Lung Cancer Patients Display Increased Expression of Bovine Meat and Milk Factor (BMMF) Proteins in Peritumor Alveolar Macrophages.

Besides smoking and exposure to specific environmental risk factors, also diet and in particular red meat consumption/exposure are described as risk factors contributing to lung cancer development. Incidence of non-smoking associated lung cancer is rising rapidly, globally. Global epidemiology supports an association between lung cancer incidence and consumption of bovine products. The search for meat-/milk-associated cancer risk factors led to the isolation of plasmid DNA termed Bovine Meat and Milk Factors (BMMFs). Due to detection of increased expression levels of a conserved BMMF-encoded protein (Rep) in tissues of colorectal cancer patients, BMMFs have been proposed as causal risk factors for cancer acting via inflammation-driven indirect carcinogenesis. Yet, their presence and possible contribution to lung cancer remained elusive. In this study, Rep expression was quantified in paired tumor/peritumor tissues from lung cancer patients (n = 35) as well as cancer-free individuals (n = 19, tissues adjacent to benign hamartoma) by immunohistochemistry, co-immunofluorescence microscopy, immunodetection/mass spectroscopy and genomics/transcriptomics screening. In all patients tested, Rep expression was immunohistochemically observed in CD68+ CD163+ alveolar lung macrophages, which were present at higher numbers in peritumor tissues of cancer patients compared to controls. Expression was inversely correlated with smoking intensity, supporting BMMFs' function as a new, smoking-independent biomarker and possible driver for lung cancer. BMMF+ macrophages revealed a cancer-promoting M2-like phenotype upon scRNA-seq, suggesting BMMF as target for both prevention and therapy. BMMFs might contribute to lung cancer by inducing pro-tumorigenic macrophage populations and serve as marker for (early) cancer detection and prevention.