Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, Germany.
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, Germany.
Cancer Res. 2018 Jun 15;78(12):3220-3232. doi: 10.1158/0008-5472.CAN-17-3415. Epub 2018 Apr 19.
Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategies 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- retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA 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 ATRA 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 tumor types. Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment. http://cancerres.aacrjournals.org/content/canres/78/12/3220/F1.large.jpg .
内在和适应性耐药阻碍了抗血管生成治疗（AAT）的成功，特别是在乳腺癌中，这种治疗方式已被证明效果甚微。因此，需要有新的策略来提高 AAT 的疗效。乳腺癌等实体瘤的特征是髓系来源的抑制细胞（MDSC）的高度浸润，而 MDSC 是导致 AAT 耐药的关键驱动因素。因此，我们假设全反式视黄酸（ATRA）可以诱导 MDSC 分化为成熟细胞，从而提高 AAT 的疗效。在临床前乳腺癌模型中，ATRA 单独使用和与化疗联合使用均可提高抗 VEGFR2 抗体的疗效。ATRA 逆转了抗 VEGFR2 诱导的肿瘤内 MDSC 的积累，减轻了缺氧，并对抗了肿瘤微血管的紊乱。机制研究表明，ATRA 治疗阻断了 AAT 诱导的高血管破坏 S100A8 分泌 MDSC 的扩张。因此，同时使用 ATRA 有可能改善乳腺癌和其他肿瘤类型的 AAT。通过减少赋予耐药性的髓样来源的抑制细胞来提高抗血管生成药物的治疗效率，可能会改善乳腺癌的治疗效果。http://cancerres.aacrjournals.org/content/canres/78/12/3220/F1.large.jpg。
