Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice. (1st September 2020)

• Record Type: Journal Article
• Authors: Kiyasu, Yoshiyuki; Kawada, Kenji; Hirai, Hideyo; Ogawa, Ryotaro; Hanada, Keita; Masui, Hideyuki; Nishikawa, Gen; Yamamoto, Takamasa; Mizuno, Rei; Itatani, Yoshiro; Kai, Masayuki; Taketo, Makoto Mark; Sakai, Yoshiharu
• Is Part Of: Cancer letters. Volume 487(2020)
• Page Start: 53
• Page End: 62
• Publication Date: 2020-09-01
• Subjects: Colorectal cancer -- CCR1 -- Tumor microenvironment -- Myeloid cell; CRC colorectal cancer -- TME tumor microenvironment -- TAN tumor-associated neutrophil -- TAM tumor-associated macrophage -- MDSC myeloid-derived suppressor cell -- HCC hepatocellular carcinoma -- mAb monoclonal antibody -- CMT93-luc CMT93 with luciferase -- BM bone marrow -- IHC immunohistochemistry -- MMP matrix metalloproteinase -- iNOS inducible nitric oxide synthase -- VEGF vascular endothelial growth factor -- Treg regulatory T cell -- PDCA pancreatic ductal cell carcinoma; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.05.028
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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.