title: Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF)-D and its homolog VEGF-C influence lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3), and have been implicated in lymphatic tumor spread. Nodal dissemination of gastric adenocarcinomas critically determines clinical outcome and therapeutic options of affected patients. Therefore, we analyzed expression and prognostic significance of VEGF-D along with VEGF-C, and VEGFR-3 in gastric adenocarcinomas.
  
  
  METHODS
  VEGF-C, VEGF-D, and VEGFR-3 were analyzed in 91 R(0)-resected primary gastric adenocarcinomas, corresponding noncancerous gastric mucosa, and lymph node metastases employing immunohistochemistry and/or in situ hybridization. Blood and lymph vessel densities were assessed after staining with CD31 and LYVE-1-specific antibodies.
  
  
  RESULTS
  VEGF-D and VEGF-C were detected in 67.0% and 50.5% of gastric cancers, respectively. Healthy gastric mucosa was negative for VEGF-C and in 12.5% positive for VEGF-D. Presence of VEGF-D (P = .005) or VEGF-C (P = .006) was correlated with lymphatic metastases and decreased survival (VEGF-D, P < .05; VEGF-C, P < .05). VEGFR-3 was correlated with reduced carcinoma-specific survival (P < .05), and Cox multivariate regression analysis qualified VEGF-D and VEGFR-3, but not VEGF-C, as independent prognostic parameters. In lymph node-positive gastric cancers, presence of VEGF-D/VEGFR-3 was associated with poor survival, whereas absence of VEGF-D/VEGFR-3 defined a subgroup of patients with clearly favorable prognosis.
  
  
  CONCLUSIONS
  VEGF-D and VEGFR-3 are novel independent prognostic marker molecules aiding to identify patients with poor prognosis after curative resection of gastric adenocarcinomas. Combined analysis of the VEGF-C/VEGF-D/VEGFR-3 system can be useful to identify patients with unfavorable clinical outcome and thereby may help to refine therapeutic decisions in gastric cancer.
authors.affiliation: Laboratory for Angiogenesis and Tumor Metastasis, Charité, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jüttner
authors.forename: Christoph
authors.initials: C
authors.lastname: Wissmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Jöns
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.forename: Johannes
authors.initials: J
authors.lastname: Hertel
authors.forename: Stephan
authors.initials: S
authors.lastname: Gretschel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schlag
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kemmner
authors.forename: Michael
authors.initials: M
authors.lastname: Höcker
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D013274:Stomach Neoplasms / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality*; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis / Q000235:genetics; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis* / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000032:analysis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3