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.
OBJECTIVE
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.


METHODS
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.
Hutchison
Gillian J
GJ
Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital NHS Trust, Manchester, United Kingdom.
Valentine
Helen R
HR
Loncaster
Juliette A
JA
Davidson
Susan E
SE
Hunter
Robert D
RD
Roberts
Stephen A
SA
Harris
Adrian L
AL
Stratford
Ian J
IJ
Price
Patricia M
PM
West
Catharine M L
CM
D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017736:Ion-Selective Electrodes; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D009593:Nitroimidazoles / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D011379:Prognosis; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000532:radiotherapy / Q000556:secondary
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors; C033815:pimonidazole; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D010100:Oxygen