Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix.

Abstract

PURPOSE:

Hypoxia-inducible factor (HIF)-1alpha expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy.

EXPERIMENTAL DESIGN:

HIF-1alpha expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9.

RESULTS:

High HIF-1alpha expression showed a weak correlation with low pO2 (r = -0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1alpha and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1alpha expression and radiotherapy outcome was examined in 99 patients. HIF-1alpha expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1alpha alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1alpha expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1alpha and tumor size for survival (P = 0.046) and local control (P = 0.009).

CONCLUSIONS:

In this study, HIF-1alpha had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1alpha expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1alpha. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.

• Authors: Gillian J Hutchison, Helen R Valentine, Juliette A Loncaster, Susan E Davidson, Robert D Hunter, Stephen A Roberts, Adrian L Harris, Ian J Stratford, Patricia M Price, Catharine M L West
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 24 Pg. 8405-12 (Dec 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15623619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nitroimidazoles
• Radiation-Sensitizing Agents
• Transcription Factors
• pimonidazole
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases
• Oxygen

Topics

• Antigens, Neoplasm (metabolism)
• Biomarkers, Tumor (metabolism)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (metabolism)
• Disease-Free Survival
• Female
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ion-Selective Electrodes
• Middle Aged
• Neoplasm Recurrence, Local (metabolism, pathology, radiotherapy)
• Nitroimidazoles (therapeutic use)
• Oxygen (metabolism)
• Prognosis
• Radiation-Sensitizing Agents (therapeutic use)
• Survival Rate
• Transcription Factors (metabolism)
• Treatment Outcome
• Uterine Cervical Neoplasms (metabolism, radiotherapy, secondary)