Circulating Thrombospondin-2 and FGF-2 in Patients with Advanced Non-small Cell Lung Cancer: Correlation with Survival

  • W. Naumnik
  • M. Ossolińska
  • I. Płońska
  • E. Chyczewska
  • J. Nikliński
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 833)

Abstract

Thrombospondin-2 (TSP-2) is an endogenous negative regulator of vascularization in human cancer. TSP-2 regulates angiogenesis through binding and sequestration of the proangiogenic fibroblast growth factor-2 (FGF-2). However, it is unclear whether TSP-2 and FGF-2 are related to prognosis in non-small cell lung cancer (NSCLC). To study this issue, we measured serum (Elisa) levels of TSP-2 and FGF-2 in 40 NSCLC patients (before chemotherapy) and 22 healthy subjects. Both TSP-2 and FGF-2 concentrations were elevated in the NSCLC group compared with control (TSP-2: 26.72 ± 8.00 vs. 18.64 ± 5.50 ng/ml, p = 0.002; FGF-2: 11.90 ± 5.80 vs. 7.26 ± 3.90 pg/ml, p = 0.01). Receiver-operating characteristic (ROC) curves were applied to find the cut-off serum levels of TSP-2 and FGF-2 (NSCLC vs. healthy: TSP-2 = 15.09 ng/ml, FGF-2 = 2.23 pg/ml). Patients before treatment with the TSP-2 level <24.15 ng/ml had a median survival of 23.7 months, but those with TSP-2 > 24.15 ng/ml had only 9 months’ median survival (p = 0.007). Patients with FGF-2 level >11.21 pg/ml had significantly shorter survival than patients with FGF-2 < 11.21 pg/ml (7.5 months vs. 16 months, p = 0.034). We conclude that NSCLC patients have higher serum concentrations of TSP-2 and FGF-2 than healthy people. High levels of TSP-2 and FGF-2 may predict worse survival.

Keywords

Fibroblast growth factor-2 Lung cancer Survival Thrombospondin-2 

Notes

Acknowledgments

This work was granted by Polish Ministry of Science and Higher Education (NN401230134; 2301/B/P01/2008/34).

Conflicts of Interest

The authors had no conflicts of interest to declare in relation to this article.

References

  1. Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253PubMedCentralPubMedCrossRefGoogle Scholar
  2. Behrens C, Lin HY, Lee JJ, Raso MG, Hong WK, Wistuba II, Lotan R (2008) Immunohistochemical expression of basic fibroblast growth factor and fibroblast growth factor receptors 1 and 2 in the pathogenesis of lung cancer. Clin Cancer Res 14:6014–6022PubMedCrossRefGoogle Scholar
  3. Brattström D, Bergqvist M, Larsson A, Holmertz J, Hesselius P, Rosenberg L, Brodin O, Wagenius G (1998) Basic fibroblast growth factor and vascular endothelial growth factor in sera from non-small cell lung cancer patients. Anticancer Res 18:1123–1127PubMedGoogle Scholar
  4. Brattström D, Bergqvist M, Hesselius P, Larsson A, Lamberg K, Wernlund J, Brodin O, Wagenius G (2002) Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumours and poorer survival in non-small cell lung cancer patients. Lung Cancer 37:57–63PubMedCrossRefGoogle Scholar
  5. Brattström D, Bergqvist M, Hesselius P, Larsson A, Wagenius G, Brodin O (2004) Serum VEGF and bFGF adds prognostic information in patients with normal platelet counts when sampled before, during and after treatment for locally advanced non-small cell lung cancer. Lung Cancer 43:55–62PubMedCrossRefGoogle Scholar
  6. Chijiwa T, Abe Y, Inoue Y, Matsumoto H, Kawai K, Matsuyama M, Miyazaki N, Inoue H, Mukai M, Ueyama Y, Nakamura M (2009) Cancerous, but not stromal, thrombospondin-2 contributes prognosis in pulmonary adenocarcinoma. Oncol Rep 22:279–283PubMedGoogle Scholar
  7. Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis DS, Stravalaci M, Tomaselli S, Giavazzi R, Rusnati M, Presta M, Zetta L, Mosher DF, Ribatti D, Gobbi M, Taraboletti G (2010) Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds. J Chem Biol 285:8733–8742CrossRefGoogle Scholar
  8. Corn PG, Wang F, McKeehen W, Navone N (2013) Targeting fibroblast growth factor pathways in prostate cancer. Clin Cancer Res 19:5856–5866PubMedCentralPubMedCrossRefGoogle Scholar
  9. Fontanini G, Boldrini L, Calcinai A, Chine S, Lucchi M, Mussi A, Angeletti CA, Basolo F, Bevilacqua G (1999) Thrombospondins I and II messenger RNA expression in lung carcinoma: relationship with p53 alterations, angiogenic growth factors, and vascular density. Clin Cancer Res 5:155–161PubMedGoogle Scholar
  10. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L, International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions (2007) The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2:706–714PubMedCrossRefGoogle Scholar
  11. Golledge J, Clancy P, Hankey GJ, Norman PE (2013) Relation between serum thrombospondin-2 and cardiovascular mortality in older men screened for abdominal aortic aneurysm. Am J Cardiol 111:1800–1804PubMedCrossRefGoogle Scholar
  12. Joensuu H, Anttonen A, Eriksson M, Mäkitaro R, Alfthan H, Kinnula V, Leppä S (2002) Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer. Cancer Res 62:5210–5217PubMedGoogle Scholar
  13. Kuhn H, Kopff C, Konrad J, Riedel A, Gessner C, Wirtz H (2004) Influence of basic fibroblast growth factor on the proliferation of non-small cell lung cancer cell lines. Lung Cancer 44:167–174PubMedCrossRefGoogle Scholar
  14. Lawler J (2000) The functions of thrombospondin-1 and -2. Curr Opin Cell Biol 12:634–640PubMedCrossRefGoogle Scholar
  15. Lawler J, Detmar M (2004) Tumor progression: the effects of thrombospondin-1 and -2. Int J Biochem Cell Biol 36:1038–1045PubMedCrossRefGoogle Scholar
  16. Lawler PR, Lawler J (2012) Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med 2:a006627PubMedCentralPubMedCrossRefGoogle Scholar
  17. Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137PubMedCrossRefGoogle Scholar
  18. Ribatti D, Vacca A, Rusnati M, Presta M (2007) The discovery of basic fibroblast growth factor/fibroblast growth factor-2 and its role in haematological malignancies. Cytokine Growth Factor Rev 18:327–334PubMedCrossRefGoogle Scholar
  19. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  20. Tokunaga T, Nakamura M, Oshika Y, Abe Y, Ozeki Y, Fukushima Y, Hatanaka H, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Tamaoki N, Ueyama Y (1999) Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer. Br J Cancer 79:354–359PubMedCentralPubMedCrossRefGoogle Scholar
  21. Ueno K, Inoue Y, Kawaguchi T, Hosoe S, Kawahara M (2001) Increased serum levels of basic fibroblast growth factor in lung cancer patients: relevance to response of therapy and prognosis. Lung Cancer 31:213–219PubMedCrossRefGoogle Scholar
  22. Zhang X, Lawler J (2007) Thrombospondin-based antiangiogenic therapy. Microvasc Res 74:90–99PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • W. Naumnik
    • 1
    • 2
  • M. Ossolińska
    • 1
  • I. Płońska
    • 3
  • E. Chyczewska
    • 1
  • J. Nikliński
    • 2
  1. 1.Department of Lung DiseasesMedical University of BialystokBialystokPoland
  2. 2.Department of Clinical Molecular BiologyMedical University of BialystokBialystokPoland
  3. 3.Municipal Hospital in BialystokBialystokPoland

Personalised recommendations