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

• Mitamura, T.

• Pradeep, S.

• McGuire, M.

• Wu, S Y

• Ma, S.

• Hatakeyama, H.

• Lyons, Y A

• Hisamatsu, T.

• Noh, K.

• Villar-Prados, A

• Chen, X.

• Ivan, C.

• Rodriguez-Aguayo, C

• Hu, W.

• Lopez-Berestein, G

• Coleman, R L

• Sood, A K

書誌事項

タイトル別名

• Proangiogenic effects of MSMP in ovarian cancer

抄録

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.

収録刊行物

• Oncogene

  Oncogene 37 (6), 722-731, 2018-02-08

  Nature Publishing Group

キーワード

• MSMP
• CCR2
• anti-VEGF antibody
• human ovarian cancer
• bevacizumab
• adaptive resistance

詳細情報

• CRID: 1050282814001941632
• NII論文ID: 120006456412
• HANDLE: 2115/68863
• ISSN: 09509232
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles