title: Hypoxia inducible factor-1alpha correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma.
abstract: BACKGROUND
  The role of angiogenesis in the pathogenesis of renal cell carcinoma is well recognized, however, the influence of tumor cells in this activity has not yet been fully clarified. The aim of this study was to analyze the expression of hypoxia inducible factor-1alpha (HIF-1alpha), a regulatory factor of angiogenic switch, in comparison to vascular endothelial growth factor A and C (VEGF-A and VEGF-C), recognized to be involved in blood and lymph vessel neoangiogenesis, with potential association in the prognosis of patients with renal cell carcinoma.
  
  
  METHODS
  Ninety-four patients with diagnosis of clear cell renal cell carcinomas (CCRCC), all clinicopathological characteristics and overall survival were unrolled in this study. Immunohistochemicaly VEGF-A, VEGF-C, HIF-1alpha and Ki67 were detected on tumor cells and the staining was performed on tissue microarrays (TMA). The staining was evaluated as a percentage of cytoplasmic or nuclear positive tumor cells.
  
  
  RESULTS
  Variable expression of all three proteins was confirmed. Both angiogenic factors demonstrated perimembranous or diffuse cytoplasmic staining, with diffuse pattern positively associated (p < 0.001). Nuclear HIF-1alpha expression (nHIF-1alpha) showed inverse correlation with diffuse cytoplasmic VEGF-A (p = 0.002) and VEGF-C (p = 0.053), while cytoplasmic HIF-1alpha expression (cHIF-1alpha) showed positive correlation with diffuse staining of both angiogenic factors (p < 0.001; p < 0.001, respectively). In comparison to clinicopathological characteristics, a higher nuclear grade (p = 0.006; p < 0.001, respectively), larger tumor size (p = 0.009; p = 0.015, respectively), higher stage (p = 0.023; p = 0.027, respectively) and shorter survival (p = 0.018; p = 0.024, respectively) were associated with overexpression of cHIF-1alpha and diffuse cytoplasmic VEGF-A expression. In contrary, overexpression of nHIF-1alpha was associated with better diagnostic parameters i.e. lower nuclear grade (p = 0.006), smaller tumor size (p = 0.057), and longer survival (p = 0.005).
  
  
  CONCLUSIONS
  Overexpression of VEGF-A and cHIF-1alpha in tumor cells highlights a more aggressive subtype of CCRCC that might have some clinical implications. The significance of nHIF-1alpha expression associated with better differentiated tumors should be further elucidated.
authors.affiliation: Department of Pathology, Rijeka University School of Medicine, Rijeka, Croatia. dgordana@yahoo.com
authors.forename: Gordana
authors.initials: G
authors.lastname: Dorević
authors.forename: Koviljka
authors.initials: K
authors.lastname: Matusan-Ilijas
authors.forename: Emina
authors.initials: E
authors.lastname: Babarović
authors.forename: Ita
authors.initials: I
authors.lastname: Hadzisejdić
authors.forename: Maja
authors.initials: M
authors.lastname: Grahovac
authors.forename: Blazenka
authors.initials: B
authors.lastname: Grahovac
authors.forename: Nives
authors.initials: N
authors.lastname: Jonjić
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D011379:Prognosis; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C