Abstract
Introduction
Angiogenesis and lymphangiogenesis are essential processes for the formation of blood and lymphatic vessels that allow tumour growth and spread. The binding of VEGF and VEGF-C factors with their receptors (VEGFR2, VEGFR3) in endothelial cells triggers signals that regulate these processes. We compared preoperative serum VEGF and VEGF-C levels with samples obtained after completion of surgery and adjuvant treatment in patients with gastric cancer. In addition, we determined the prognostic value and relationship to survival of serum VEGF and VEGF-C levels.
Methods
We used a prospective cohort study of 59 gastric cancer patients who underwent surgery. Serum VEGF and VEGF-C were measured by enzyme-linked immunosorbent assay (ELISA) the day before surgery and 6 months later, after completion of adjuvant treatment.
Results
Serum VEGF values decreased after treatment in patients with resectable tumours (mean ± SD) (405.42 ± 298.38 vs. 306.38 ± 212.47 pg/ml; p < 0.01), poorly differentiated and undifferentiated tumours (G3, G4) (438 ± 339.71 vs. 322.47 ± 210.71 pg/ml; p = 0.01), locally advanced gastric tumours (T4 stage) (424.27 ± 323.08 vs. 333.62 ± 221.72 pg/ml; p = 0.03) and tumours with a greater number of involved regional lymph nodes (N3) (442.38 ± 311.52 vs. 337.4 ± 203.64 pg/ml; p = 0.04). Serum preoperative VEGF values over 761 pg/ml were associated with shorter patient survival. The mean overall survival time for patients with serum VEGF levels higher than 761 pg/ml was 7 ± 2.99 months (95 % CI 1.14–12.86) while for patients with serum VEGF levels of less than 761 pg/ml was 21.18 ± 2.88 (95 % CI 15.54–26.83) The mean disease-specific survival time for patients with serum VEGF levels higher than 761 pg/ml was 6.25 ± 2.53 months (95 % CI 1.29–11.21) while for patients with serum VEGF levels of less than 761 pg/ml was 27.57 ± 3.45 (95 % CI 20.80–34.35). Multivariate analysis identified preoperative serum VEGF levels as an independent prognostic factor (HR = 0.144; p = 0.03).
Conclusions
Serum VEGF levels decreased after the completion of treatment in patients with resected tumours, suggesting VEGF tracking may be useful in monitoring progression. Preoperative measurement of serum VEGF may help us identify patients with a poor prognosis.
Similar content being viewed by others
References
Folkman J (1992) The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71
Cheong JH, Hong SY, Zheng Y, Noh SH (2011) Eupatilin inhibits gastric cancer cell growth by blocking STAT3-mediated VEGF expression. J Gastric Cancer 11:16–22
Osinsky S, Bubnovskaya L, Ganusevich I, Kovelskaya A, Gumenyuk L, Olijnichenko G et al (2011) Hypoxia, tumour-associated macrophages, microvessel density, VEGF and matrix metalloproteinases in human gastric cancer: interaction and impact on survival. Clin Transl Oncol 13:133–138
Christopoulos A, Ahn SM, Klein JD, Kim S (2011) Biology of vascular endothelial growth factor and its receptors in head and neck cancer: beyond angiogenesis. Head Neck 33:1220–1229
Al-Rawi MA, Mansel RE, Jiang WG (2005) Molecular and cellular mechanisms of lymphangiogenesis. Eur J Surg Oncol 31:117–121
Nagahashi M, Ramachandran S, Rashid OM, Takabe K (2010) Lymphangiogenesis: a new player in cancer progression. World J Gastroenterol 16:4003–4012
Fondevila C, Metges JP, Fuster J, Grau JJ, Palacin A, Castells A et al (2004) p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 90:206–215
Chen J, Li T, Wu Y, He L, Zhang L, Shi T et al (2011) Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a meta-analysis. J Cancer Res Clin Oncol 137:1799–1812
Duff SE, Li C, Jeziorska M, Kumar S, Saunders MP, Sherlock D et al (2003) Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy. Br J Cancer 89:426–430
Han FH, Li HM, Zheng DH, He YL, Zhan WH (2010) The effect of the expression of vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 on the clinical outcome in patients with gastric carcinoma. Eur J Surg Oncol 36:1172–1179
Ding S, Lin S, Dong X, Yang X, Qu H, Huang S et al (2005) Potential prognostic value of circulating levels of vascular endothelial growth factor-A in patients with gastric cancer. In Vivo (Athens, Greece) 19:793–795
Werther K, Christensen IJ, Nielsen HJ (2002) Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma. Br J Cancer 86:417–423
Bouvier AM, Sant M, Verdecchia A, Forman D, Damhuis R, Willem Coebergh J et al (2010) What reasons lie behind long-term survival differences for gastric cancer within Europe? Eur J Cancer 46:1086–1092
Bentrem D, Gerdes H, Tang L, Brennan M, Coit D (2007) Clinical correlation of endoscopic ultrasonography with pathologic stage and outcome in patients undergoing curative resection for gastric cancer. Ann Surg Oncol 14:1853–1859
Washington K (2010) 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol 17:3077–3079
Mazumdar M, Smith A, Bacik J (2003) Methods for categorizing a prognostic variable in a multivariable setting. Stat Med 22:559–571
De Vita F, Orditura M, Lieto E, Infusino S, Morgillo F, Martinelli E et al (2004) Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma. Cancer 100:270–278
Karayiannakis AJ, Bolanaki H, Syrigos KN, Asimakopoulos B, Polychronidis A, Anagnostoulis S et al (2003) Serum vascular endothelial growth factor levels in pancreatic cancer patients correlate with advanced and metastatic disease and poor prognosis. Cancer Lett 194:119–124
Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ (2004) Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 100:1385–1392
Carrillo-de Santa Pau E, Carrillo Arias F, Caso Pelaez E, Muguruza Trueba I, Sanchez Hernandez I, Munoz Molina GM et al (2009) Vascular endothelial growth factor (VEGF) serum levels are associated with survival in early stages of lung cancer patients. Cancer Invest 28:393–398
Zusterzeel PL, Span PN, Dijksterhuis MG, Thomas CM, Sweep FC, Massuger LF (2009) Serum vascular endothelial growth factor: a prognostic factor in cervical cancer. J Cancer Res Clin Oncol 135:283–290
Vidal O, Metges JP, Elizalde I, Valentini M, Volant A, Molina R et al (2009) High preoperative serum vascular endothelial growth factor levels predict poor clinical outcome after curative resection of gastric cancer. Br J Surg 96:1443–1451
Karayiannakis AJ, Syrigos KN, Polychronidis A, Zbar A, Kouraklis G, Simopoulos C et al (2002) Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg 236:37–42
Tamura M, Ohta Y (2003) Serum vascular endothelial growth factor-C level in patients with primary nonsmall cell lung carcinoma: a possible diagnostic tool for lymph node metastasis. Cancer 98(6):1217–1222
Yu XM, Lo CY, Lam AK, Leung P, Luk JM (2008) Serum vascular endothelial growth factor C correlates with lymph node metastases and high-risk tumor profiles in papillary thyroid carcinoma. Ann Surg 247:483–489
Krzystek-Korpacka M, Matusiewicz M, Diakowska D, Grabowski K, Blachut K, Banas T (2007) Up-regulation of VEGF-C secreted by cancer cells and not VEGF-A correlates with clinical evaluation of lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Cancer Lett 249:171–177
Wang TB, Deng MH, Qiu WS, Dong WG (2007) Association of serum vascular endothelial growth factor-C and lymphatic vessel density with lymph node metastasis and prognosis of patients with gastric cancer. World J Gastroenterol 13:1794–1797
Bogos K, Renyi-Vamos F, Dobos J, Kenessey I, Tovari J, Timar J et al (2009) 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 15:1741–1746
Alabi AA, Suppiah A, Madden LA, Monson JR, Greenman J (2009) Preoperative serum levels of serum VEGF-C is associated with distant metastasis in colorectal cancer patients. Int J Colorectal Dis 24:269–274
Sung JY, Lee S, Kim YW, Park YK (2008) Vascular endothelial growth factor receptor-3 is a favorable prognostic factor in advanced gastric carcinoma. Oncol Rep 19:939–944
Mouawad R, Spano JP, Comperat E, Capron F, Khayat D (2009) Tumoural expression and circulating level of VEGFR-3 (Flt-4) in metastatic melanoma patients: correlation with clinical parameters and outcome. Eur J Cancer 45:1407–1414
Kirk R (2011) Targeted therapies: should we be aghast at the AVAGAST data? Nat Rev Clin Oncol 8:567
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Villarejo-Campos, P., Padilla-Valverde, D., Martin, R.M. et al. Serum VEGF and VEGF-C values before surgery and after postoperative treatment in gastric cancer. Clin Transl Oncol 15, 265–270 (2013). https://doi.org/10.1007/s12094-012-0908-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-012-0908-x