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Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice.
Cancer Letters ( IF 9.1 ) Pub Date : 2020-05-27 , DOI: 10.1016/j.canlet.2020.05.028
Yoshiyuki Kiyasu 1 , Kenji Kawada 1 , Hideyo Hirai 2 , Ryotaro Ogawa 1 , Keita Hanada 1 , Hideyuki Masui 1 , Gen Nishikawa 1 , Takamasa Yamamoto 1 , Rei Mizuno 1 , Yoshiro Itatani 1 , Masayuki Kai 3 , Makoto Mark Taketo 4 , Yoshiharu Sakai 1
Affiliation  

Tumor-stromal interaction is implicated in tumor progression. Although CCR1 expression in myeloid cells could be associated with pro-tumor activity, it remains elusive whether disruption of CCR1-mediated myeloid cell accumulation can suppress tumor progression. Here, we investigated the role of CCR1 depletion in myeloid cells in two syngeneic colorectal cancer mouse models: MC38, a transplanted tumor model and CMT93, a liver metastasis model. Both cells induced tumor accumulation of CCR1+ myeloid cells that express MMP2, MMP9, iNOS, and VEGF. Lack of the Ccr1 gene in host mice dramatically reduced MC38 tumor growth as well as CMT93 liver metastasis. To delineate the contribution of CCR1+ myeloid cells, we performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type or Ccr1−/− mice. Mice reconstituted with Ccr1−/− BM exhibited marked suppression of MC38 tumor growth and CMT93 liver metastasis, compared with control mice. Consistent with these results, administration of a neutralizing anti-CCR1 monoclonal antibody, KM5908, significantly suppressed MC38 tumor growth and CMT93 liver metastases. Our findings highlight the importance of the application of CCR1 blockade as a therapeutic strategy.



中文翻译:

CCR1介导的髓样细胞积累的破坏抑制了小鼠结肠直肠癌的进展。

肿瘤-基质相互作用与肿瘤进展有关。尽管CCR1在髓样细胞中的表达可能与促肿瘤活性有关,但是,对CCR1介导的髓样细胞积累的破坏能否抑制肿瘤的进展尚不清楚。在这里,我们研究了两种同源结肠直肠癌小鼠模型中CCR1耗竭在髓样细胞中的作用:MC38是移植的肿瘤模型,而CMT93是肝转移模型。两种细胞均诱导表达MMP2,MMP9,iNOS和VEGF的CCR1 +髓样细胞的肿瘤积累。宿主小鼠中缺乏Ccr1基因会大大降低MC38肿瘤的生长以及CMT93肝转移。划定CCR1 +的贡献在骨髓细胞中,我们进行了骨髓(BM)转移实验,其中用来自野生型或Ccr1 -/-小鼠的BM重构了亚致死区照射的野生型小鼠。与对照小鼠相比,用Ccr1 -/- BM重构的小鼠表现出对MC38肿瘤生长和CMT93肝转移的显着抑制。与这些结果一致,中和抗CCR1单克隆抗体KM5908的给药显着抑制了MC38肿瘤的生长和CMT93肝转移。我们的发现突出了应用CCR1阻断作为治疗策略的重要性。

更新日期:2020-05-27
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