Epigenetic therapy inhibits metastases by disrupting premetastatic niches View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-02-26

AUTHORS

Zhihao Lu, Jianling Zou, Shuang Li, Michael J. Topper, Yong Tao, Hao Zhang, Xi Jiao, Wenbing Xie, Xiangqian Kong, Michelle Vaz, Huili Li, Yi Cai, Limin Xia, Peng Huang, Kristen Rodgers, Beverly Lee, Joanne B. Riemer, Chi-Ping Day, Ray-Whay Chiu Yen, Ying Cui, Yujiao Wang, Yanni Wang, Weiqiang Zhang, Hariharan Easwaran, Alicia Hulbert, KiBem Kim, Rosalyn A. Juergens, Stephen C. Yang, Richard J. Battafarano, Errol L. Bush, Stephen R. Broderick, Stephen M. Cattaneo, Julie R. Brahmer, Charles M. Rudin, John Wrangle, Yuping Mei, Young J. Kim, Bin Zhang, Ken Kang-Hsin Wang, Patrick M. Forde, Joseph B. Margolick, Barry D. Nelkin, Cynthia A. Zahnow, Drew M. Pardoll, Franck Housseau, Stephen B. Baylin, Lin Shen, Malcolm V. Brock

ABSTRACT

Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy. More... »

PAGES

284-290

References to SciGraph publications

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  • Journal

    TITLE

    Nature

    ISSUE

    7798

    VOLUME

    579

    Author Affiliations

  • Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
  • Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
  • Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
  • State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Medical University, Xi’an, China
  • Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • Department of Thoracic Surgery, The Seventh Medical Center of PLA General Hospital, Beijing, China
  • Department of Surgery, University of Illinois College of Medicine, Chicago, IL, USA
  • Division of Medical Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario, Canada
  • Department of Surgery, Anne Arundel Medical Center, Annapolis, MD, USA
  • Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Division of Hematology-Oncology, Medical University of South Carolina, Charleston, SC, USA
  • Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, TN, USA
  • School of Biomedical Engineering, Dalian University of Technology, Dalian, China
  • Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, USA
  • Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41586-020-2054-x

    DOI

    http://dx.doi.org/10.1038/s41586-020-2054-x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1125114206

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32103175


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