Expression of GLUT1 is associated with increasing grade of malignancy in non-invasive and invasive urothelial carcinomas of the bladder

Abstract

Glucose Transporter 1 (GLUT1) belongs to the expanding mammalian facilitative glucose transporter family. Elevated GLUT1 protein expression has been observed in the majority of urothelial carcinomas, with various effects on clinicopathological parameters. Whereas malignant cells have an accelerated metabolism with increased energy requirements, the membranous expression of GLUTs is amplified. GLUT1 protein expression was evaluated in urothelial tumours of increasing grade of malignancy, supplemented by a tumour proliferation analysis. Particular attention was paid to non-invasive precursors of urothelial carcinoma. A total of 105 paraffin-embedded samples were classified (normal urothelium, low/high-grade papillary carcinoma, carcinoma in situ and invasive carcinoma). Grading and staging were conducted using the 1998 ISUP/2004 WHO criteria. The staining intensity of GLUT1 was assessed with a standard immunoreactive score (IRS). The Ki-67 index was assessed by counting positive nuclei in representative urothelial hot spots. Results showed that an increased GLUT1-IRS and mean count of Ki-67-positive cells were significantly associated with an increased grade of malignancy (p<0.0001), particularly in non-invasive tumours. GLUT1-IRS was significantly associated with a Ki-67-labelled proliferative fraction (p<0.0001). No significant association regarding tumour grade or stage was observed within the invasive carcinoma group. GLUT1 protein expression was found to be strongly correlated with increased malignant potential, particularly in non-invasive urothelial carcinomas. The increase of GLUT1 expression may reflect a preinvasive metabolic switch in terms of enhanced cell metabolism concomitant to known genetic alterations. A further increase in invasive carcinomas may be related to hypoxic conditions.