Abstract
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.
Highlights
Ki67+ crypt cells were observed in close vicinity to BMMF antigens and macrophages, and probably exposed to increased levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS) in chronic inflammation
Global epidemiological patterns suggest a role of bovine infectious agents in CRC and breast cancer [2,3,4]
Based on previous studies on the mechanisms of viral infectious agents in human cancers [29], we initially anticipated that BMMF DNA should be present in cell lines derived from human colon cancers
Summary
Timo Bunda , Ekaterina Nikitinaa , Deblina Chakrabortya, Claudia Ernsta, Karin Gunsta, Boyana Bonevaa , Claudia Tessmerb, Nadine Volkc,d, Alexander Brobeilc,d, Achim Webere,f, Mathias Heikenwalderg, Harald zur Hausena, , and Ethel-Michele de Villiersa,. The isolation of a number of novel single-stranded (ss) circular DNA molecules from bovine sera and dairy products (bovine meat and milk factors, BMMF) resulted in experimental tools for subsequent analyses of potential infections of such agents in humans and in specific human cell types [7,8,9,10,11,12]. BMMF represent plasmid-like, zoonotic infectious agents with an indirect role in cancer formation by inducing chronic inflammation leading to oxidative stress and DNA mutation in nearby replicating cells, which may develop into polyps as progenitors for colon cancer. This stimulated the search for and the identification of a zoonotic infectious agent involved as a carcinogen It resulted in the isolation of presently more than 120 BMMF genomes from bovine sera, milk, and additional dairy products [7,8,9,10,11]. This report describes the presence of a specific BMMF1-type DNA and BMMF Rep protein in inflammatory foci of peritumor interstitial cells of the colon
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