TY - JOUR
T1 - Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways
AU - Previdi, Sara
AU - Maroni, Paola
AU - Matteucci, Emanuela
AU - Broggini, Massimo
AU - Bendinelli, Paola
AU - Desiderio, Maria Alfonsina
PY - 2010/6
Y1 - 2010/6
N2 - 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 β-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 β-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and β-catenin-TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporter TOPFLASH (containing multiple TCF/LEF-consensus sites) was measured, as index of β-catenin functionality. In 1833 cells, human and mouse HGF increased Met and β-catenin tyrosine phosphorylation and expression in nuclear and perinuclear compartments, β-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 β-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/β-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.
AB - 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 β-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 β-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and β-catenin-TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporter TOPFLASH (containing multiple TCF/LEF-consensus sites) was measured, as index of β-catenin functionality. In 1833 cells, human and mouse HGF increased Met and β-catenin tyrosine phosphorylation and expression in nuclear and perinuclear compartments, β-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 β-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/β-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.
KW - β-Catenin
KW - Bone-breast cancer metastases
KW - HGF
KW - Met receptor
KW - Tumour microenvironment
UR - http://www.scopus.com/inward/record.url?scp=77952581424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952581424&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2010.02.036
DO - 10.1016/j.ejca.2010.02.036
M3 - Article
C2 - 20350802
AN - SCOPUS:77952581424
VL - 46
SP - 1679
EP - 1691
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 9
ER -