Hypoxia inducible factors 1alpha and 2alpha are associated with VEGF expression and angiogenesis in gallbladder carcinomas.
OBJECTIVE
To investigate the significance of the hypoxia inducible factors HIF-1alpha and HIF-2alpha in gallbladder adenocarcinomas and their relation to angiogenesis and to the expression of VEGF, an angiogenic factor transcriptionally regulated by HIFalphas.


METHODS
HIF-1alpha and 2alpha expression was assessed immunohistochemically in 60 patients with early gallbladder adenocarcinomas, treated with surgery alone. In addition, the vascular density (VD) and the expression of the angiogenic factors VEGF and thymidine phosphorylase (TP) were examined. The results were correlated with clinico-pathological features and prognosis.


RESULTS
Overexpression of HIF-1alpha and 2alpha was significantly associated with increased tumor angiogenesis and VEGF expression, while HIF-2alpha was linked with upregulation of TP. None of these factors were associated with T-stage and tumor grade. Although HIFs did not relate significantly with prognosis, patients with HIF-1/2 expression who failed to switch-on VEGF or intratumoral angiogenesis had a favorable outcome.


CONCLUSIONS
Hypoxia inducible factors are upregulated in a large proportion of gallbladder adenocarcinomas, a feature strongly related to increased expression of VEGF and intensified angiogenesis.
Giatromanolaki
A
A
Department of Pathology, Democritus University of Thrace Medical School, Alexandroupolis, Greece. targ@her.forthnet.gr
Sivridis
E
E
Simopoulos
C
C
Polychronidis
A
A
Gatter
K C
KC
Harris
A L
AL
Koukourakis
M I
MI
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000502:physiology; D005260:Female; D005706:Gallbladder Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1