Hypoxia-Inducible Factor 1α Expression as an Intrinsic Marker of Hypoxia

Abstract

Purpose: Hypoxia-inducible factor (HIF)-1␣ 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-1␣ 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-1␣ expression showed a weak correlation with low pO 2 (r ‫؍‬ ؊0.26; P ‫؍‬ 0.030; n ‫؍‬ 72). Weak significant correlations were found between HIF-1␣ 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-1␣ expression and radiotherapy outcome was examined in 99 patients. HIF-1␣ expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1␣ alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1␣ expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1␣ and tumor size for survival (P ‫؍‬ 0.046) and local control (P ‫؍‬ 0.009).Conclusions: In this study, HIF-1␣ had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1␣ expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1␣. 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.

Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas

“…Our finding agrees with a study of 146 Japanese patients, mainly with distal gastric cancer (Urano et al, 2006), and with some published reports showing HIF-1a has no prognostic significance in cervical (Haugland et al, 2002;Hutchison et al, 2004), colorectal (Yoshimura et al, 2004) and ovarian (Birner et al, 2001) cancers. In contrast, two further studies in gastric cancer showed HIF-1a expression was an adverse prognostic factor in multivariate analyses Sumiyoshi et al, 2006).…”

“…It has been suggested that HIF-1a expression may be a less important prognostic factor in surgically treated patients as the major influence of hypoxia-induced radiation resistance is lacking (Beasley et al, 2002). However, studies in patients with cervical cancer who underwent radiotherapy showed either a trend towards improved prognosis (Mayer et al, 2004) or an improved prognosis in a subgroup of patients (Hutchison et al, 2004). Although differences in staining and scoring methods cannot be ruled out completely, differences in prognostic outcome observed in numerous studies may reflect the differential regulation by HIF-1a of a range of downstream target molecules.…”

Prognostic significance of HIF-2.ALPHA. expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy

“…In uterine cervical cancer, some papers (31)(32)(33)(34) reported that overexpression of HIF-1α in pretreatment uterine cervical cancer cells served as a predictive marker for poor prognosis after treatment by radiotherapy. However, there has been no study examining the relationship between the expression of HIF-2α and uterine cervical cancer.…”

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

“…Patients were biopsied 12 -20 h after receiving pimonidazole. A semiquantitative scoring system was used to quantify pimonidazole binding as described elsewhere (Hutchison et al, 2004).…”

“…The staining and scoring methods for MVD (Cooper et al, 1998), VEGF (Loncaster et al, 2000), HIF-1a (Hutchison et al, 2004), HIF2a (Beasley et al, 2002), CA IX ) and Glut-1 (Airley et al, 2001) have been described elsewhere Only tumour nuclear HIF-1a was scored as described elsewhere (Aebersold et al, 2001). All scoring was performed in a double-blind manner by two independent investigators.…”