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Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP)
Title: | Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP) |
Other Titles: | Proangiogenic effects of MSMP in ovarian cancer |
Authors: | Mitamura, T.1 Browse this author | Pradeep, S.2 Browse this author | McGuire, M.3 Browse this author | Wu, S Y4 Browse this author | Ma, S.5 Browse this author | Hatakeyama, H.6 Browse this author | Lyons, Y A7 Browse this author | Hisamatsu, T.8 Browse this author | Noh, K.9 Browse this author | Villar-Prados, A10 Browse this author | Chen, X.11 Browse this author | Ivan, C.12 Browse this author | Rodriguez-Aguayo, C13 Browse this author | Hu, W.14 Browse this author | Lopez-Berestein, G15 Browse this author | Coleman, R L16 Browse this author | Sood, A K17 Browse this author |
Authors(alt): | Mitamura, Takashi1 | Pradeep, Sunila2 | McGuire, Michael3 | Wu, Sherry4 | Ma, Shaolin5 | Hatakeyama, Hiroto6 | Lyons, Yasmin A.7 | Hisamatsu, Takeshi8 | Noh, Kyunghee9 | Villar-Prados, Alejandro10 | Chen, Xiuhui11 | Ivan, Cristina12 | Rodriguez-Aguayo, Cristian13 | Hu, Wei14 | Lopez-Berestein, Gabriel15 | Coleman, Robert L.16 | Sood, Anil K.17 |
Keywords: | MSMP | CCR2 | anti-VEGF antibody | human ovarian cancer | bevacizumab | adaptive resistance |
Issue Date: | 8-Feb-2018 |
Publisher: | Nature Publishing Group |
Journal Title: | Oncogene |
Volume: | 37 |
Issue: | 6 |
Start Page: | 722 |
End Page: | 731 |
Publisher DOI: | 10.1038/onc.2017.348 |
Abstract: | Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors. MSMP secretion from cancer cells was induced by hypoxia, triggering MAPK signaling in endothelial cells to promote tube formation in vitro. Recruitment of the transcriptional repressor CCCTC-binding factor (CTCF) to the MSMP enhancer region was decreased by histone acetylation under hypoxic conditions in cancer cells. MSMP siRNA, delivered in vivo using the DOPC nanoliposomes, restored tumor sensitivity to anti-VEGF therapy. In ovarian cancer patients treated with bevacizumab, serum MSMP concentration increased significantly only in non-responders. These findings imply that MSMP inhibition combined with the use of antiangiogenesis drugs may be a new strategy to overcome resistance to antiangiogenesis therapy. |
Type: | article (author version) |
URI: | http://hdl.handle.net/2115/68863 |
Appears in Collections: | 北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 三田村 卓
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