PURPOSE: Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches. EXPERIMENTAL DESIGN: The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma. RESULTS: EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the anti-apoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murine tumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell division, apoptosis in tumor tissue, and decreased microvascular density. CONCLUSIONS: EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.
PURPOSE:Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches. EXPERIMENTAL DESIGN: The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma. RESULTS:EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the anti-apoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murinetumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell division, apoptosis in tumor tissue, and decreased microvascular density. CONCLUSIONS:EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.
Authors: Whitney A Spannuth; Lingegowda S Mangala; Rebecca L Stone; Amy R Carroll; Masato Nishimura; Mian M K Shahzad; Sun-Joo Lee; Myrthala Moreno-Smith; Alpa M Nick; Ren Liu; Nicholas B Jennings; Yvonne G Lin; William M Merritt; Robert L Coleman; Pablo E Vivas-Mejia; Yue Zhou; Valery Krasnoperov; Gabriel Lopez-Berestein; Parkash S Gill; Anil K Sood Journal: Mol Cancer Ther Date: 2010-08-03 Impact factor: 6.261
Authors: Wen-Bin Ou; Christopher Hubert; Joseph M Corson; Raphael Bueno; Daniel L Flynn; David J Sugarbaker; Jonathan A Fletcher Journal: Neoplasia Date: 2011-01 Impact factor: 5.715
Authors: Ren Liu; Benjamin D Ferguson; Yue Zhou; Kranthi Naga; Ravi Salgia; Parkash S Gill; Valery Krasnoperov Journal: BMC Cancer Date: 2013-05-30 Impact factor: 4.430
Authors: Benjamin D Ferguson; Ren Liu; Cleo E Rolle; Yi-Hung Carol Tan; Valery Krasnoperov; Rajani Kanteti; Maria S Tretiakova; Gustavo M Cervantes; Rifat Hasina; Robyn D Hseu; A John Iafrate; Theodore Karrison; Mark K Ferguson; Aliya N Husain; Leonardo Faoro; Everett E Vokes; Parkash S Gill; Ravi Salgia Journal: PLoS One Date: 2013-07-02 Impact factor: 3.240