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Glucose Transporter-1 Protein and Carbonic Anhydrase May Be Independent Prognostic Markers in Bladder Cancer Patients

Both hypoxia modification and accelerated treatment may be valid treatment options in bladder cancer, say researchers.

Hypoxia appears to be strongly associated with tumour propagation, malignant progression and resistance to therapy. Although the binding of pimonidazole adducts is an accepted marker of cellular hypoxia, the technique requires an injection of pimonidazole to be scheduled prior to surgical procedures.

Subsequently, there has been a growing interest in hypoxia-regulated proteins, such as glucose transporter-1 protein (GLUT1) and carbonic anhydrase IX (CAIX), as potential surrogates for more invasive techniques.

Dr. Peter J. Hoskin of CR UK Tumour Biology and Radiation Therapy Group, Mount Vernon Cancer Centre, Middlesex, United Kingdom, and colleagues performed a study to compare CAIX and GLUT1 with pimonidazole binding and determine the prognostic significance of the proteins.

The study involved 2 series of patients. In the first series, 21 patients with transitional cell carcinoma of the bladder received 0.5 gm(-2) pimonidazole (Hydroxyprobe-1t, Natural Pharmacia Inc., Belmont, Massachusetts, United States). Serial tumour samples were stained for pimonidazole, GLUT1 and CAIX and compared.

In the second series, tissue samples were collected from 64 patients previously treated for invasive bladder cancer in a phase II trial of radical radiotherapy with carbogen and nicotinamide (ARCON) and stained for GLUT1 and CAIX together with Ki-67 and CD31/34.

Analysis of staining patterns revealed geographical colocalisation of both intrinsic markers with pimonidazole and a highly significant agreement in individual patients. In both series of patients, the intrinsic hypoxia markers were highly correlated with each other and a correlation with proliferation was also evident.

Furthermore, GLUT1 and CAIX were independent predictors for overall and cause specific survival. In univariate analysis, the 5-year overall survival rate in tumours expressing higher than median values of GLUT1 was 32% compared with 72% in low levels, and for CAIX the figures were 35% and 71%.

In multivariate analysis, CAIX and GLUT1 showed high independent significance for both cause-specific and overall survival when considered individually. However, when both variables were entered into analysis the significance was lost, suggesting that CAIX or GLUT1 are interchangeable as individual prognostic markers, but a second marker does not enhance predictive value.

"The data from this study establish that muscle-invasive bladder cancer is a relatively rapidly proliferating, hypoxic tumour where a rationale for alternative treatments such as ARCON is justified," the researchers conclude.


Br J Cancer 2003 Oct 6;89:7:1290-1297. "GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON"

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