Lack of apoptotic protease activating factor-1 expression and resistance to hypoxia-induced apoptosis in cervical cancer

Purpose: Clinical observations suggest that intratumoral hypoxia increases the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein apoptotic protease activating factor-1 (Apaf-1) in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Furthermore, the effect of hypoxia and apoptosis on survival was examined. Experimental Design: In 56 patients, intratumoral oxygenation measurements and subsequent needle biopsies were done. The obtained tissue was analyzed by terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling assays and by immunohistochemistry with an Apaf-1 antibody. Results: Apaf-1 was expressed in 86% of cancers. The median apoptosis rate was 1.0%. There was no correlation between Apaf-1 expression and intratumoral hypoxia. However, Apaf-1 expression was negative in 37.5% of hypoxic cervical cancers (pO(2) <= 10 mmHg) with low apoptosis rates (<= 1.0%) compared with only 5.0% in nonhypoxic cancers and hypoxic cancers with high apoptosis (P = 0.005; Fisher's exact test). With a median follow-up period of 44 months, there was a nonsignificant trend toward worse prognosis in the hypoxic low-apoptotic group (P = 0.08). Conclusions: Although Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a lack of Apaf-1 expression. This finding suggests that loss of Apaf-1 expression is a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis. Thus, low Apaf-1 expression in hypoxic tumors may be an unfavorable prognostic factor.