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Target Concepts:
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Query: UMLS:C0153690 (
bone metastases
)
6,382
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Breast cancer is one of the most common and devastating malignancies among women worldwide. Recent evidence suggests that malignant progression is also driven by processes involving the sphingolipid molecule sphingosine 1-phosphate (S1P) and its binding to cognate receptor subtypes on the cell surface. To investigate the effect of this interaction on the metastatic phenotype, we used the breast cancer cell line MDA-MB-231 and the sublines 4175 and 1833 derived from lung and
bone metastases
in nude mice, respectively. In both metastatic cell lines expression of the S1P
3
receptor was strongly upregulated compared to the parental cells and correlated with higher S1P-induced intracellular calcium ([Ca
2+
]
i
), higher cyclooxygenase (COX)-2 and microsomal prostaglandin (PG) E
2
synthase expression, and consequently with increased PGE
2
synthesis. PGE
2
synthesis was decreased by antagonists and siRNA against S1P
3
and S1P
2
. Moreover, in parental MDA-MB-231 cells overexpression of S1P
3
by cDNA transfection also increased PGE
2
synthesis, but only after treatment with the
DNA methyltransferase
inhibitor 5-aza-2-deoxycytidine, indicating reversible silencing of the COX-2 promoter. Functionally, the metastatic sublines showed enhanced migration and Matrigel invasion in adapted Boyden chamber assays, which further increased by S1P stimulation. This response was abrogated by either S1P
3
antagonism, COX-2 inhibition or PGE
2
receptor 2 (EP
2
) and 4 (EP
4
) antagonism, but not by S1P
2
antagonism. Our data demonstrate that in breast cancer cells overexpression of S1P
3
and its activation by S1P has pro-inflammatory and pro-metastatic potential by inducing COX-2 expression and PGE
2
signaling via EP
2
and EP
4
.
...
PMID:Upregulation of the S1P
3
receptor in metastatic breast cancer cells increases migration and invasion by induction of PGE
2
and EP
2
/EP
4
activation. 2761 30
Our translational research deals with the influence of microenvironment on the phenotype and colonization of
bone metastases
from breast carcinoma, and on pre-metastatic niche formation. The aim of the present study was to clarify the origin of hepatocyte growth factor (HGF), ligand of Met receptor, the control of the axis HGF/Met by DNA methylation, and its importance for the nexus supportive cells-metastatic cells and for metastasis outgrowth. In bone metastasis of the 1833-xenograft model,
DNA methyltransferase
blockade using the chemotherapic drug 5-aza-2'-deoxycytidine (decitabine) strongly reduced the expression of HGF/Met receptor axis and of E-cadherin, with decrease of metastasis wideness and osteolysis, prolonging mice survival. Thus, DNA methylation events acted as commanders of breast carcinoma cells metastatizing to bone influencing the epithelial phenotype. HGF emerged as a bone-marrow stimulus, and the exosomes seemed to furnish HGF to metastatic cells. In fact, decitabine treatment similarly affected some markers of these microvesicles and HGF, indicating that its supply to recipient cells was prevented. Notably, in bone metastasis the hypomethylation of HGF, Met and E-cadherin promoters did not appear responsible for their elevated expression, but we suggest the involvement of hypermethylated regulators and of Wwox oncosuppressor, the latter being affected by decitabine. Wwox expression increased under decitabine strongly localizing in nuclei of
bone metastases
. We hypothesize a role of Wwox in Met activity since in vitro Wwox overexpression downregulated the level of nuclear-Met protein fragment and Met stability, also under long exposure of 1833 cells to decitabine. HGF enhanced phosphoMet and the activity in nuclei, an effect partially prevented by decitabine. Altogether, the data indicated the importance to target the tumor microenvironment by blocking epigenetic mechanisms, which control critical events for colonization such as HGF/Met axis and Wwox, as therapy of bone metastasis.
...
PMID:Epigenetic regulation of HGF/Met receptor axis is critical for the outgrowth of bone metastasis from breast carcinoma. 2815 81
