen MQ, Wang XC, Wu ZP, Chen Y, et al. A comparative study of gene vaccines encoding different extracellular domains of the vascular endothelial growth factor receptor 2 in the mouse model of colon adenocarcinoma CT-26. Cancer Biol Ther. 2008;7(4):502–9.CrossRefPubMed
28.
go back to reference Yi AK, Yoon JG, Hong SC, Redford TW, Krieg AM. Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-alpha production through activation of NF-kappaB. Int Immunol. 2001;13(11):1391–404.CrossRefPubMed Yi AK, Yoon JG, Hong SC, Redford TW, Krieg AM. Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-alpha production through activation of NF-kappaB. Int Immunol. 2001;13(11):1391–404.CrossRefPubMed
31.
go back to reference Xiang R, Mizutani N, Luo Y, Chiodoni C, Zhou H, Mizutani M, et al. A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res. 2005;65(2):553–61.PubMed Xiang R, Mizutani N, Luo Y, Chiodoni C, Zhou H, Mizutani M, et al. A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res. 2005;65(2):553–61.PubMed
32.
go back to reference Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med. 2002;8(12):1369–75. doi:10.1038/nm794.CrossRefPubMed Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med. 2002;8(12):1369–75. doi:10.​1038/​nm794.CrossRefPubMed
33.
go back to reference Kurenova EV, Hunt DL, He D, Fu AD, Massoll NA, Golubovskaya VM, et al. Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo. Cell Cycle. 2009;8(14):2266–80.CrossRefPubMedPubMedCentral Kurenova EV, Hunt DL, He D, Fu AD, Massoll NA, Golubovskaya VM, et al. Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo. Cell Cycle. 2009;8(14):2266–80.CrossRefPubMedPubMedCentral
34.
go back to reference Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454(7204):656–60. doi:10.1038/nature07083.CrossRefPubMed Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454(7204):656–60. doi:10.​1038/​nature07083.CrossRefPubMed
35.
go back to reference Shimizu K, Kubo H, Yamaguchi K, Kawashima K, Ueda Y, Matsuo K, et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci. 2004;95(4):328–33.CrossRefPubMed Shimizu K, Kubo H, Yamaguchi K, Kawashima K, Ueda Y, Matsuo K, et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci. 2004;95(4):328–33.CrossRefPubMed
38.
go back to reference Longatto Filho A, Martins A, Costa SM, Schmitt FC. VEGFR-3 expression in breast cancer tissue is not restricted to lymphatic vessels. Pathol Res Pract. 2005;201(2):93–9.CrossRefPubMed Longatto Filho A, Martins A, Costa SM, Schmitt FC. VEGFR-3 expression in breast cancer tissue is not restricted to lymphatic vessels. Pathol Res Pract. 2005;201(2):93–9.CrossRefPubMed
39.
go back to reference Bogos K, Renyi-Vamos F, Dobos J, Kenessey I, Tovari J, Timar J, et al. High VEGFR-3-positive circulating lymphatic/vascular endothelial progenitor cell level is associated with poor prognosis in human small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(5):1741–6. doi:10.1158/1078-0432.CCR-08-1372.CrossRef Bogos K, Renyi-Vamos F, Dobos J, Kenessey I, Tovari J, Timar J, et al. High VEGFR-3-positive circulating lymphatic/vascular endothelial progenitor cell level is associated with poor prognosis in human small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(5):1741–6. doi:10.​1158/​1078-0432.​CCR-08-1372.CrossRef
Metadata
Title
An orally administered DNA vaccine targeting vascular endothelial growth factor receptor-3 inhibits lung carcinoma growth
Authors
Yan Chen
Xin Liu
Cong Guo Jin
Yong Chun Zhou
Roya Navab
Kristine Raaby Jakobsen
Xiao Qun Chen
Jia Li
Ting Ting Li
Lu Luo
Xi Cai Wang
Publication date
01-02-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 2/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4061-3

Other articles of this Issue 2/2016

Tumor Biology 2/2016 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine