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Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP)

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/68863

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)

Submitter: 三田村 卓

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