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. 2008 Nov 16:8:335.
doi: 10.1186/1471-2407-8-335.

Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1 alpha) expression in serous ovarian cancer: an immunohistochemical study

Alexandros Daponte  1 , Maria Ioannou, Ilias Mylonis, George Simos, Marcos Minas, Ioannis E Messinis, George Koukoulis
Affiliations

Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1 alpha) expression in serous ovarian cancer: an immunohistochemical study

Alexandros Daponte et al. BMC Cancer. .

Abstract

Background: The hypoxia-inducible factor (HIF) has emerged as an attractive target for cancer therapy. The few publications addressing the prognostic significance of Hypoxia-Inducible Factor 1 alpha (HIF-1 alpha) cellular expression in ovarian cancer produced contradictory findings which are not permissible to widely acceptable conclusions and clinical applications. Our study was designed to investigate this by including a comparatively large number of cases and by using a combination of antibodies to analyze immunohistochemically the expression of HIF-1 alpha.

Methods: One hundred (n = 100) neoplastic and 20 benign (controls) pathological samples from paraffin-embedded tissue were included. They were classified after surgery as stage I (n = 23) and stage III G3 (n = 55). Also 22 borderline serous adenocarcinoma patients and 20 benign controls were stained. The mean follow up was 3 years. Only patients with the diagnosis of serous carcinoma of stage III, G3 who received 6 cycles of postoperative TC (175-180 mg/m2 paclitaxel and carboplatin after calculating the area under the concentration curve) with complete medical records (n = 55) were selected for survival analysis. The survival analysis of the samples compared two groups after the patients were dichotomized by HIF-1 alpha final score to positive and negative.

Results: The frequency of the nuclear expression of HIF-1 alpha in benign tumours was significantly lower (median: no expression) than in borderline and ovarian cancer tumours combined (p < 0.001). HIF-1 alpha expression in serous ovarian carcinoma was not stage dependent. The overall survival of patients with tumours that stained strongly for HIF-1 alpha was significantly shorter than that of patients with tumours that stained weakly or were negative for HIF-1 alpha (p = 0.01). Kaplan-Meier survival curves confirmed that HIF-1 alpha "positive" had decreased overall survival compared to HIF-1 alpha "negative" patients (p = 0.003) and this was an independent adverse prognostic factor (multivariable analysis p = 0.006). HIF-1 alpha "positive" patients displayed a shorter median progress free interval (PFI) (not statistically significant p > 0.05). Interestingly the overall PFI of the subgroup of patients that have undergone suboptimal cytoreduction at primary surgery (n = 21) with tumours that stained strongly for HIF-1 alpha was significantly worse than that of patients with tumours that stained weakly or were negative for HIF- 1 alpha (p = 0.03).

Conclusion: Our report confirms the prognostic value of HIF-1 alpha when restricted to poorly differentiated serous ovarian carcinoma. In addition it shows that this association is elusive, since it is not only methodology-related but it can be antibody-depended. There is adequate evidence to speculate that targeting HIF-1 alpha could improve the long-term prognosis of these patients In order to increase the overall sensitivity of the immunoassay, maintaining acceptable levels of specificity, a panel of antibodies should be used.

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Figures

Figure 1
Figure 1
A – Serous carcinoma. Immunostaining for HIF1α with polyclonal antibody made in the University of Thessaly. B – Serous carcinoma. Immunostaining for HIF1α with rabbit polyclonal antibody (Santa Cruz).note variable cytoplasmic staining in addition to the variable nuclear staining. C – Serous carcinoma. Immunostaining for HIF1α with monoclonal antibody 54/HIF-1α (BD Biosciences). Note focal nuclear staining and lack of cytoplasmic staining. D – Serous carcinoma. Immunostaining for HIF1α with monoclonal antibody H!a67 (Neomarkers). Note focal nuclear staining and lack of cytoplasmic staining. E – Serous carcinoma. Immunostaining for HIF1α with monoclonal antibody H1a67 (Abcam). Note focal and weak nuclear staining and lack of cytoplasmic staining in this case. Cytoplasmic staining was seen in other cases. F – Serous tumor of low malignant potential. Note weak staining in several nuclei and focal intense staining of the nuclei at the tip of the papilla (see arrow and insert). Immunostaining with clone H1a67 (Abcam).
Figure 2
Figure 2
Survival analysis HIF(+) vs HIF (-).
Figure 3
Figure 3
Progress free interval) PFI_survival analysis in HIF(+) vs HIF (-) patients with incomplete cytoreductive surgery.
Figure 4
Figure 4
Progress free interval and overall survival curves (p > 0.05) using only Abcams antibody to define HIF1a positive/negative.
See this image and copyright information in PMC

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