Skip to main content

Advertisement

SpringerLink
Log in

Blood-based biomarkers for monitoring antiangiogenic therapy in non-small cell lung cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Tumor angiogenesis pathways have been identified as important therapeutic targets in non-small cell lung cancer. However, no biomarkers have been described as predictors of response to antiangiogenic therapy in these patients. In this study, plasma levels of VEGF, bFGF, E-selectin, and S-ICAM and gene expression profiles of peripheral blood mononuclear cells from non-small cell lung cancer patients treated with chemotherapy plus bevacizumab were analyzed before and after treatment. Values were correlated with clinicopathological characteristics and treatment response. Plasma factor levels were measured using commercially available ELISA kits. The TaqMan® human angiogenesis array was used to investigate the effect of treatment on gene expression profiles. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis was performed for differentially expressed genes using WEB-based GEne SeT AnaLysis Toolkit. Our results suggest a benefit for patients with increased plasma levels of VEGF, E-selectin, and S-ICAM in the course of bevacizumab treatment. Also, we identified differentially expressed genes between paired blood samples from patients before and after treatment, and significantly perturbed pathways were predicted. These changes in gene expression and levels of plasma factors could be used to assess the effectiveness of antiangiogenic therapy, in addition to standard clinical and radiological evaluations.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005. doi:10.1016/j.bbrc.2005.05.132.

    PubMed  Google Scholar 

  2. Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature. 2005. doi:10.1038/nature03987.

    PubMed  Google Scholar 

  3. Thurston G. Complementary actions of VEGF and angiopoietin-1 on blood vessel growth and leakage. J Anat. 2002;200(6):575–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol. 2009. doi:10.1038/nrclinonc.2009.110.

    PubMed  Google Scholar 

  5. Economopoulou P, Kotsakis A, Kapiris I, Kentepozidis N. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015. doi:10.2147/CMAR.S77400.

    PubMed  PubMed Central  Google Scholar 

  6. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006. doi:10.1056/NEJMoa061884.

    PubMed  Google Scholar 

  7. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010. doi:10.1093/annonc/mdq020.

    Google Scholar 

  8. Liu KJ, Ding LY, Wu HY. Bevacizumab in combination with anticancer drugs for previously treated advanced non-small cell lung cancer. Tumour Biol. 2015. doi:10.1007/s13277-014-2962-1.

    Google Scholar 

  9. Zhang J, Liu J, Chen H, Wu W, Li X, Wu Y, et al. The impact of histological types on the efficacy of angiogenesis inhibitors in the treatment of advanced NSCLC: a meta-analysis of randomized controlled trials. Onco Targets Ther. 2015. doi:10.2147/OTT.S90407.

    Google Scholar 

  10. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015. doi:10.3322/caac.21262.

    PubMed  Google Scholar 

  11. D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010. doi:10.1093/annonc/mdq189.

    PubMed  Google Scholar 

  12. Crino L, Dansin E, Garrido P, Griesinger F, Laskin J, Pavlakis N, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol. 2010. doi:10.1016/S1470-2045(10)70151-0.

    PubMed  Google Scholar 

  13. Zhao L, Li W, Zhang H, Hou N, Guo L, Gao Q. Angiogenesis inhibitors rechallenge in patients with advanced non-small-cell lung cancer: a pooled analysis of randomized controlled trials. Onco Targets Ther. 2015. doi:10.2147/OTT.S88102.

    Google Scholar 

  14. Sessa C, Guibal A, Del Conte G, Ruegg C. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat Clin Pract Oncol. 2008. doi:10.1038/ncponc1150.

    PubMed  Google Scholar 

  15. Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res. 2008. doi:10.1158/1078-0432.CCR-07-1154.

    PubMed Central  Google Scholar 

  16. da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009. doi:10.1093/nar/gkn923.

    Google Scholar 

  17. Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013. doi:10.1093/nar/gkt439.

    Google Scholar 

  18. Kut C, Mac-Gabhann F, Popel AS. Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer. Br J Cancer. 2007. doi:10.1038/sj.bjc.6603923.

    PubMed  PubMed Central  Google Scholar 

  19. Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. 2014. doi:10.1007/s10456-014-9420-y.

    PubMed  Google Scholar 

  20. Pajares MJ, Agorreta J, Larrayoz M, Vesin A, Ezponda T, Zudaire I, et al. Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung. J Clin Oncol. 2012. doi:10.1200/JCO.2011.37.4231.

    PubMed  PubMed Central  Google Scholar 

  21. Sorenson S, Fohlin H, Lindgren A, Lindskog M, Bergman B, Sederholm C, et al. Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy. Eur J Cancer. 2013. doi:10.1016/j.ejca.2012.07.032.

    PubMed  Google Scholar 

  22. Seto T, Higashiyama M, Funai H, Imamura F, Uematsu K, Seki N, et al. Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer. Lung Cancer. 2006. doi:10.1016/j.lungcan.2006.02.009.

    PubMed  Google Scholar 

  23. Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol. 2001;19(4):1207–25.

    CAS  PubMed  Google Scholar 

  24. Bertolini F. Chemotherapy and the tumor microenvironment: the contribution of circulating endothelial cells. Cancer Metast Rev. 2008. doi:10.1007/s10555-007-9110-y.

    Google Scholar 

  25. Zaman K, Driscoll R, Hahn D, Werffeli P, Goodman SL, Bauer J, et al. Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs. conservative therapy. Int J Cancer. 2006. doi:10.1002/ijc.21408.

    PubMed  Google Scholar 

  26. Stefanini MO, Wu FT, Mac Gabhann F, Popel AS. Increase of plasma VEGF after intravenous administration of bevacizumab is predicted by a pharmacokinetic model. Cancer Res. 2010. doi:10.1158/0008-5472.CAN-10-1419.

    PubMed  PubMed Central  Google Scholar 

  27. Finley SD, Popel AS. Effect of tumor microenvironment on tumor VEGF during anti-VEGF treatment: systems biology predictions. J Natl Cancer Inst. 2013. doi:10.1093/jnci/djt093.

    PubMed Central  Google Scholar 

  28. Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J Natl Cancer Inst. 2002;94(12):883–93.

    Article  PubMed  Google Scholar 

  29. Smirnov DA, Foulk BW, Doyle GV, Connelly MC, Terstappen LW, O’Hara SM. Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res. 2006. doi:10.1158/0008-5472.CAN-05-4003.

    Google Scholar 

  30. Hardwick JS, Yang Y, Zhang C, Shi B, McFall R, Koury EJ, et al. Identification of biomarkers for tumor endothelial cell proliferation through gene expression profiling. Mol Cancer Ther. 2005. doi:10.1158/1535-7163.MCT-04-0209.

    PubMed  Google Scholar 

  31. Ergun S, Kilik N, Ziegeler G, Hansen A, Nollau P, Gotze J, et al. CEA-related cell adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell. 2000;5(2):311–20.

    Article  CAS  PubMed  Google Scholar 

  32. Muller MM, Singer BB, Klaile E, Obrink B, Lucka L. Transmembrane CEACAM1 affects integrin-dependent signaling and regulates extracellular matrix protein-specific morphology and migration of endothelial cells. Blood. 2005. doi:10.1182/blood-2004-09-3618.

    Google Scholar 

  33. Muturi HT, Dreesen JD, Nilewski E, Jastrow H, Giebel B, Ergun S, et al. Tumor and endothelial cell-derived microvesicles carry distinct CEACAMs and influence T-cell behavior. PLoS One. 2013. doi:10.1371/journal.pone.0074654.

    Google Scholar 

  34. Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, et al. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 2001. doi:10.1074/jbc.M010660200.

    PubMed  Google Scholar 

  35. Iams WT, Lovly CM. Anaplastic lymphoma kinase as a therapeutic target in non-small cell lung cancer. Cancer J. 2015. doi:10.1097/PPO.0000000000000142.

    PubMed  Google Scholar 

  36. Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, Kenessey I, et al. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res. 2005. doi:10.1158/1078-0432.CCR-05-1077.

    PubMed  Google Scholar 

  37. LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature. 2001. doi:10.1038/35091000.

    PubMed  Google Scholar 

  38. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014. doi:10.1016/S0140-6736(14)60845-X.

    PubMed  Google Scholar 

  39. Das M, Wakelee H. Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC. Transl Lung Cancer Res. 2014. doi:10.3978/j.issn.2218-6751.2014.09.05.

    PubMed  PubMed Central  Google Scholar 

  40. Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014. doi:10.1016/S1470-2045(13)70586-2.

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by Fundación Médica Mutua Madrileña (MMA 2009/075) and partly under a collaboration agreement between Fundación “Rafael del Pino” and Instituto de Investigación Hospital 12 de Octubre (i+12). The funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author contributions

All the authors gave substantial contributions to the conception and design of the study, data acquisition, and interpretation. They all revised the manuscript and approved the final version.

Author information

Author notes

    Authors and Affiliations

    1. Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain

      Analia Rodríguez Garzotto, Santiago Ponce, José A. López-Martín, Luis Paz-Ares & Lara Iglesias

    2. Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Avda de Córdoba s/n, 28041, Madrid, Spain

      C. Vanesa Díaz-García, Alba Agudo-López, Elena Prieto García, José A. López-Martín, Luis Paz-Ares & M. Teresa Agulló-Ortuño

    Authors
    1. Analia Rodríguez Garzotto
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. C. Vanesa Díaz-García
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Alba Agudo-López
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Elena Prieto García
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Santiago Ponce
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. José A. López-Martín
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Luis Paz-Ares
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Lara Iglesias
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. M. Teresa Agulló-Ortuño
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to M. Teresa Agulló-Ortuño.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Ethical standard

    All procedures performed in this study were in accordance with the ethical standards of the institutional research committee (Comité Ético de Investigación Clínica del Hospital Universitario 12 de Octubre) and with the 1964 Helsinki Declaration and its later amendments.

    Informed consent

    Informed consent was obtained from all individual participants included in the study.

    Additional information

    Lara Iglesias and M. Teresa Agulló-Ortuño have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 5 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Rodríguez Garzotto, A., Díaz-García, C.V., Agudo-López, A. et al. Blood-based biomarkers for monitoring antiangiogenic therapy in non-small cell lung cancer. Med Oncol 33, 105 (2016). https://doi.org/10.1007/s12032-016-0824-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • DOI: https://doi.org/10.1007/s12032-016-0824-y

    Keywords

    Search

    Navigation