Abstract
Purpose
There is a need for biomarkers that may help in selecting the most effective anticancer treatments for each patient. We have investigated the prognostic value of a set of angiogenesis, inflammation and coagulation markers in patients treated for advanced non-small cell lung cancer.
Patients and methods
Peripheral blood samples were obtained from 60 patients before first line platinum-based chemotherapy ± bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Angiogenesis, inflammation and coagulation markers vascular endothelial growth factor (VEGF), their soluble receptors 1 (VEGFR1) and 2 (VEGFR2), thrombospondin-1 (TSP-1), interleukin-6 (IL6), sialic acid (SA) and tissue factor (TF) were quantified by ELISA.
Results
Except for TSP-1, pre- and post-treatment levels of all markers were higher in patients than in controls (p < 0.05). There was a positive and significant correlation between VEGF and VEGFR2 before treatment. VEGF also correlated with inflammatory markers IL-6 and SA. Moreover, there was a positive and significant correlation between levels of VEGFR1 and TF. Decreased levels of TSP-1 and increased levels of VEGF were associated with shorter survival. Bevacizumab significantly modified angiogenesis parameters and caused a decrease of VEGF and an increase of TSP-1.
Conclusion
Angiogenesis, inflammation and coagulation markers were increased in NSCLC patients. Increased levels of VEGF and low levels of TSP-1 correlated with a poor prognosis.
Similar content being viewed by others
References
Herbst R, Onn A, Sandler A. Angiogenesis and lung cancer:prognostic and therapeutic implications. J Clin Oncol. 2005;23:3243–56.
Hicklin DJ, Ellis LM. Role of the vascular endotelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.
Delmotte P, Martin B, Paesmans M, Berghmans T, Mascaux C, Meert AP, et al. VEGF and survival of patients with lung cancer: a systematic literature review and meta-analysis. Rev Mal Respir. 2002;19:577–84.
Dudek AZ, Mahaseth H. Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. Cancer Invest. 2005;23:193–200.
Lopez-Dee Z, Pidcock K, Gutierrez LS. Thrombospondin-1: multiple paths to inflammation. Mediat Inflamm. 2011;2011:296069.
Papadaki C, Tsaroucha E, Kaklamanis L, Lagoudaki E, Trypaki M, Tryfonidis K, et al. Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer. Br J Cancer. 2011;104:316–23.
Anderson JC, McFarland BC, Gladson CL. New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med. 2008;10:e23. doi:10.1017/S1462399408000768.
Yamaji H, Iizasa T, Koh E, Suzuki M, Otsuji M, Chang H, et al. Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer. Cancer Immunol Immunother. 2004;53:786–92.
Miyagi T, Wada T, Yamaguchi K, Shiozaki K, Sato I, Kakugawa Y, et al. Human sialidase as a cancer marker. Proteomics. 2008;8:3303–11.
Celen O, Yildirim E, Ozen N, Sonmez C. Predictive value of relative changes in serum total sialic acid level for response to neoadjuvant chemotherapy in patients with locally advanced breast carcinoma. Neoplasma. 2006;53:347–51.
Ruf W, Disse J, Carneiro-Lobo TC, Yokota N, Schaffner F. Tissue factor and cell signalling in cancer progression and thrombosis. J Thromb Haemost. 2011;1:306–15.
Goldin-Lang P, Tran QV, Fichtner I, Eisenreich A, Antoniak S, Schulze K, et al. Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis. Oncol Rep. 2008;20:123–8.
Koomägi R, Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int J Cancer. 1998;79:19–22.
Regina S, Rollin J, Bléchet C, Iochmann S, Reverdiau P, Gruel Y. Tissue factor expression in non-small cell lung cancer: relationship with vascular endothelial growth factor expression, microvascular density, and K-ras mutation. J Thorac Oncol. 2008;3:689–97.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors (RECIST Guidelines). J Natl Cancer Inst. 2000;92:205–16.
Martínez-Sales V, Vila V, Ferrando M, Reganon E. Atorvastatin neutralizes the up-regulation of thrombospondin-1 induced by thrombin in human umbilical vein endothelial cells. Endothelium. 2007;14:233–8.
Jantus-Lewintre E, Sanmartín E, Sirera R, Blasco A, Sanchez JJ, Tarón M, et al. Combined VEGF and VEGFR-2 concentrations in plasma: diagnostic and prognostic implications in patients with advanced NSCLC. Lung Cancer. 2011;74:326–31.
Pajares MJ, Agorreta J, Larrayoz M, Vesin A, Ezponda T, Zudaire I, et al. Expression of tumor-derived vascular endotelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung. J Clin Oncol. 2012;30:1129–36.
Heist RS, Zhai R, Liu G, Zhou W, Lin X, Su L, et al. VEGF polymorphisms and survival in early-stage non small cell lung cancer. J Clin Oncol. 2008;26:856–62.
Angelo L, Kurzrock R. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res. 2007;13:2825–30.
Kita H, Shiraishi Y, Watanabe K, Suda K, Ohtsuka K, Koshiishi Y, et al. Does postoperative serum interleukin-6 influence early recurrence after curative pulmonary resection of lung cancer? Ann Thorac Cardiovasc Surg. 2011;17:454–60.
Koh E, Lizasa T, Yamaji H. Significance of the correlation between the expression of interleukin 6 and clinical features in patients with non-small cell lung cancer. Int J Surg Pathol. 2012;20:233–9.
Chang CH, Hsiao CF, Yeh YM, Chang GC, Tsai YH, Chen YM, et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced non small cell lung cancer patients treated with chemotherapy. Int J Cancer; 2012 doi:10.1002/ijc.27892. [Epub ahead of print].
Zhou B, Liu J, Wang ZM, Xi T. C-reactive protein, interleukin 6 and lung cancer risk: a meta-analysis. PLoS ONE. 2012;7:e43075.
Reynés G, Vila V, Martín M, Parada A, Fleitas T, Reganon E, et al. Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma. J Neurooncol. 2011;102:35–41.
Sawhney H, Kumar CA. Correlation of serum biomarkers (TSA & LSA) and epithelial dysplasia in early diagnosis of oral precancer and oral cancer. Cancer Biomark. 2012;10:43–9.
Almaraz RT, Tian Y, Bhattarcharya R, Tan E, Chen SH, Dallas MR, et al. Metabolic flux increases glycoprotein sialylation: implications for cell adhesion and cancer metastasis. Mol Cell Proteomics 2012; 11:M112.017558. doi:10.1074/mcp.M112.017558.
Versteeg HH, Schaffner F, Kerver M, Petersen HH, Ahamed J, Felding-Habermann B, et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood. 2008;11:190–9.
Corrales-Rodriguez L, Blais N. Lung cancer associated venous thromboembolic disease: a comprehensive review. Lung Cancer. 2012;75:1–8.
Acknowledgments
This study was supported in part by Fundación para la investigación, Hospital Universitario La Fe-Bancaja.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fleitas, T., Martínez-Sales, V., Vila, V. et al. VEGF and TSP1 levels correlate with prognosis in advanced non-small cell lung cancer. Clin Transl Oncol 15, 897–902 (2013). https://doi.org/10.1007/s12094-013-1020-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-013-1020-6