Activation of c-MET induces a stem-like phenotype in human prostate cancer

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...

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Published in:	PloS one 2011-11, Vol.6 (11), p.e26753
Main Authors:	van Leenders, Geert J L H, Sookhlall, Rajesh, Teubel, Wilma J, de Ridder, Corrina M A, Reneman, Suzanne, Sacchetti, Andrea, Vissers, Kees J, van Weerden, Wytske, Jenster, Guido
Format:	Article
Language:	eng
Subjects:	Allografts Analysis Animal tissues Animals Biological effects Biology c-Met protein Cancer CD44 antigen Cell activation Cell adhesion & migration Cell Line, Tumor Down-regulation Flow cytometry Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Genetic aspects Growth factors HEK293 Cells Hepatocyte growth factor Hepatocyte Growth Factor - pharmacology Humans Infiltration Integrin alpha2 - metabolism Integrin alpha6 - metabolism Invasiveness Kinases Male Malignancy Mediation Medical research Medicine Metastases Mice Muridae Neoplasm Invasiveness Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Notch protein Pathology Phenotype Prostate Prostate cancer Prostatectomy Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Prostatic Neoplasms - surgery Protein Transport - drug effects Proto-Oncogene Proteins c-met - deficiency Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Receptors, Notch - metabolism Reproducibility of Results Rodents Signal Transduction - drug effects Sox9 protein Stem cell transplantation Stem cells Tumors Urology Western blotting
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Summary:	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.
ISSN:	1932-6203 1932-6203