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.
Highlights
Within the prostate epithelium, tissue homeostasis is mediated by stem cells residing in the basal glandular epithelium [1]
Various membranous markers are differentially expressed in stem and differentiated cells in benign rodent and human prostate epithelium including Sca-1+, a6-integrin/CD49f+, a2-integrin/CD49b+, CD133+, CD117+, CD44+ and CD242 [2,3,4,5,6,7,8,9]
Phenotypic and biological characteristics contributed to stem cells can be gained, when more differentiated cells undergo epithelial-mesenchymal transition (EMT) either by forced depression of E-cadherin or by factors secreted by the micro-environment such as Hepatocyte Growth Factor (HGF) [15,16]
Summary
Tissue homeostasis is mediated by stem cells residing in the basal glandular epithelium [1]. CD44+/CD242 cells isolated from prostate cancer cell lines demonstrate high tumour-forming potential in vivo [4] In spite of their apparent variability in clonogenic and tumour-initiating potential, the mutual relation between immature and differentiated cells is still poorly understood. In correspondence to their relation in normal tissues, a strict hierarchic relation between so-called cancer stem cells (CSC’s) and differentiated cells has been postulated [12,13,14]. Since its exact nature and relation with other cell types are still controversial, we refer to the cell population displaying stem cell characteristics as stem-like cells
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