Medical College of Wisconsin
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Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene 2018 Feb 08;37(6):722-731

Date

10/24/2017

Pubmed ID

29059175

Pubmed Central ID

PMC6040890

DOI

10.1038/onc.2017.348

Scopus ID

2-s2.0-85041519424 (requires institutional sign-in at Scopus site)   41 Citations

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.

Author List

Mitamura T, Pradeep S, McGuire M, Wu SY, Ma S, Hatakeyama H, Lyons YA, Hisamatsu T, Noh K, Villar-Prados A, Chen X, Ivan C, Rodriguez-Aguayo C, Hu W, Lopez-Berestein G, Coleman RL, Sood AK

Author

Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiogenesis Inhibitors
Animals
Apoptosis
Bevacizumab
Biomarkers, Tumor
Cell Hypoxia
Cell Proliferation
Drug Resistance, Neoplasm
Fallopian Tube Neoplasms
Female
Follow-Up Studies
Humans
Male
Mice
Mice, Nude
Neoplasm Proteins
Neovascularization, Pathologic
Peritoneal Neoplasms
Prognosis
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A
Xenograft Model Antitumor Assays