Browse > Article
http://dx.doi.org/10.5230/jgc.2017.17.e1

Gastric Cancer and Angiogenesis: Is VEGF a Useful Biomarker to Assess Progression and Remission?  

Macedo, Filipa (Portuguese Oncology Institute - Coimbra)
Ladeira, Katia (Portuguese Oncology Institute - Lisbon)
Longatto-Filho, Adhemar (Life and Health Science Research Institute, School of Health Sciences, University of Minho)
Martins, Sandra F. (Life and Health Science Research Institute, School of Health Sciences, University of Minho)
Publication Information
Journal of Gastric Cancer / v.17, no.1, 2017 , pp. 1-10 More about this Journal
Abstract
Gastric cancer (GC) has high mortality owing to its aggressive nature. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of GC. The aim of this work was to review the angiogenic biomarkers related to the behavior of GC, documented in the literature. A search of the PubMed database was conducted with the MeSH terms: "Stomach neoplasms/blood [MeSH] or stomach neoplasms/blood supply [MeSH] and angiogenic proteins/blood [Major]". A total of 30 articles were initially collected, and 4 were subsequently excluded. Among the 26 articles collected, 16 examined the role of vascular endothelial growth factor (VEGF), 4 studied endostatin, 3 investigated angiopoietin (Ang)-2, 2 studied the Ang-like protein 2 (ANGTPL2), and 1 each examined interleukin (IL)-12, IL-8, and hypoxia inducible factor. Regarding VEGF, 6 articles concluded that the protein was related to lymph node metastasis or distant metastases. Five articles concluded that VEGF levels were elevated in the presence of GC and decreased following tumor regression, suggesting that VEGF levels could be a predictor of recurrence. Four articles concluded that high VEGF levels were correlated with poor prognosis and lower survival rates. Ang-2 and ANGTPL2 were elevated in GC and associated with more aggressive disease. Endostatin was associated with intestinal GC. VEGF is the most extensively studied angiogenic factor. It is associated with the presence of neoplastic disease and lymph node metastasis. It appears to be a good biomarker for disease progression and remission, but not for diagnosis. The data regarding other biomarkers are inconclusive.
Keywords
Angiogenic proteins; Stomach neoplasms; Lymph nodes; Neoplasm metastasis; Vascular endothelial growth factor A; Recurrence;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ferro A, Peleteiro B, Malvezzi M, Bosetti C, Bertuccio P, Levi F, et al. Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype. Eur J Cancer 2014;50:1330-1344.   DOI
2 Xie K, Huang S. Regulation of cancer metastasis by stress pathways. Clin Exp Metastasis 2003;20:31-43.   DOI
3 Villarejo-Campos P, Padilla-Valverde D, Martin RM, Menendez-Sanchez P, Cubo-Cintas T, Bondia-Navarro JA, et al. Serum VEGF and VEGF-C values before surgery and after postoperative treatment in gastric cancer. Clin Transl Oncol 2013;15:265-270.   DOI
4 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.   DOI
5 Zhuo W, Luo C, Wang X, Song X, Fu Y, Luo Y. Endostatin inhibits tumour lymphangiogenesis and lymphatic metastasis via cell surface nucleolin on lymphangiogenic endothelial cells. J Pathol 2010;222:249-260.   DOI
6 Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett 2013;328:18-26.   DOI
7 Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55-60.   DOI
8 Tsirlis TD, Kostakis A, Papastratis G, Masselou K, Vlachos I, Papachristodoulou A, et al. Predictive significance of preoperative serum VEGF-C and VEGF-D, independently and combined with Ca19-9, for the presence of malignancy and lymph node metastasis in patients with gastric cancer. J Surg Oncol 2010;102:699-703.   DOI
9 He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 2005;65:4739-4746.   DOI
10 Wang TB, Deng MH, Qiu WS, Dong WG. 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 2007;13:1794-1797.   DOI
11 Kikuchi S, Obata Y, Yagyu K, Lin Y, Nakajima T, Kobayashi O, et al. Reduced serum vascular endothelial growth factor receptor-2 (sVEGFR-2) and sVEGFR-1 levels in gastric cancer patients. Cancer Sci 2011;102:866-869.   DOI
12 Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V, et al. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 1998;80:171-175.   DOI
13 Marrelli D, Pinto E, De Stefano A, Farnetani M, Garosi L, Roviello F. Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer. Am J Surg 2001;181:16-19.   DOI
14 Engin H, Ustundag Y, Ozel Tekin I, Gokmen A. Plasma concentrations of Ang-1, Ang-2 and Tie-2 in gastric cancer. Eur Cytokine Netw 2012;23:21-24.
15 Mehta S, Shelling A, Muthukaruppan A, Lasham A, Blenkiron C, Laking G, et al. Predictive and prognostic molecular markers for cancer medicine. Ther Adv Med Oncol 2010;2:125-148.   DOI
16 Wang TB, Wang J, Wei XQ, Wei B, Dong WG. Serum vascular endothelial growth factor-C combined with multi-detector CT in the preoperative diagnosis of lymph node metastasis of gastric cancer. Asia Pac J Clin Oncol 2012;8:180-186.   DOI
17 Wang ZH, Zhu ZT, Xiao XY, Sun J. Correlation of serum levels of endostatin with tumor stage in gastric cancer: a systematic review and meta-analysis. Biomed Res Int 2015;2015:623939.
18 Koc M, Gocmen E, Kilic M, Ozbay M, Oktem M, Tez M. Serum endostatin levels in gastric cancer patients: correlation with clinicopathological parameters. Hepatogastroenterology 2006;53:616-618.
19 Woo IS, Kim KA, Jeon HM, Hong SH, Rho SY, Koh SJ, et al. Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma. Int J Cancer 2006;119:2901-2906.   DOI
20 Jo MJ, Lee JH, Nam BH, Kook MC, Ryu KW, Choi IJ, et al. Preoperative serum angiopoietin-2 levels correlate with lymph node status in patients with early gastric cancer. Ann Surg Oncol 2009;16:2052-2057.   DOI
21 Yoshinaga T, Shigemitsu T, Nishimata H, Takei T, Yoshida M. Angiopoietin-like protein 2 is a potential biomarker for gastric cancer. Mol Med Rep 2015;11:2653-2658.   DOI
22 Toiyama Y, Tanaka K, Kitajima T, Shimura T, Imaoka H, Mori K, et al. Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients. Carcinogenesis 2015;36:1474-1483.
23 Voest EE, Kenyon BM, O'Reilly MS, Truitt G, D'Amato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995;87:581-586.   DOI
24 Park J, Seo AN, Yoon C, Ku GY, Coit DG, Strong VE, et al. Serum VEGF-A and tumor vessel VEGFR-2 levels predict survival in caucasian but not Asian patients undergoing resection for gastric adenocarcinoma. Ann Surg Oncol 2015;22 Suppl 3:S1508-S1515.   DOI
25 Seo HY, Park JM, Park KH, Kim SJ, Oh SC, Kim BS, et al. Prognostic significance of serum vascular endothelial growth factor per platelet count in unresectable advanced gastric cancer patients. Jpn J Clin Oncol 2010;40:1147-1153.   DOI
26 Sheng SL, Bao SH, Huang G, Wang LM. Development of time-resolved immunofluorometric assays for vascular endothelial growth factor and application on plasma of patients with gastric tumours. Clin Exp Immunol 2008;151:459-466.   DOI
27 Ding S, Lin S, Dong X, Yang X, Qu H, Huang S, et al. Potential prognostic value of circulating levels of vascular endothelial growth factor-A in patients with gastric cancer. In Vivo 2005;19:793-795.
28 Vidal O, Metges JP, Elizalde I, Valentini M, Volant A, Molina R, et al. High preoperative serum vascular endothelial growth factor levels predict poor clinical outcome after curative resection of gastric cancer. Br J Surg 2009;96:1443-1451.   DOI
29 Bilgic CI, Tez M. Serum VEGF levels in gastric cancer patients: correlation with clinicopathological parameters. Turk J Med Sci 2015;45:112-117.   DOI
30 Ilhan N, Ilhan N, Ilhan Y, Akbulut H, Kucuksu M. C-reactive protein, procalcitonin, interleukin-6, vascular endothelial growth factor and oxidative metabolites in diagnosis of infection and staging in patients with gastric cancer. World J Gastroenterol 2004;10:1115-1120.   DOI
31 Masiak W, Szponar A, Chodorowska G, Dabrowski A, Pedowski T, Wallner G. Evaluation of endostatin and EGF serum levels in patients with gastric cancer. Pol Przegl Chir 2011;83:42-47.
32 Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, et al. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 2001;61:6548-6554.
33 Nakayama Y, Inoue Y, Nagashima N, Katsuki T, Matsumoto K, Shibao K, et al. Relationships between local and systemic expression of interleukin-12 and plasma levels of vascular endothelial growth factor in patients with gastric cancer. Anticancer Res 2004;24:3289-3294.
34 Konno H, Ohta M, Baba M, Suzuki S, Nakamura S. The role of circulating IL-8 and VEGF protein in the progression of gastric cancer. Cancer Sci 2003;94:735-740.   DOI
35 Blank S, Deck C, Dreikhausen L, Weichert W, Giese N, Falk C, et al. Angiogenic and growth factors in gastric cancer. J Surg Res 2015;194:420-429.   DOI
36 Park DJ, Yoon C, Thomas N, Ku GY, Janjigian YY, Kelsen DP, et al. Prognostic significance of targetable angiogenic and growth factors in patients undergoing resection for gastric and gastroesophageal junction cancers. Ann Surg Oncol 2014;21:1130-1137.   DOI
37 Gao ZL, Zhang C, Du GY, Lu ZJ. Clinical significance of changes in tumor markers, extracellular matrix, MMP-9 and VEGF in patients with gastric carcinoma. Hepatogastroenterology 2007;54:1591-1595.
38 Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379:88-91.   DOI
39 Oh SY, Kwon HC, Kim SH, Jang JS, Kim MC, Kim KH, et al. Clinicopathologic significance of HIF-1alpha, p53, and VEGF expression and preoperative serum VEGF level in gastric cancer. BMC Cancer 2008;8:123.   DOI