High expression of insulin receptor on tumour-associated blood vessels in invasive bladder cancer predicts poor overall and progression-free survival.
Bladder cancer is a frequently recurring disease with a very poor prognosis once progressed to invasive stages, and tumour-associated blood vessels play a crucial role in this process. In order to identify novel biomarkers associated with progression, we isolated blood vascular endothelial cells (BECs) from human invasive bladder cancers and matched normal bladder tissue, and found that tumour-associated BECs greatly up-regulated the expression of insulin receptor (INSR). High expression of INSR on BECs of invasive bladder cancers was significantly associated with shorter progression-free and overall survival. Furthermore, increased expression of the INSR ligand IGF-2 in invasive bladder cancers was associated with reduced overall survival. INSR may therefore represent a novel biomarker to predict cancer progression. Mechanistically, we observed pronounced hypoxia in human bladder cancer tissue, and found a positive correlation between the expression of the hypoxia marker gene GLUT1 and vascular INSR expression, indicating that hypoxia drives INSR expression in tumour-associated blood vessels. In line with this, exposure of cultured BECs and human bladder cancer cell lines to hypoxia led to increased expression of INSR and IGF-2, respectively, and IGF-2 increased BEC migration through the activation of INSR in vitro. Taken together, we identified vascular INSR expression as a potential biomarker for progression in bladder cancer. Furthermore, our data suggest that IGF-2/INSR mediated paracrine crosstalk between bladder cancer cells and endothelial cells is functionally involved in tumour angiogenesis and may thus represent a new therapeutic target. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
['Roudnicky|Filip|F|0000-0001-7156-2383', 'Dieterich|Lothar C|LC|', 'Poyet|Cedric|C|', 'Buser|Lorenz|L|', 'Wild|Peter|P|', 'Tang|Dave|D|', 'Camenzind|Peter|P|', 'Ho|Chien Hsien|CH|', 'Otto|Vivianne I|VI|', 'Detmar|Michael|M|']
D000818:Animals D015703:Antigens, CD D014408:Biomarkers, Tumor D004195:Disease Models, Animal D018450:Disease Progression D018572:Disease-Free Survival D042783:Endothelial Cells D004730:Endothelium, Vascular D005260:Female D020869:Gene Expression Profiling D015972:Gene Expression Regulation, Neoplastic D051272:Glucose Transporter Type 1 D006801:Humans D000860:Hypoxia D007335:Insulin-Like Growth Factor II D008810:Mice, Inbred C57BL D009389:Neovascularization, Pathologic D019899:Paracrine Communication D011379:Prognosis D011972:Receptor, Insulin D015854:Up-Regulation D001749:Urinary Bladder Neoplasms
insulin receptor bladder cancer angiogenesis insulin-like growth factor 2 tumour hypoxia vascular endothelium