title: Wnt2 as a new therapeutic target in malignant pleural mesothelioma.
abstract: Malignant mesothelioma of the pleura (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. A better understanding of its pathogenesis is essential to developing alternative therapeutic strategies. We previously demonstrated that the Wnt signaling pathway is activated in MPM through the overexpression of disheveled proteins. To extend our knowledge of Wnt signaling activation in MPM, we performed Wnt-specific microarrays in normal pleura and MPM. We found that the most common event in MPM was the upregulation of Wnt2. We inhibited Wnt2 by siRNA and a monoclonal anti-Wnt2 antibody and analyzed their effects on apoptosis and downstream signaling effectors. We then assessed the antiproliferative effects of the Wnt2 antibody and Alimta, one of the current standard treatments of MPM. We confirmed Wnt2 overexpression at the mRNA and protein level in MPM cell lines and tissues. We then demonstrated that inhibition of Wnt2 by siRNA or a monoclonal antibody induces programmed cell death in MPM cells. We next analyzed the effects of the anti-Wnt2 antibody and of Alimta on MPM cell proliferation. We found that although Wnt2 antibody by itself had less antiproliferative potency than Alimta, the two in combination had substantially more activity than Alimta alone. We thus propose that inhibition of Wnt2 is of therapeutic interest in the development of more effective treatments for MPM.
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.forename: Liang
authors.initials: L
authors.lastname: You
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: Sarah
authors.initials: S
authors.lastname: Twogood
authors.forename: Amie Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Noemi
authors.initials: N
authors.lastname: Reguart
authors.forename: Sonny
authors.initials: S
authors.lastname: Batra
authors.forename: Iwao
authors.initials: I
authors.lastname: Mikami
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D020869:Gene Expression Profiling; D006801:Humans; D008654:Mesothelioma / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010997:Pleural Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering