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

• Published in: Oncogene Vol. 37; no. 6; pp. 722 - 731
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-02-2018; Nature Publishing Group
• Subjects: 631/67/1517/1709; 631/67/2328; Acetylation; Angiogenesis Inhibitors - pharmacology; Animals; Apoptosis; Bevacizumab; Bevacizumab - pharmacology; Biomarkers, Tumor; Cancer therapies; Carcinoma, Ovarian Epithelial - drug therapy; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; Care and treatment; Cell Biology; Cell Hypoxia; Cell Proliferation; Cellular proteins; Development and progression; Drug resistance; Drug Resistance, Neoplasm; Endothelial cells; Fallopian Tube Neoplasms - drug therapy; Fallopian Tube Neoplasms - metabolism; Fallopian Tube Neoplasms - pathology; Female; Follow-Up Studies; Gene expression; Genetic aspects; Genomic analysis; Health aspects; Human Genetics; Humans; Hypoxia; Internal Medicine; Male; MAP kinase; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Nude; Monoclonal antibodies; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization; Neovascularization, Pathologic; Oncology; original-article; Ovarian cancer; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - pathology; Prognosis; Prostate; Secretion; siRNA; Targeted cancer therapy; Tumor Cells, Cultured; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.348

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.