HIF-1α and VEGF are associated with disease progression in esophageal carcinoma.
BACKGROUND
Hypoxia inducible factor-1alpha (HIF-1α) is a transcription factor that regulates the transcription of genes associated with cell proliferation and angiogenesis. The purpose of this study is to clarify the correlation of HIF-1α protein expression with vascular endothelial growth factor (VEGF) and inducible (iNOS), endothelial (eNOS), and neuronal nitric oxide synthase (nNOS) expression in esophageal tumors. Additionally, vascular density in tumor tissue was assessed.


METHODS
Eighty-eight esophageal carcinomas were analyzed by immunohistochemistry in paraffin embedded sections.


RESULTS
HIF-1α immunoreactivity was seen in 71.2 % of the tumors. Squamous cell carcinomas expressed more often HIF-1α than adenocarcinomas (P = 0.009). HIF-1α immunoreactivity was associated with iNOS (P = 0.049), and iNOS positivity was also more commonly seen in squamous cell carcinomas than adenocarcinomas (P = 0.016). VEGF immunoreaction tended to associate with HIF-1α (P = 0.073) and iNOS (P = 0.08). ENOS did not associate with HIF-1α, but tended to associate with VEGF (P = 0.072). T1-T2 tumors were more often VEGF negative than T3-T4 tumors (P = 0.063). In the subgroup of 78 operatively treated ECs patients with HIF-1α positivity (> +) had more often distant metastases (P = 0.036). There was no association between iNOS, eNOS, nNOS, or VEGF, and microvessel density in tumor tissue, tumor marginal zone, or in peripheral tissue.


CONCLUSIONS
These results show that there is a link in expression between HIF-1α, iNOS, (eNOS), and VEGF in esophageal cancer. This is in line with the fact of HIF-1α's function as a transcriptional factor for these angiogenic factors. Results also show that squamous cell and adenocarcinomas differ in their expression of HIF-1α and iNOS. VEGF appear to have association with depth of invasion in esophageal carcinomas. In our material HIF-1α positivity was associated with distant metastases, but not with patient survival.
Takala
Heikki
H
Department of Surgery, University Hospital of Oulu, Oulu, Finland. heikki.takala@ppshp.fi
Saarnio
Juha
J
Wiik
Heikki
H
Ohtonen
Pasi
P
Soini
Ylermi
Y
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III