Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene 2018 Feb 08;37(6):722-731
Date
10/24/2017Pubmed ID
29059175Pubmed Central ID
PMC6040890DOI
10.1038/onc.2017.348Scopus ID
2-s2.0-85041519424 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
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 AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Angiogenesis InhibitorsAnimals
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