title: High VEGF-D and Low MMP-2 Serum Levels Predict Nodal-Positive Disease in Invasive Bladder Cancer.
abstract: BACKGROUND
  To investigate stromal variables including angiogenesis, lymphangiogenesis, and matrix metalloproteinase (MMP) in the serum of patients with urothelial carcinoma of the bladder (UCB) and to evaluate their association with histopathological characteristics and clinical outcome.
  
  
  METHODS
  Protein levels of vascular endothelial growth factors-A, -C, -D (VEGF-A/-C/-D), their receptors- VEGF-R2 and -R3 (VEGF-R2/-R3), and matrix metalloproteinases 2, -3, and -7 (MMP-2, MMP-3, MMP-7) were quantified in the blood serum samples of 71 patients with UCB before radical cystectomy (RC). Samples of patients with non-invasive UCB or no history of UCB were investigated as controls (n=20). Protein levels in the serum were measured using a flow cytometric cytokine assay.
  
  
  RESULTS
  A positive association for VEGF-D (p<0.001) and an inverse association for MMP-2 (p=0.017) were observed in patients with positive lymph node (LN) status at the time of RC. VEGF-A (p<0.001), VEGF-C (p<0.001), MMP-2 (p<0.001), and MMP-7 (p=0.005) serum levels were different in serum of patients with invasive UCB compared with non-invasive UCB or healthy individuals. None of the serum markers were associated with disease progression.
  
  
  CONCLUSIONS
  High VEGF-D and low MMP-2 serum levels predict LN metastasis in patients with UCB at the time of RC. VEGF-A, VEGF-C, MMP-2, and MMP-7 serum levels varied significantly between invasive and non-invasive disease as well as in comparison with healthy individuals. Clinical implementation of these marker serum measurements may be valuable to select high-risk patients with more invasive or nodal-positive disease.
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Benoit
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Etienne X
authors.initials: EX
authors.lastname: Keller
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Pirmin
authors.initials: P
authors.lastname: Wolfsgruber
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermanns
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Günthart
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Banzola
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Tullio
authors.initials: T
authors.lastname: Sulser
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Provenzano
authors.affiliation: Department of Urology, University Hospital, University of Zürich, Zürich, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Poyet
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011237:Predictive Value of Tests; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000097:blood* / Q000473:pathology / Q000556:secondary; D042643:Vascular Endothelial Growth Factor D / Q000097:blood*
chemical_list: D014408:Biomarkers, Tumor; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2