The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer

Abstract

Regulation by hypoxia may underlie the expression of vascular endothelial growth factor in bladder cancer. We have compared the distribution of vascular endothelial growth factor mRNA with a hypoxia marker, carbonic anhydrase 9 (CA IX). vascular endothelial growth factor mRNA was analysed by in situ hybridisation and CA IX by immunochemistry in 22 cases of bladder cancer. The relationship of microvessels to the distribution of CA IX was determined. In a separate series of 49 superficial tumours, CA IX immunostaining was compared with clinico-pathological outcome. In superficial and invasive disease there was overlap in the expression of vascular endothelial growth factor and CA IX, CA IX being more widespread. Both were expressed predominantly on the luminal surface, and surrounding areas of necrosis (invasive tumours). Expression of both factors was greater in superficial disease. Expression was absent within ∼80 μm of microvessels. Unlike vascular endothelial growth factor, CA IX did not predict outcome in superficial disease. Differential responses to reoxygenation provide one explanation: vascular endothelial growth factor mRNA declined rapidly, while CA IX expression was sustained for >72 h. Expression of vascular endothelial growth factor mRNA in bladder tumours is consistent with hypoxic regulation and suggests differential regulation in superficial vs invasive disease. The expression of CA IX on the luminal surface justifies investigation of its utility as a therapeutic target/prognostic indicator. British Journal of Cancer (2002) 86 , 1276–1282. DOI: 10.1038/sj/bjc/6600215 www.bjcancer.com © 2002 Cancer Research UK

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

“…We and others have previously shown the importance of angiogenic factors, such as vascular endothelial growth factor (VEGF) measured in the urine or in the tumour, in mediating bladder tumour angiogenesis (Chow et al, 1999;Crew et al, 1999;Crew et al, 2000). We showed striking luminal induction of VEGF in superficial bladder cancer (Turner et al, 2002). Vascular endothelial growth factor is a key angiogenic factor and microvessel density as a measure of angiogenesis has been shown to be highly associated with poor outcome in invasive bladder cancer (Bochner et al, 1995).…”

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

“…In this study, there was no correlation between recurrence and GLUT1 expression. CAIX expression was noted to be greater in superficial disease compared to invasive disease (Turner et al, 2002) and to show siginificant overlap with VEGF mRNA expression; CAIX did not predict outcome in superficial disease. In contrast, another study of patients treated by cystectomy for muscle-invasive bladder cancer found a significantly worse overall survival if they had 410% GLUT1-stained fraction compared to those with less staining (Younes et al, 2001).…”

“…In an initial series of bladder cancers, CAIX was found to colocalise with pimonidazole (Wykoff et al, 2000). More recently, in superficial and muscleinvasive bladder cancer there was overlap in the expression of vascular endothelial growth factor (VEGF) and CAIX, CAIX being more widespread (Turner et al, 2002). It was noted that the expression of CAIX was absent within 80 mm of microvessels and a similar experience has now been reported with GLUT1 in cervical cancer (Airley et al, 2001).…”

Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

“…Thus, identifying patients who will benefit from the other, or more intense treatment protocols is clinically important. CA IX has been related to prognosis and prediction of radio-and/or chemotherapy success in several types of solid tumours Koukourakis et al, 2001;Loncaster et al, 2001;Hui et al, 2002;Turner et al, 2002). Its association with prognosis has been reported earlier in breast cancer , although this study included patients treated by adjuvant systemic therapy.…”

“…Exons 10 and 11 encode a transmembrane anchor and an intracytoplasmic tail, respectively (Opavsky et al, 1996). Studies have reported on CA IX expression in several carcinomas such as renal cell (Liao et al, 1997), colorectal (Saarnio et al, 1998), nonsmall lung (Vermylen et al, 1999;Giatromanolaki et al, 2001), cervical (Olive et al, 2001), bladder (Turner et al, 2002) and nasopharyngeal carcinoma (Hui et al, 2002), while being absent from most normal tissues. Its role in tumour growth and disease progression has been attributed to its effect on reducing pericellular pH in response to hypoxia, thereby facilitating the breakdown of extracellular matrix , but CA IX might also play a role in cell -cell communications.…”