Abstract
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.
Highlights
The dynamic plasticity of metastases is largely dependent on epigenetic mechanisms and is responsible for opportunistic adaptations, in the absence of DNA sequence modifications.[1,2,3] Because of the changes of microenvironmental context, metastases need to adapt to the external cues during the various steps of the process from invasion/ dissemination until outgrowth at the secondary site.[4]
Bone marrow is hospitable for breast carcinoma metastases,[12] and the microenvironment stimuli may determine the transcription factors and the signaling pathways activated for the epithelialmesenchymal transition (EMT)-MET switch in metastatic cells.[4,13,14]
For the first time we investigated the methylation-dependent control of the couple Hepatocyte growth factor (HGF) ligandMet receptor in bone metastases from breast carcinoma
Summary
The dynamic plasticity of metastases is largely dependent on epigenetic mechanisms and is responsible for opportunistic adaptations, in the absence of DNA sequence modifications.[1,2,3] Because of the changes of microenvironmental context, metastases need to adapt to the external cues during the various steps of the process from invasion/ dissemination until outgrowth at the secondary site.[4]. EMT promotes invasion of primary tumors like breast carcinoma, and dissemination of metastatic cells, while MET contributes to the establishment of distant skeletal metastases.[4,5] numerous unresolved problems regarding the molecular mechanisms underlying metastasis phenotype still remain.[9] Intermediate phenotypic changes between the two end points of epithelium and mesenchyme occur in human carcinomas, each of which is characterized by different patterns of markers and signaling pathways.[5] The growth factor network contributes to a metastable or hybrid phenotype in bone metastasis,[4] reinforcing the concept of dynamic epithelial-mesenchymal plasticity (EMP).[2] Hepatocyte growth factor (HGF) confers to metastatic cells anoikis resistance and survival together with stem-cell characteristics through Wnt-pathway, typical of EMT phenotype, but. Bone marrow is hospitable for breast carcinoma metastases,[12] and the microenvironment stimuli may determine the transcription factors and the signaling pathways activated for the EMT-MET switch in metastatic cells.[4,13,14]. HGF downregulates the nuclear co-factor Wwox leading to phosphoTwist 1 access to nuclei, and the activation of Twist-transcription factor: when Wwox accedes into nuclei, unphosphorylated Twist is extruded ending its function
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