To clarify the reciprocal interaction between human-breast cancer metastatic cells and bone microenvironment, we studied the influence of HGF/Met system on a proposed-prognostic marker of aggressiveness, the b-catenin/Wnt pathway. For in vitro and in vivo experiments we used 1833-bone metastatic clone, derived from human-MDA-MB231 cells. In osteolytic bone metastases and in metastatic cells, Met was expressed in nuclei and at plasma membrane, and abnormally co-localised at nuclear level with b-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and bcatenin- TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporterTOPFLASH (containing multiple TCF/LEF-consensus sites) wasmeasured, as index of b-catenin functionality. In 1833 cells,humanand mouseHGF increased Met and b-catenin tyrosine phosphorylation and expression in nuclearand perinuclear compartments, b-catenin nuclear translocation via Kank and TOPFLASH transactivation. Human HGF was autocrine/intracrine in bone metastasis, and mouse HGF originating from the adjacent host-bone marrow, was found inside the metastatic nuclei. Parental MDA-MB231 cell nuclei did not show functional b-catenin, for TCF-transactivating activity, and the regulation by HGF. Our study highlighted the importance of the metastasis-stroma interaction in human-breast cancer metastatisation and first identified the HGF/nuclear Met/phospho-c-Src/b-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.
|Titolo:||Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways|
BENDINELLI, PAOLA (Penultimo)
DESIDERIO, MARIA ALFONSINA (Ultimo)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||27-mar-2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejca.2010.02.036|
|Appare nelle tipologie:||01 - Articolo su periodico|