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

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Title
Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP)
Author(s)
T Mitamura; S Pradeep; M McGuire; S Y Wu; S Ma; H Hatakeyama; Y A Lyons; T Hisamatsu; Kyung Hee Noh; A Villar-Prados; X Chen; C Ivan; C Rodriguez-Aguayo; W Hu; G Lopez-Berestein; R L Coleman; A K Sood
Bibliographic Citation
Oncogene, vol. 37, no. 6, pp. 722-731
Publication Year
2018
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
ISSN
0950-9232
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/onc.2017.348
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
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