title: Activation of c-MET induces a stem-like phenotype in human prostate cancer.
abstract: 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.
authors: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands. g.vanleenders@erasmusmc.nl
authors: Geert J L H
authors: GJ
authors: van Leenders
authors: Rajesh
authors: R
authors: Sookhlall
authors: Wilma J
authors: WJ
authors: Teubel
authors: Corrina M A
authors: CM
authors: de Ridder
authors: Suzanne
authors: S
authors: Reneman
authors: Andrea
authors: A
authors: Sacchetti
authors: Kees J
authors: KJ
authors: Vissers
authors: Wytske
authors: W
authors: van Weerden
authors: Guido
authors: G
authors: Jenster
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D021381:Protein Transport / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D039421:Integrin alpha2; D039503:Integrin alpha6; D051880:Receptors, Notch; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met