Epigenetic therapy inhibits metastases by disrupting premetastatic niches Journal Article
| Authors: | Lu, Z.; Zou, J.; Li, S.; Topper, M. J.; Tao, Y.; Zhang, H.; Jiao, X.; Xie, W.; Kong, X.; Vaz, M.; Li, H.; Cai, Y.; Xia, L.; Huang, P.; Rodgers, K.; Lee, B.; Riemer, J. B.; Day, C. P.; Yen, R. W. C.; Cui, Y.; Wang, Y.; Wang, Y.; Zhang, W.; Easwaran, H.; Hulbert, A.; Kim, K. B.; Juergens, R. A.; Yang, S. C.; Battafarano, R. J.; Bush, E. L.; Broderick, S. R.; Cattaneo, S. M.; Brahmer, J. R.; Rudin, C. M.; Wrangle, J.; Mei, Y.; Kim, Y. J.; Zhang, B.; Wang, K. K. H.; Forde, P. M.; Margolick, J. B.; Nelkin, B. D.; Zahnow, C. A.; Pardoll, D. M.; Housseau, F.; Baylin, S. B.; Shen, L.; Brock, M. V. |
| Article Title: | Epigenetic therapy inhibits metastases by disrupting premetastatic niches |
| 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | clinical article; controlled study; human tissue; cancer surgery; primary tumor; unclassified drug; human cell; overall survival; genetics; drug efficacy; nonhuman; pyridines; cancer adjuvant therapy; disease free survival; chemotherapy, adjuvant; chemotherapy; cancer staging; antineoplastic agent; genetic analysis; neoplasm; neoplasms; mouse; phenotype; animal; cytology; animals; mice; animal tissue; low drug dose; metastasis; breast cancer; tumor volume; animal experiment; animal model; down-regulation; evidence based practice; lung cancer; cell motion; cell differentiation; drug effect; physiology; cancer survivor; disease model; cancer inhibition; lung metastasis; dna; epigenetics; epigenesis, genetic; adjuvant chemotherapy; bone; neoplasm metastasis; gene therapy; cell migration; cell movement; down regulation; tumor; disease models, animal; esophagus cancer; genetic epigenesis; chemokine receptor ccr2; receptors, ccr2; bioaccumulation; azacitidine; pyridine derivative; inhibition; tumor microenvironment; benzamide derivative; benzamides; entinostat; ccr2 protein, mouse; gene expression level; tumor invasion; chemokine receptor cxcr2; genetic therapy; cancer; human; male; female; priority journal; article; myeloid-derived suppressor cells; myeloid-derived suppressor cell; protein expression level; rs 504393; receptors, interleukin-8b |
| Journal Title: | Nature |
| Volume: | 579 |
| Issue: | 7798 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-03-12 |
| Start Page: | 284 |
| End Page: | 290 |
| Language: | English |
| DOI: | 10.1038/s41586-020-2054-x |
| PUBMED: | 32103175 |
| PROVIDER: | scopus |
| PMCID: | PMC8765085 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
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