Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process.
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 232+/-43 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 microM of the SDF-1 inhibitor T140. However, 10 microM 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.
Hart
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CA
PromPT Genito-Urinary Cancer Research, Cancer Research UK Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
Brown
M
M
Bagley
S
S
Sharrard
M
M
Clarke
N W
NW
D001854:Bone Marrow Cells / Q000502:physiology*; D002450:Cell Communication; D002465:Cell Movement; D018920:Coculture Techniques; D004727:Endothelium / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D008297:Male; D018613:Microscopy, Confocal; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000494:pharmacology; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology; D014407:Tumor Cells, Cultured
D009842:Oligopeptides; D019718:Receptors, CXCR4; C116977:T140 peptide