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.

SOX9 drives WNT pathway activation in prostate cancer

“…Peak calling by the model-based analysis for (-1 kb to +1 kb; -2 kb to +2 kb; -3 kb to +3 kb of TSSs); downstream elements (-1 kb to +1 kb; -2 kb to +2 kb; -3 kb to +3 kb of transcription stop sites); gene body ( 5′UTR, 3′UTR the strongest correlation in both the TCGA and MSKCC data sets, which may in part reflect the reported NOTCH regulation of SOX9 expression (29)(30)(31). The correlation with MAPK signaling may also reflect the reported SOX9 induction through activation of receptor tyrosine kinases, including FGFRs and MET (16,32).…”

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

“…23 The inhibition of c-Met/hepatocyte growth factor (HGF) signaling was previously shown to decrease the growth and metastasis formation in melanoma. 24 Its activation was recognized to induce a stem-like phenotype in prostate cancer 25,26 and support stem-like phenotype in glioblastoma. 27 Therefore, we decided to test whether the targeting of this signaling axis in combination with the cytotoxic treatment resulted in a long-term anti-tumor effect.…”

Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

“…Xenograft and in vitro data showed that MET expression increases following androgen deprivation (10,11). HGF further induces cell invasion associated with stem cell features (12). In these models, MET knockdown leads to inhibited growth (13,14).…”