期刊
CANCER RESEARCH
卷 78, 期 12, 页码 3220-3232出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3415
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资金
- Max-Eder group leader program from the German Cancer Aid
- Heisenberg professorship from the German Research Council (DFG) [LO1863/4-1]
- Margarethe Clemens Stiftung
- Erwin-Schrodinger postdoctoral fellowship from the Austrian Science Fund (FWF) [J3664-B19]
- Werner Otto fellowship from the Werner Otto foundation
- Medical Faculty of the University of Hamburg (FFM program)
- VIB TechWatch program
- Federal Government Belgium grant [IUAP7/03]
- long-term structural Methusalem by the Flemish Government
- Research Foundation Flanders (FWO-Vlaanderen)
- Foundation against Cancer [2012-175, 2016-078]
- Kom op Tegen Kanker (Stand Up to Cancer, Flemish Cancer Society)
- ERC Advanced Research Grant [EU-ERC743074]
- European Research Council Investigator Grant DISSECT [269081]
- German Research Foundation (DFG) [CRC 1009 B8, CRC 1009 B9]
- Federal Ministry of Education and Research (BMBF), project AID-NET and E-RARE, Treat-AID
- Austrian Science Fund (FWF) [J3664] Funding Source: Austrian Science Fund (FWF)
Intrinsic and adaptive resistance hampers the sucess of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategics to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all-trans retinoic add (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. A IRA increased the efficacy of anti-VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models, ATRA reverted the anti-VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that AT RA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other minor types. Significance: Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment. (C) 2018 AACR.
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