Lipopolysaccharide Enhances Mouse Lung Tumorigenesis

Abstract

The association between pulmonary inflammation and lung cancer is well-established. However, currently there are no appropriate models that recapitulate inflammation-related lung cancer in humans. In the present study, we examined, in two tumor bioassays, enhancement by bacterial lipopolysaccharide (LPS) of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. Mice that were treated with NNK alone developed 29.6 ± 9.8 and 36.2 ± 4.1 lung tumors/mouse in experiment 1 and 2, respectively. Chronic intranasal instillation of LPS to NNK-treated mice increased the multiplicity of lung tumors to 47.3 ± 16.1 and 51.2 ± 4.8 lung tumors/mouse in experiment 1 and 2, corresponding to a significant increase by 60% and 41%, respectively. Moreover, administration of LPS to NNK-pretreated mice significantly increased the multiplicity of larger tumors and histopathologically more advanced lesions (adenoma with dysplasia and adenocarcinoma), macrophage recruitment to the peritumoral area and expression of inflammation-, cell proliferation- and survival-related proteins. Overall, our findings demonstrated the promise of the NNK-LPS-A/J mice model to better understand inflammation-driven lung cancer, dissect the molecular pathways involved and identify more effective preventive and therapeutic agents against lung cancer.

Dietary Diindolylmethane Suppresses Inflammation-Driven Lung Squamous Cell Carcinoma in Mice

“…In the present study, in order to develop a mouse model of inflammation-driven LSCC that closely resembles human LSCC, mice were treated with a lower dose of NTCU (about 100-fold lower than the dose used in previous studies) and a COPD-like air way inflammation was induced via repetitive exposure to LPS. Previous studies with mice have shown that LPS-induced inflammatory and pathologic changes closely mimic those observed in human COPD (35,36) and repetitive exposure of NNK-pretreated mice to LPS doubled lung tumor multiplicity, markedly increased tumor size and increased peritumoral accumulation of macrophages (37). In the present study, combinatory treatment with a lower dose of NTCU (0.5 mmol/L, about 100-fold lower than the dose used in previous studies) and LPS was as potent as or even more potent than the standard dose of NTCU (40 mmol/L) (29,30) in inducing LSCC.…”

The Microbiome in Lung Cancer Tissue and Recurrence-Free Survival

“…However, there are several mechanisms by which the lung microbiota could contribute to lung carcinogenesis, including genotoxic pathways, bacterial metabolite effects, and induction of host inflammatory pathways (15). For example, intranasal administration of lipopolysaccharide (a membrane component of Gram-negative bacteria) in a mouse model of lung cancer significantly enhanced pulmonary inflammation and lung tumorigenesis (39). We previously showed in a human study that airway Veillonella and Streptococcus were associated with upregulation of ERK and PI3K signaling pathways in the airway, pathways regulating cell proliferation, survival, and differentiation, which are upregulated in patients with lung cancer (9).…”

The microbiome and cancer

“…Several findings indicate a possible role for bacteria in the promotion of lung cancer, such as the increased bacterial colonization in chronic obstructive pulmonary disease (COPD 59,60 ; which is a known risk factor for lung cancer development 61 ), a lower incidence of lung cancer in germ-free male rats, and the promotion of lung cancer by LPS or by chronic respiratory infections 24,62 . Similarly, the reduced rate of skin cancer in germ-free rats 23 and in mice lacking receptors or adaptor molecules for pro-inflammatory bacterial MAMPs 63–65 also suggests a possible role for the bacterial microbiota in skin carcinogenesis.…”