AIMS: In osteosarcoma patients the development of metastases, often to the lungs, is the most frequent cause of death. The aim of this study was to elucidate the molecular mechanisms governing osteosarcoma development and dissemination and, thereby, to identify possible novel drug targets for improved treatment. METHODS AND RESULTS: Osteosarcoma samples were characterized using genome-wide microarrays: increased expression of the EphA2 receptor and its ligand EFNA1 was detected. In addition, increased expression of EFNB1, EFNB3 and EphA3 was suggested. Immunohistochemistry revealed an absence of EphA2 in normal bone, and de novo expression in osteosarcomas. EFNA1 was expressed in normal bone, but was significantly elevated in tumours. Further in vitro investigations on the functional role of EphA2 and EFNA1 showed that EFNA1 ligand binding induced increased tyrosine phosphorylation, receptor degradation and downstream mitogen-activated protein kinase (MAPK) activation. Interference with the MAPK pathway unravelled a potential autoregulatory loop governing mainly EFNA1 expression via the same pathway. CONCLUSION: Upregulation and de novo expression of ephrins in osteosarcomas are involved in oncogenic signalling and thus might stimulate osteosarcoma metastasis.
AIMS: In osteosarcomapatients the development of metastases, often to the lungs, is the most frequent cause of death. The aim of this study was to elucidate the molecular mechanisms governing osteosarcoma development and dissemination and, thereby, to identify possible novel drug targets for improved treatment. METHODS AND RESULTS:Osteosarcoma samples were characterized using genome-wide microarrays: increased expression of the EphA2 receptor and its ligand EFNA1 was detected. In addition, increased expression of EFNB1, EFNB3 and EphA3 was suggested. Immunohistochemistry revealed an absence of EphA2 in normal bone, and de novo expression in osteosarcomas. EFNA1 was expressed in normal bone, but was significantly elevated in tumours. Further in vitro investigations on the functional role of EphA2 and EFNA1 showed that EFNA1 ligand binding induced increased tyrosine phosphorylation, receptor degradation and downstream mitogen-activated protein kinase (MAPK) activation. Interference with the MAPK pathway unravelled a potential autoregulatory loop governing mainly EFNA1 expression via the same pathway. CONCLUSION: Upregulation and de novo expression of ephrins in osteosarcomas are involved in oncogenic signalling and thus might stimulate osteosarcoma metastasis.
Authors: Arantzazu Alfranca; Lucia Martinez-Cruzado; Juan Tornin; Ander Abarrategi; Teresa Amaral; Enrique de Alava; Pablo Menendez; Javier Garcia-Castro; Rene Rodriguez Journal: Cell Mol Life Sci Date: 2015-05-03 Impact factor: 9.261
Authors: Vaibhav Saini; Curtis D Hose; Anne Monks; Kunio Nagashima; Bingnan Han; Dianne L Newton; Angelena Millione; Jalpa Shah; Melinda G Hollingshead; Karen M Hite; Mark W Burkett; Rene M Delosh; Thomas E Silvers; Dominic A Scudiero; Robert H Shoemaker Journal: PLoS One Date: 2012-08-03 Impact factor: 3.240
Authors: A N Rettew; E D Young; D C Lev; E S Kleinerman; F W Abdul-Karim; P J Getty; E M Greenfield Journal: Oncogenesis Date: 2012-11-19 Impact factor: 7.485
Authors: Janne Nordberg; John Patrick Mpindi; Kristiina Iljin; Arto Tapio Pulliainen; Markku Kallajoki; Olli Kallioniemi; Klaus Elenius; Varpu Elenius Journal: PLoS One Date: 2012-12-05 Impact factor: 3.240