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[Cancer Research 62, 2942-2950, May 15, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Expression of the Type 1 Insulin-like Growth Factor Receptor Is Up-Regulated in Primary Prostate Cancer and Commonly Persists in Metastatic Disease1

Giles O. Hellawell, Gareth D. H. Turner, David R. Davies, Richard Poulsom, Simon F. Brewster and Valentine M. Macaulay2

Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS [G. O. H., V. M. M.]; Department of Cellular Pathology, John Radcliffe Hospital, Oxford OX3 9DU [G. D. H. T., D. R. D.]; Histopathology Unit, Cancer Research UK Laboratories, Lincoln’s Inn Fields, London WC2A 3PX [R. P.]; and Department of Urology, Churchill Hospital, Oxford OX3 7LJ [G. O. H., S. F. B.], United Kingdom

The type 1 insulin-like growth factor receptor (IGF1R) mediates tumor cellgrowth, adhesion, and protection from apoptosis. High plasma IGF-I levels predispose to prostate cancer, but there is no consensus regarding IGF1R expression in primary and metastatic prostate cancer. Recent studies in a human cell line and a mouse model suggest that metastatic prostate cancer cell detachment may be favored by impairing cadherin function via loss of expression of insulin receptor substrate-1 (IRS-1), the principal IGF1R docking molecule. This may be accompanied by PTEN mutation, reactivating a key antiapoptotic pathway, and by IGF1R down-regulation to prevent Shc-mediated differentiation. We studied IGF1R expression in 54 samples of primary prostate tissue including 44 archival and 10 prospectively collected biopsies. We performed semiquantitative immunostaining for the IGF1R, IRS-1, and PTEN, and in situ hybridization for IGF1R. The IGF1R was significantly up-regulated at the protein and mRNA level in primary prostate cancer compared with benign prostatic epithelium. There was a trend toward increased expression of IRS-1 in the malignant biopsies. We also measured IGF1R, IRS-1, and PTEN expression in 12 paired biopsies of primary prostate cancer and subsequent bone metastases. In four cases, IGF1R and IRS-1 levels were lower in the metastases than in the primary tumors. Three of these metastases also lacked significant PTEN staining, compatible with findings in the model systems described above. However, this pattern was relatively uncommon, and 8 of 12 cases expressed detectable IGF1R and IRS-1 in both primary and metastatic biopsies. These findings challenge earlier reports of IGF1R down-regulation in metastatic disease and reinforce the importance of the IGF1R in prostate cancer biology.




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