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: Geert J L H van Leenders, Rajesh Sookhlall, Wilma J Teubel, Corrina M A de Ridder, Suzanne Reneman, Andrea Sacchetti, Kees J Vissers, Wytske van Weerden, Guido Jenster
• Journal: PloS one (PLoS One) Vol. 6 Issue 11 Pg. e26753 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22110593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alpha2
• Integrin alpha6
• Receptors, Notch
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• HEK293 Cells
• Hepatocyte Growth Factor (pharmacology)
• Humans
• Integrin alpha2 (metabolism)
• Integrin alpha6 (metabolism)
• Male
• Mice
• Neoplasm Invasiveness
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Phenotype
• Prostatectomy
• Prostatic Neoplasms (genetics, metabolism, pathology, surgery)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-met (deficiency, genetics, metabolism)
• Receptors, Notch (metabolism)
• Reproducibility of Results
• Signal Transduction (drug effects)