Abstract
Chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, is an independent risk factor for lung cancer. Lung tissues obtained from human smokers with COPD and lung cancer demonstrate hypoxia and up-regulated hypoxia inducible factor-1 (HIF-1). HIF-1 activation is the central mechanism for controlling the cellular response to hypoxia during inflammation and tumor development. These facts suggest a link between COPD-related airway inflammation, HIF-1, and lung cancer. We have previously established a mouse model of COPD-like airway inflammation that promotes lung cancer in a K-ras mutant mouse model (CC-LR). Here we show that tumors in the CC-LR model have significantly elevated levels of HIF-1α and HIF-1 activity. To determine the tumor-promoting functions of HIF-1 in CC-LR mice, the gene Hif1a which encodes HIF-1α and is required for HIF-1 activity, was disrupted in the lung epithelium of CC-LR animals. Airway epithelial specific HIF-1α deficient mice demonstrated significant reductions in lung surface tumor numbers, tumor angiogenesis, and tumor cell proliferation in the absence or presence of COPD-like airway inflammation. In addition, when CC-LR mice were bred with transgenic animals that overexpress a constitutively active mutant form of human HIF-1α in the airway epithelium, both COPD- and adenocarcinoma-like phenotypes were observed. HIF-1α overexpressing CC-LR mice had significant emphysema, and they also showed potentiated tumorigenesis, angiogenesis, and cell proliferation accompanied by an invasive metastatic phenotype. Our gain and loss of function studies support a key role for HIF-1α in the promotion of lung cancer by COPD-like inflammation.
Highlights
Cigarette smoking is the principal cause of chronic obstructive pulmonary disease (COPD) and lung cancer [1, 2]
In order to study the causal role of HIF-1α in lung cancer promotion, we have targeted its expression in the airway epithelium of the CC-CCSPCre/LSL– KrasG12D (LR) mouse by crossing this mouse to a conditional knock out mouse with both alleles www.oncotarget.com of exon 2 of Hif1a flanked by loxP sites [24]
HIF-1α deficiency in the airway epithelium significantly reduced the number of visible tumors on the lung surface of CC-LR mice by >50% (2.2-fold) after inducing COPD-like airway inflammation using 8 weekly NTHi lysate exposures (162 ± 5 in CC-LR NTHi treated vs 72 ± 7 in LR/HIF-1αΔ/Δ NTHi treated) (Figure 2A, 2B)
Summary
Cigarette smoking is the principal cause of chronic obstructive pulmonary disease (COPD) and lung cancer [1, 2]. Repeated cycles of respiratory tract epithelial mucosal damage and repair in response to chronic cigarette smoke exposure and/or infection in COPD can result in epithelial hyperplasia and metaplasia [8]. Metaplasia is initially an adaptive response to persistent irritation, clinical surveillance has demonstrated that lung cancer often develops within metaplastic microenvironments [9]. Under non-neoplastic conditions, hyperplastic lesions can be induced transiently by inflammation or injury. When these lesions transit from having poorly controlled to uncontrolled proliferation, they take on neoplastic and atypical adenomatous appearances. The neoplastic transformation may be further accompanied by the acquisition of the growth, angiogenic, invasive, and metastatic characteristics of malignancy [10]
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