The Serum VEGF-A、 VEGF-D、 VEGFR-1Level In Patients With Gastric Cancer And Their Clinical Significance

BackgroundCancer cell dissemination throughout the body usually results from direct seedingof primary tumor cells into the body via lymphatic or blood vessels and further spreadinto distant organs.Many data from clinical and animal studies suggest that tumorassociated vasculogenesis and lymphangiogenesis occurs in many carcinomas and cansignificantly promote the metastatic process. The vascular endothelial growth factor(VEGF) family of cytokines (VEGF-A,-B,-C,-D and Placental Growth Factor) hasshown to play an integral role in angiogenesis, lymphangiogenesis and vasculogenesisthrough their molecular interaction with the three vascular endothelial growth factorreceptor protein-thyrosine kinases(VEGFR-1for VEGF-A and B,VEGFR-2forVEGF-A, C, D and E and VEGFR-3for VEGF-C and D) in endothelial cells.We kown that solid tumor growth and metastasis is angiogenesis-dependent.Itsuggests a potential value of blood and tissue angiogenic markers as prognostic andsurvival. VEGF-A is adimeric, heparin-binding glycoprotein that functions as a potentmitogen of vascular endothelial cells, providing an opportunity for their migration andorganization for the neovascularization of micrometastases。Experimental studiesusing different approaches clearlydemonstrate that VEGF-A promotes tumor growth,angiogenesis,and metastasis formation. VEGF-A expression at both the mRNA andprotein level has also been demonstrated in vivo in a variety of gastrointestinal tumorsincluding gastric cancer, with reflecting intratumoral microvessel density, the presenceof lymph node and hepatic metastases, and survival.VEGF-D has been identified as one of the best characterized lymphangiogenicgrowth factors.How VEGF-D expression is regulated is largely unknown. It issuggested that VEGF-D acts as competitive agonist with VEGF-A for the process oflymphatic invasion and detant metastasis. The decrease of VEGF-D may allow a morefree interaction of VEGF-A with the VEGFR-2and VEGFR-3.In gastric cancer，tumor growth, invasion and metastasis are closely related tothe tumor blood supply. The new capillaries in tumor area is the material basis of thetumor. Tumor need new vessels for growing rapidly tumor cells which could providenutritional and discharge metabolic waste. VEGF famiy is a cell factor which plays aregulatory role through binding to receptors in the endothelial cell surface to stimulateendothelia cell division, migration and promote angiogenesis. Soluble forms of vascular endothelial growth factor are also detectable in the serumand other biologic fluids from cancer patients.However, there are limited dataregarding the clinical and prognostic significance of serum VEGF levels in gastriccancer patients.In this study, we evaluated serum VEGF-A、VEGF-D、VEGFR-1levels inhealthy controls and in gastric cancer patients,and then we also correlated these levelswith clinicopathologic features to predict distant metastasis in gastric cancer.OBJECTIVEThe aim of this study is to evaluate the correlations between the serum circulatingconcentrations of vascular endothelial growth factor-A(VEGF-A),vascular endothelialgrowth factor-D (VEGF-D),vascular endothelial growth factor receptor-1(VEGFR-1) levels of gastric cancer patients and the clinicopathologic features and toinvestigate whether serum levels of VEGF-A,VEGF-D and VEGFR-1could be usefultumor markers in gastric cancer patients with distant metastasis.MATERIALS AND METHODSTo examined VEGF-A、VEGF-D and VEGFR-1concentrations of serum samplesfrom20healthy controls and68gastric cancer patients using enzyme-linkedimmunosorbent assay (ELISA)，and the association with the clinicopathologicalfeaturesof the gastric cancer patients. ROC curves was implemented to analyze thepredictive significance of VEGF-A,VEGF-D independently and the combination ofthe two factor compared with CEA and CA19-9.RESULTS1. Serum VEGF-A concentrations levels in gastric cancer patients were significantlyhigher than those in healthy controls（P=0.000）,but Serum VEGF-D of gastriccancer patients were lower as compared with controls（P=0.009）.2. There was a significant association between serum VEGF-A levels of gastriccancer and invasion depth of the tumor,lymph node metastasis,the presence ofdistant metastasis and TNM stage（all P <0.001），There was a significantassociation between serum VEGF-D levels of gastric cancer and the presence ofdistant metastasis,pathological subtype and TNM stage,but not associate with thesex,age of the patients(P=0.015,0.005).3. The serum levels of VEGF-A in gastric cancer patients had negative correlationwith that of VEGF-D（r=-0.394;P=0.001). 4. ROC curve analysis identified VEGF-A cut-off value of>1346pg/ml for thepresence of distant metastasis in gastric cancer, with79.2%sensitivity and90%specificity,AUC0.92;VEGF-D cut-off value of <496pg/ml for the presence ofdistant metastasis in gastric cancer, with93.7%sensitivity and45%specificity,AUC0.719and the combination of VEGF-A/VEGF-D cut-off valueof>4.58for the presence of distant metastasis in gastric cancer, with85%sensitivity and90%specificity，AUC0.883. All above were higher than CEAwith35.4%sensitivity and95%specificity,AUC0.698when cut-off valueof>10ng/ml,and CA19-9with54.2%sensitivity and90%specificity,AUC0.803when cut-off value of>30U/ml in predicting distant metastasis of gastric cancer.CONCLUSIONSVEGF-A、VEGF-D and VEGFR-1concentrations of serum correlate with invasiondepth of the tumor,lymph node metastasis. Circulating levels of VEGF-A andVEGF-D could play a role as biomarkers for predicting distant metastasis in gastriccancer.