Promotion of Lung Carcinogenesis by Chronic Obstructive Pulmonary Disease–Like Airway Inflammation in a K-ras–Induced Mouse Model

Abstract

Lung cancer is the leading cause of cancer deaths in the United States. In addition to genetic abnormalities induced by cigarette smoke, several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs, have an increased risk of lung cancer (1.3-to 4.9-fold) compared to smokers without COPD. This suggests a link between chronic airway inflammation and lung carcinogenesis, independent of tobacco smoke exposure. We studied this association by assaying the inflammatory impact of products of nontypeable Haemophilus influenzae, which colonizes the airways of patients with COPD, on lung cancer promotion in mice with an activated Kras mutation in their airway epithelium. Two new mouse models of lung cancer were generated by crossing mice harboring the LSL-Kras G12D allele with mice containing Cre recombinase inserted into the Clara cell secretory protein (CCSP) locus, with or without the neomycin cassette excised (CCSP Cre and CCSP Cre-Neo , respectively). Lung lesions in CCSP Cre-Neo /LSL-K-ras G12D and CCSP Cre /LSL-Kras G12D mice appeared at 4 and 1 month of age, respectively, and were classified as epithelial hyperplasia of the bronchioles, adenoma, and adenocarcinoma. Weekly exposure of CCSP Cre /LSL-Kras G12D mice to aerosolized nontypeable Haemophilus influenzae lysate from age 6-14 weeks resulted in neutrophil/macrophage/ CD8 T-cell-associated COPD-like airway inflammation, a 3.2-fold increase in lung surface tumor number (156 6 9 versus 45 6 7), and an increase in total lung tumor burden. We conclude that COPD-like airway inflammation promotes lung carcinogenesis in a background of a G12D-activated K-ras allele in airway secretory cells.

Neutrophils in cancer: neutral no more

“…Tumors in various mouse models of KRAS-driven lung cancer -such as Cc10-Cre;Kras G12D (also known as Ccsp-Cre;Kras G12D ), Adeno-Cre;Kras G12D and Kras LA1 modelsupregulate neutrophil-related chemokines and display expansion of neutrophils 90,[106][107][108][109] ( Figure 2). These phenotypes may be a result of direct upregulation of neutrophil-related cytokines like GM-CSF and CXCL8 by KRAS signaling 29,30,110 .…”

Macrophages as a Key Factor in the Process of Tumour From the Initiation to the Therapy of Cancer.

“…[69] Myeloid-specific ablation of intergrin αV also results in an ulcerative colitis that induces colonic tumors. [70] Ablation in myeloid cells of stat3, a transcription factor which function suppresses inflammatory responses because it is a major target of immunosuppressive cytokine IL-10. [71] causes inflammation in the colon.…”

The value of low-molecular-weight DNA of blood plasma in the diagnostic of the patological processes of different genesis

“…Такой путь регуляции задействован в клетках дыхательного эпителия в ответ на воздействие воздушных поллютантов [35]. В настоящее время показано, что соматические мутации Васильева, Зинкин RAS и EGFR (рецептор эпидермального фактора роста), как врождённые, так и приобретенные, ассоциируются с ХОБЛ и способствуют развитию злокачественных новообразований активированием мутантных аллелей K-ras [36,37]. Точечные мутации гена K-ras, обнаруживаемые в циркулирующей ДНК, определяются не только у онкологичеких больных, но в ряде случаев и у здоровых.…”