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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3215704?pdf=render |
| _version_ | 1818931612080930816 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Geert J L H van Leenders |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T04:19:21Z |
| format | Article |
| id | doaj.art-431f6bd87c96437da1fa61c2a6d7647f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T04:19:21Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-431f6bd87c96437da1fa61c2a6d7647f2022-12-21T19:53:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01611e2675310.1371/journal.pone.0026753Activation of c-MET induces a stem-like phenotype in human prostate cancer.Geert J L H van LeendersRajesh SookhlallWilma J TeubelCorrina M A de RidderSuzanne RenemanAndrea SacchettiKees J VissersWytske van WeerdenGuido JensterProstate 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.http://europepmc.org/articles/PMC3215704?pdf=render |
| spellingShingle | 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 Activation of c-MET induces a stem-like phenotype in human prostate cancer. PLoS ONE |
| title | Activation of c-MET induces a stem-like phenotype in human prostate cancer. |
| title_full | Activation of c-MET induces a stem-like phenotype in human prostate cancer. |
| title_fullStr | Activation of c-MET induces a stem-like phenotype in human prostate cancer. |
| title_full_unstemmed | Activation of c-MET induces a stem-like phenotype in human prostate cancer. |
| title_short | Activation of c-MET induces a stem-like phenotype in human prostate cancer. |
| title_sort | activation of c met induces a stem like phenotype in human prostate cancer |
| url | http://europepmc.org/articles/PMC3215704?pdf=render |
| work_keys_str_mv | AT geertjlhvanleenders activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT rajeshsookhlall activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT wilmajteubel activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT corrinamaderidder activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT suzannereneman activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT andreasacchetti activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT keesjvissers activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT wytskevanweerden activationofcmetinducesastemlikephenotypeinhumanprostatecancer AT guidojenster activationofcmetinducesastemlikephenotypeinhumanprostatecancer |