Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model) or represent an inducible population emerging upon appropriate stimulation of differentiated cells.
Hepatocyte Growth Factor (
HGF) receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in
prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145
prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'). We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its
ligands Jagged-1 and Delta-like 4. Small molecules
SU11274 and
PHA665752 targeting c-MET activity were both able to block the molecular and
biologic effects of HGF. Knock-down of c-MET by
shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in
prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in
prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this
malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.