1. ¹PromPT Genito-Urinary Cancer Research, Cancer Research UK Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK
2. ²Advanced Imaging Facility, Cancer Research UK, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK
3. ³YCR Cancer Research Unit, Biology Department, The University of York, York YO10 5YW, UK
4. ⁴Department of Urology, Salford Royal Hospital, Eccles Old Road, Salford, UK
5. ⁵Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK

Correspondence: Dr M Brown, E-mail: mbrown@picr.man.ac.uk

Received 14 October 2004; Revised 9 November 2004; Accepted 19 November 2004; Published online 25 January 2005.

Abstract

Prostate cancer has a predilection to metastasise to the bone marrow stroma (BMS) by an as yet uncharacterised mechanism. We have defined a series of coculture models of invasion, which simulate the blood/BMS boundary and allow the elucidation of the signalling and mechanics of trans-endothelial migration within the complex bone marrow environment. Confocal microscopy shows that prostate epithelial cells bind specifically to bone marrow endothelial-to-endothelial cell junctions and initiate endothelial cell retraction. Trans-endothelial migration proceeds via an epithelial cell pseudopodial process, with complete epithelial migration occurring after 23243 min. Stromal-derived factor-1 (SDF-1)/CXCR4 signalling induced PC-3 to invade across a basement membrane although the level of invasion was 3.5-fold less than invasion towards BMS (P=0.0007) or bone marrow endothelial cells (P=0.004). Maximal SDF-1 signalling of invasion was completely inhibited by 10 M of the SDF-1 inhibitor T140. However, 10 M T140 only reduced invasion towards BMS and bone marrow endothelial cells by 59% (P=0.001) and 29% (P=0.011), respectively. This study highlights the need to examine the potential roles of signalling molecules and/or inhibitors, not just in single-cell models but in coculture models that mimic the complex environment of the bone marrow.