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

Oncogene volume 37, pages 722–731 (2018)Cite this article

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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.

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Acknowledgements

SP is supported by a Foundation for Women’s Cancer grant and Ovarian Cancer Research Fund Alliance. SW is supported by Ovarian Cancer Research Fund Alliance, Foundation for Women’s Cancer, Texas Center for Cancer Nanomedicine, and Cancer Prevention and Research Institute of Texas training grants (RP101502 and RP101489, respectively). KN is supported by the Ovarian Cancer Research Fund Alliance (grant 292015) and KRIBB Research Initiative Program. TH is supported by Uehara Memorial Foundation Research Fellowships for Research Abroad. Portions of this work were supported by the National Institutes of Health grants (CA016672, CA109298, P50 CA083639, P50 CA098258 and UH3 TR000943), Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), American Cancer Society Research Professor Award, Blanton-Davis Ovarian Cancer Research Program, RGK Foundation and the Frank McGraw Memorial Chair in Cancer Research.

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Authors and Affiliations

  1. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T Mitamura, S Pradeep, M McGuire, S Y Wu, S Ma, H Hatakeyama, Y A Lyons, T Hisamatsu, K Noh, A Villar-Prados, X Chen, W Hu, R L Coleman & A K Sood

  2. Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    T Mitamura

  3. Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA

    S Pradeep

  4. Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Dajeon, Republic of Korea

    K Noh

  5. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Ivan, C Rodriguez-Aguayo, G Lopez-Berestein & A K Sood

  6. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Ivan, C Rodriguez-Aguayo & G Lopez-Berestein

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  1. T Mitamura
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Correspondence to A K Sood.

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Mitamura, T., Pradeep, S., McGuire, M. et al. Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene 37, 722–731 (2018). https://doi.org/10.1038/onc.2017.348

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