title: Gastric cancer-associated enhancement of von Willebrand factor is regulated by vascular endothelial growth factor and related to disease severity.
abstract: BACKGROUND
  von Willebrand factor (vWF) is a potent regulator of angiogenesis, tumor growth, and metastasis. Yet, the expression pattern of vWF in human gastric cancer (GC) tissues and its relation to clinicopathological features of these cases remains unknown.
  
  
  METHODS
  Tumor and 5-cm adjacent non-tumoral parenchyma specimens were collected from 99 patients with GC (early stages I/II and late stages III/IV), and normal specimens were collected from 32 healthy controls (reference group). Plasma vWF antigen (vWF:Ag) and vWF activity were assessed by ELISA. The role of vascular endothelial growth factor (VEGF) in differential vWF expression was investigated using cultured human umbilical vein endothelial cells (HUVECs). vWF and VEGF protein and mRNA expression levels were investigated by qRT-PCR, western blotting and immunohistochemistry (IHC) respectively. The correlation of IHC-detected vWF expression with patient clinicopathological characteristics was analyzed.
  
  
  RESULTS
  Compared to the reference group, the patients with late GC showed significantly higher levels of vWF:Ag (72% (21-115) vs. 101% (40-136)) and vWF activity (62% (20-112) vs. 117% (33-169)) (both P < 0.001). The GC tumor tissues also showed higher vWF mRNA and protein levels than the adjacent non-tumoral parenchyma. Patients at late GC stage had significantly higher median number of vWF-positive cells than patients at early GC stage (P < 0.05). VEGF induced vWF mRNA and protein expression in HUVECs in dose- and time-dependent manners. Patients with late GC stage also had significantly higher serum VEGF than patients at early GC stage (23 ± 26 vs. 10 ± 12 pg/mL, P < 0.01). Most of the undifferentiated GC tumor tissues at late disease stage exhibited strong VEGF and VEGFR2 protein staining, which co-localized with the vWF protein staining pattern.
  
  
  CONCLUSIONS
  GC-related plasma vWF:Ag and vWF activity levels become substantially elevated in the late stage of disease. The higher mRNA and protein expression of vWF in GC tumor stroma may be regulated by the VEGF-VEGFR2 signaling pathway in vitro and may contribute to GC progression in vivo.
authors.affiliation: Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China. oceanyx@126.com.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China. 1103123096@qq.com.
authors.forename: Hai-jian
authors.initials: HJ
authors.lastname: Sun
authors.affiliation: Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China. 154798291@qq.com.
authors.forename: Zhi-rong
authors.initials: ZR
authors.lastname: Li
authors.affiliation: Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China. 332055019@qq.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, First People's Hospital of Guiyang, Guiyang, 550002, PR China. 275978358@qq.com.
authors.forename: Wei-jun
authors.initials: WJ
authors.lastname: Yang
authors.affiliation: Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China. 914054186@qq.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Ni
authors.affiliation: Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, PR China. wuyuzhang20006@sohu.com.
authors.forename: Yu-zhang
authors.initials: YZ
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002415:Cats; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor