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22110593
Activation of c-MET induces a stem-like phenotype in human prostate cancer.

PLoS One, 2011;6(11):e26753.

van Leenders GJ[1], Sookhlall R, Teubel WJ, de Ridder CM, Reneman S, Sacchetti A, Vissers KJ, van Weerden W, Jenster G

Affiliations

PMID: 22110593DOI: 10.1371/journal.pone.0026753

Impact factor: 3.752

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.
MeSH terms
Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; Hepatocyte Growth Factor; Humans; Integrin alpha2; Integrin alpha6; Male; Mice; Neoplasm Invasiveness; Neoplastic Stem Cells; Phenotype; Prostatectomy; Prostatic Neoplasms; Protein Transport; Proto-Oncogene Proteins c-met; Receptors, Notch; Reproducibility of Results; Signal Transduction
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