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Lung cancer patients display increased expression of Bovine Meat and Milk Factor (BMMF) proteins in peritumor alveolar macrophages

ABSTRACT: 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 IHC, 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. Mass Spectroscopy was used to support immunohistologic and immunoblotting data for BMMF Rep protein detection data on the protein level after anti-BMMF Rep-specific immunoprecipitation of lung tissue lysates.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

DISEASE(S): Lung Carcinoma

SUBMITTER: Timo Bund

LAB HEAD: Timo Bund

PROVIDER: PXD077096 | Pride | 2026-06-03

REPOSITORIES: Pride

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Project description:Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure. We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change>1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p=0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers. Experiment Overall Design: Overall, 180 adenocarcinoma and non-tumor tissue samples were selected for the analyses, including duplicate or triplicate samples from 14 subjects for quality control. From the original 180 samples, 148 provided sufficient quantity of high-quality RNA for microarray analyses; 13 additional samples were excluded because of problematic assays. Normalization was conducted on the remaining 135 microarrays. After normalization, 13 samples were excluded because of low percentage of tumor cells in the tumor tissues. This report is based on 122 samples, of which 15 duplicates were averaged, resulting in 107 final expression values from 58 tumor and 49 non-tumor tissues from 20 never smokers, 26 former smokers, and 28 current smokers.

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Lung cancer patients display increased expression of Bovine Meat and Milk Factor (BMMF) proteins in peritumor alveolar macrophages

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