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Up-Regulation of EphB4 in Mesothelioma and Its Biological Significance

Authors' Affiliations: Departments of ¹ Medicine, ² Pathology, ³ Surgery, and ⁴ Obstetrics and Gynecology, Keck School of Medicine, University of Southern California and ⁵ VasGene Therapeutics, Inc., Los Angeles, California

Requests for reprints: Parkash S. Gill, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, NOR 6332, Los Angeles, CA 90033-9172. Phone: 323-865-3909; Fax: 323-865-0092; E-mail: parkashg{at}usc.edu.

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 antiapoptotic 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.

Key Words: Tyrosine kinase • cell growth • migration • invasion

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