Bovine milk and meat factors (BMMFs)是从牛奶、血清以及结肠直肠癌（CRC）患者的癌旁组织中分离出的类似质粒的DNA分子。BMMFs被认为是人畜共患传染病的感染因子和CRC间接致癌的推手，能引起慢性组织炎症、自由基形成和DNA损伤水平的增加。以前没有大型临床队列中BMMFs表达数据与联合标记和临床参数的相关性研究，本研究就此展开。使用CRC患者的瘤旁粘膜和肿瘤组织、低/高度不典型、健康捐赠者粘膜的组织切片，通过共同免疫荧光显微镜和免疫组织化学评分（TMA），检测BMMF复制蛋白（Rep）和CD68/CD163（巨噬细胞）的表达情况。Rep在99％的CRC患者（TMA）的癌旁粘膜中表达，在组织学上与CD68+/ CD163 +巨噬细胞有关，并且与健康对照组相比，CRC患者中Rep表达水平更高。肿瘤组织仅显示出较低的基质Rep表达。Rep在LGD中表达，但在HGD中表达较弱，然而在LGD/HGD的癌旁组织中表达强烈。尽管未达到统计学意义，CRC特异性死亡率的发生曲线会因Rep表达水平（TMA）升高而升高，高的癌旁Rep表达水平与最高死亡率发生率相关。BMMF Rep表达可能代表CRC的标志和早期危险因素。Rep和CD68表达之间的相关性支持了先前提出的一种假说，即BMMF特异性炎症调节，包括巨噬细胞，参与了CRC的发病机制。© 2023 The Authors. Molecular Oncology由John Wiley & Sons Ltd代表欧洲生物化学联合会出版。

Bovine milk and meat factors (BMMFs) are plasmid-like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co-markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor-adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low-/high-grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co-immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor-adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+ /CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD-adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC-specific death were increased for higher Rep expression (TMA), with high tumor-adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF-specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC.© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.