Division of Episomal-Persistent DNA in Cancer and Chronic Diseases, German Cancer Research Center, 69120 Heidelberg, Germany.
Monoclonal Antibody Unit, German Cancer Research Center, 69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12). doi: 10.1073/pnas.2025830118.
Consumption of Eurasian bovine meat and milk has been associated with cancer development, in particular with colorectal cancer (CRC). In addition, zoonotic infectious agents from bovine products were proposed to cause colon cancer (zur Hausen et al., 2009). Bovine meat and milk factors (BMMF) are small episomal DNA molecules frequently isolated from bovine sera and milk products, and recently, also from colon cancer (de Villiers et al., 2019). BMMF are bioactive in human cells and were proposed to induce chronic inflammation in precancerous tissue leading to increased radical formation: for example, reactive oxygen and reactive nitrogen species and elevated levels of DNA mutations in replicating cells, such as cancer progenitor cells (zur Hausen et al., 2018). Mouse monoclonal antibodies against the replication (Rep) protein of H1MSB.1 (BMMF1) were used to analyze BMMF presence in different cohorts of CRC peritumor and tumor tissues and cancer-free individuals by immunohistochemistry and Western blot. BMMF DNA was isolated by laser microdissection from immunohistochemistry-positive tissue regions. We found BMMF Rep protein present specifically in close vicinity of CD68 macrophages in the interstitial lamina propria adjacent to CRC tissues, suggesting the presence of local chronic inflammation. BMMF1 (modified H1MSB.1) DNA was isolated from the same tissue regions. Rep and CD68 detection increased significantly in peritumor cancer tissues when compared to tissues of cancer-free individuals. This strengthens previous postulations that BMMF function as indirect carcinogens by inducing chronic inflammation and DNA damage in replicating cells, which represent progress to progenitor cells for adenoma (polyps) formation and cancer.
消费欧亚牛肉和牛奶与癌症的发展有关，特别是结直肠癌（CRC）。此外，牛产品中的人畜共患传染病原体被认为会导致结肠癌（zur Hausen 等人，2009 年）。牛肉和牛奶因素（BMMF）是从小牛血清和奶制品中经常分离出来的小外源性 DNA 分子，最近也从结肠癌中分离出来（de Villiers 等人，2019 年）。BMMF 对人类细胞具有生物活性，并被提议在癌前组织中引起慢性炎症，从而导致自由基形成增加：例如，活性氧和活性氮物种以及复制细胞（如癌前体细胞）中的 DNA 突变水平升高（zur Hausen 等人，2018 年）。针对 H1MSB.1（BMMF1）复制（Rep）蛋白的鼠单克隆抗体用于通过免疫组织化学和 Western blot 分析 CRC 肿瘤周围和肿瘤组织以及无癌症个体中不同队列中 BMMF 的存在。通过激光显微切割从免疫组织化学阳性组织区域分离 BMMF DNA。我们发现 BMMF Rep 蛋白特异性存在于与 CRC 组织相邻的间质固有层中 CD68 巨噬细胞的附近，表明存在局部慢性炎症。从同一组织区域分离出 BMMF1（修饰的 H1MSB.1）DNA。与无癌症个体的组织相比，肿瘤周围癌症组织中的 Rep 和 CD68 检测显著增加。这加强了之前的假设，即 BMMF 通过在复制细胞中诱导慢性炎症和 DNA 损伤起间接致癌剂的作用，这代表了向腺瘤（息肉）形成和癌症的祖细胞进展。
