The type 1 insulin‐like growth factor receptor is over‐expressed in bladder cancer

Abstract

OBJECTIVE To analyse bladder cancer biopsies and investigate the pattern of expression of the type 1 insulin‐like growth factor receptor (IGF1R), a receptor tyrosine kinase that mediates tumour cell proliferation, motility and protection from apoptosis. MATERIALS AND METHODS Formalin‐fixed specimens of bladder cancer (40 whole‐mount, 80 cores on a tumour microarray) and normal bladder (15 samples) were stained immunohistochemically for the IGF1R. The IGF1R expression was also measured by quantitative reverse transcription‐polymerase chain reaction (Q‐RT‐PCR) on RNA extracted from fresh frozen bladder cancers (61) and benign bladder (12). RESULTS Of the 15 samples of normal bladder, 14 showed negligible (1+) or light (2+) IGF1R immunostaining. By contrast moderate (3+) or heavy (4+) staining for IGF1R was detected in 89 (74%) of the 120 samples of malignant urothelium. Q‐RT‐PCR showed significantly higher levels of steady‐state IGF1R mRNA in tumours (all cases, Ta–T4) than in normal bladder (P < 0.05), indicating up‐regulation at the transcriptional level. This difference was particularly evident when comparing normal urothelium with superficial (Ta–T1) or invasive (T2–4) tumours; only the latter showed significant IGF1R over‐expression at the RNA level (P < 0.05 vs normal bladder). CONCLUSION The IGF1R is up‐regulated in bladder cancer compared with non‐malignant bladder, and might contribute to a propensity for invasion.

The Insulin-Like Growth Factor Receptor I Promotes Motility and Invasion of Bladder Cancer Cells through Akt- and Mitogen-Activated Protein Kinase-Dependent Activation of Paxillin

“…There are currently approximately 12 anti-IGF-IR therapeutic agents undergoing clinical evaluation, including blocking antibodies and tyrosine kinase inhibitors (small molecules). The complete list of anti-IGF-IR therapeutics is summarized in a recent review by Chitnis et al 16 A definite role for the IGF-IR in transformation of urothelial cells is not clearly established, but Rochester et al 18 recently reported that the IGF-IR is up-regulated in bladder cancer tissues compared with nonmalignant tissue controls. They also showed by quantitative real-time poly- merase chain reaction (RT-PCR) that IGF-IR mRNA levels were significantly increased in invasive cancers compared with normal urothelium.…”

“…16,17 Whether the IGF-IR contributes to the transforming phenotype of urothelial cells has not been clearly established, but recent data suggest that the IGF-IR is overexpressed in bladder cancer. 18 In this study, using 5637 and T24 urothelial carcinomaderived cells, we established that activation of the IGF-IR plays a critical role in bladder cancer by promoting migration, wound healing, and invasion of cancer urothelial cells. We have also characterized the mechanism of action of the IGF-IR in cancer urothelial cells and showed that IGF-IR-dependent cell motility and invasion required the activation of the Akt and MAPK pathway and Akt-and Extracellular-signal-related kinase 1 (ERK)-dependent activation of paxillin.…”

“…Recent work by Rochester et al 18 has demonstrated by quantitative RT-PCR that IGF-IR mRNA levels were significantly increased in invasive bladder cancer tissues compared with normal urothelium. We determined by immunohistochemical analysis the level of IGF-IR expression in normal and invasive bladder cancer sections.…”

Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization

“…Although it is difficult to directly compare between cell lines due to karyotypic variability, it was surprising that IGF-II expression levels were lowest in the mesenchymal IGF-II LOI TCCSUP cell line, with higher levels being observed in the epithelial IGF-II MOI RT4 cell line. The IGF-I receptor has been shown to be significantly up-regulated in superficial and invasive UCB compared with normal urothelium (33), with a close relationship existing between IGF-I receptor and stage, grade, and recurrence (34). Reinforcing the suggestion that IGF-II LOI may effect IGF-I receptor expression (10), the undifferentiated TCCSUP IGF-II LOI cell line has been shown to have significantly more IGF-I receptor than the differentiated RT4 IGF-II MOI cell line (35).…”

miR-143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling

“…Moreover, miR-143 levels in human blood and tumor tissues are associated with cancer occurrence, metastasis and drug resistance (15), indicating the potential of miR-143 as a biomarker. The role of IGF-1R in cancerous transformation of urothelial cells is not well established, but previous studies have demonstrated that IGF-1R is overexpressed in bladder cancer (16). Given the interrelationship between IGF-1R and miR-143, we speculate that downregulation of miR-143 in bladder cancer may be involved in tumor development via the activation of IGF-1R and other downstream pathways (e.g.…”