GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON

Abstract

Glucose transporter-1 protein (GLUT1) and carbonic anhydrase IX (CAIX) are regulated by hypoxia inducible factor-1 (HIF-1) and have been studied as putative intrinsic cellular markers for hypoxia. This study directly compares CAIX and GLUT1 with pimonidazole binding in a prospective series of bladder cancer patients and also studies the prognostic significance of the markers, in combination with vascularity and proliferation, in a retrospective series of bladder cancer patients treated in a phase II trial of radical radiotherapy with carbogen and nicotinamide (ARCON). A total of 21 patients with a diagnosis of transitional cell carcinoma of the bladder received 0.5 g m À2 pimonidazole. Serial tumour sections were stained for pimonidazole, GLUT1 and CAIX and compared. Tissue sections obtained from a series of 64 patients previously treated for invasive bladder cancer using ARCON were stained for GLUT1 and CAIX together with Ki-67 and CD31/34. There was a good geographical colocalisation of both intrinsic markers with pimonidazole and a highly significant agreement in individual patients; correlation coefficients were 0.82 (P ¼ 0.0001) for GLUT1 and 0.74 (Po0.0001) for CAIX. In both series of patients, the intrinsic hypoxia markers were highly correlated with each other and a correlation with proliferation was also evident in the retrospective study. In univariate and multivariate analyses, GLUT1 and CAIX were independent predictors for overall and cause specific survival. The hypoxia markers did not predict for local control or metastases-free survival although higher Ki-67 indices showed a trend towards local failure. The data suggest that both hypoxia modification and accelerated treatment may be valid treatment options in bladder cancer.

Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer

“…Carbonic anhydrase IX is induced by hypoxia in a range of tumour cell lines in an HIF-1-dependent manner (Wykoff et al, Cancer Research, 2000), its role being to regulate tissue pH (Svastova et al, FEBS Letters, 2004). Studies have directly and indirectly validated the use of CA IX as an intrinsic surrogate marker of hypoxia (Loncaster et al 2001;Turner et al, 2002;Hoskin et al, 2003).…”

“…Carbonic anhydrase IX is induced by hypoxia in a range of tumour cell lines in an hypoxia-inducible factor-1 (HIF-1)-dependent manner (Wykoff et al, Cancer Research, 2000), its role being to regulate tissue pH (Svastova et al, FEBS Lett, 2004). Studies have directly and indirectly validated the use of CA IX, as an intrinsic surrogate marker of hypoxia (Loncaster et al, 2001;Turner et al, 2002;Hoskin et al, 2003). In order to understand the contribution of hypoxia to tumour progression, resistance to treatment, and, in the future, to exploit differential expression of hypoxia-related factors in tumours vs normal tissue for therapeutic gain, we have examined the expression of CA IX in breast cancer and related this to clinico-pathological parameters and clinical outcome.…”

Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer

“…Hoskin et al (2003) showed that GLUT1 and CAIX expressions in invasive bladder cancer were correlated with hypoxia and outcome of radiation therapy. However, there is also an individual pattern of expression for each patient.…”

In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts

“…One aim of the present study was to establish the efficacy of AQ4N in a cisplatin-based chemoradiation schedule in human xenografts using clinically relevant fractionation protocols. Lung and bladder xenografts were seen as relevant models for these evaluations as radiotherapy with platinum chemotherapy is commonly applied in the clinical setting, and hypoxia has been identified as a potential cause of therapy failure in both diseases (25).…”

“…Although the clinical importance of hypoxia is increasingly widely recognized, there remains some controversy in the choice of method for quantifying hypoxia (26). Glut1 is well recognized to be regulated by hypoxia, and there are numerous studies demonstrating its utility as a marker of endogenous hypoxia and its association with tumor aggressiveness and poor prognosis in numerous diseases (24)(25)(26)(27). The use of an endogenous marker of hypoxia such as Glut1 does not require exogenous administration of an agent such as pimonidazole and, thus, facilitates the translation of any preclinical findings into a clinical context.…”