HEIDELBERG, Germany — Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team is headed by Harald zur Hausen, MD, PhD, Division of Episomal-Persistent DNA in Cancer and Chronic Diseases, German Cancer Research Center, Heidelberg, Germany, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papilloma viruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published by the Proceedings of the National Academy of Sciences of the United States of America on March 23.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Hausen said in a related press statement.

Pathogenic Agents, Found in Vicinity of Tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

They found that the BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of pro-inflammatory macrophages.

They also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep vs just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stress, however, that further study will be required to confirm the results.

They nevertheless believe that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers, via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha (Munich) (to Hausen). Mathias Heikenwalder was supported by the EOS Foundation (Flundern), the SFBTR-179 and 209, and a European Research Council consolidator grant. The authors have disclosed no relevant financial relationships.

PNAS. Published online March 23, 2021. Full text

Translated and adapted from Medscape’s French edition.

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