title: Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90.
abstract: BACKGROUND
  Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix;
  
  
  METHODS
  We isolated CAF from prostate cancer patients of Gleason Score 6-10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay;
  
  
  RESULTS
  HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF;
  
  
  CONCLUSIONS
  We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.
authors: Medical Research Council, Centre for Reproductive Health, The Queens's Medical Research Institute, Edinburgh EH16 4TJ, UK. dr.a.henke@gmail.com.
authors: Alex
authors: A
authors: Henke
authors: Department of Urologic Surgery and Cancer Biology, Vanderbilt University, Nashville, TN 37232-2765, USA. ofrancocoronel@northshore.org.
authors: Omar E
authors: OE
authors: Franco
authors: Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. grant.stewart@ed.ac.uk.
authors: Grant D
authors: GD
authors: Stewart
authors: Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. ariddick@doctors.org.uk.
authors: Antony C P
authors: AC
authors: Riddick
authors: Division of Pathology, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. e.katz@dundee.ac.uk.
authors: Elad
authors: E
authors: Katz
authors: Department of Urologic Surgery and Cancer Biology, Vanderbilt University, Nashville, TN 37232-2765, USA. SHayward@northshore.org.
authors: Simon W
authors: SW
authors: Hayward
authors: Division of Urology, Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada. axel.thomson@mcgill.ca.
authors: Axel A
authors: AA
authors: Thomson
keywords: cancer associated fibroblast; contractility; heat shock protein; prostate cancer