Authors' Affiliations: Departments of Microbiology and Immunology and Pathology and Laboratory Medicine; Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina; and Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut.
Cancer Res. 2014 Jan 15;74(2):446-59. doi: 10.1158/0008-5472.CAN-13-1677. Epub 2013 Dec 9.
Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Furthermore, Toll-like receptors have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophage-specific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of β-catenin, increased efficiency of the DNA repair machinery, and reduced expression of proinflammatory cytokines, including interleukin (IL)-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.
巨噬细胞是炎症相关结肠癌发展的重要驱动因素，但它们的贡献的机制基础尚未完全理解。此外，Toll 样受体已被牵连到结肠癌中，但它们相关的细胞作用部位尚不清楚。在这项研究中，我们表明内质网伴侣 gp96 在肿瘤相关巨噬细胞（TAM）中对于授权其对炎症性结肠肿瘤发生的贡献是必不可少的。以巨噬细胞特异性方式在 gp96 中进行基因缺失的小鼠表现出较少的结肠炎和炎症相关的结肠肿瘤发生。这些小鼠中结肠癌的衰减与 β-连环蛋白突变率降低、DNA 修复机制效率提高以及肿瘤微环境中促炎细胞因子（包括白细胞介素（IL）-17 和 IL-23）的表达减少显著相关。TAM 相关炎症的遗传毒性性质通过 DNA 修复途径中基因表达的增加而明显。我们的工作加深了对 TAM 通过改变上皮细胞内的分子致癌程序促进致癌作用的理解，并确定 gp96 作为 TAM 中需要的关键伴侣蛋白，以授权其功能并影响结肠肿瘤发生中关键炎症细胞因子的表达。
