Tobacco Smoke Promotes Lung Tumorigenesis by Triggering IKKβ- and JNK1-Dependent Inflammation

Abstract

Summary Chronic exposure to tobacco smoke, which contains over 60 tumor-initiating carcinogens, is the major risk factor for development of lung cancer, accounting for a large portion of cancer-related deaths worldwide. It is well established that tobacco smoke is a tumor initiator, but we asked whether it also acts as a tumor promoter once malignant initiation, such as caused by K-ras activation, has taken place. Here we demonstrate that repetitive exposure to tobacco smoke promotes tumor development both in carcinogen-treated mice and in transgenic mice undergoing sporadic K-ras activation in lung epithelial cells. Tumor promotion is due to induction of inflammation that results in enhanced pneumocyte proliferation and is abrogated by IKKβ ablation in myeloid cells or inactivation of JNK1.

Flavonoid components in Scutellaria baicalensis inhibit nicotine-induced proliferation, metastasis and lung cancer-associated inflammation in vitro

“…Many common features coexist in both diseases, and the potential shared biological mechanisms are inflammation, EMT and others, especially the inflammatory factor (26,27). Recent reports demonstrated that tobacco smoke promoted lung tumorigenesis by triggering inflammatory pathways (28).…”

The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

“…The principal infectious agents are Helicobacter pylori, hepatitis B and C viruses, and the human papilloma virus, which are closely associated with gastric cancer, hepatocellular carcinoma, and cervical cancer, respectively. Moreover, about 30% of all cancers have been attributed to smoking and 20% to obesity [3], and it has been shown that both tobacco smoke and obesity can trigger inflammatory responses in the lungs and liver, respectively, which promotes tumorigenesis [4,5]. These results, together with those of other recent studies [reviewed in [6][7][8], indicate that inflammation plays an important role in promoting cancer development, and "tumor-promoting inflammation" is now included in the next generation of the criteria considered to be "hallmarks of cancer" [9].…”

“…On the other hand, proinflammatory cytokines are expressed in the tumor microenvironment, and such cytokine signaling is also important for cancer development through the activation of downstream transcription factors [6]. Among them, TNF- and IL-6 activate NF-B and Stat3, respectively, and both the TNF-/NF-B and 4 IL-6/Stat3 pathways have shown to be important for the development of inflammation-associated intestinal tumorigenesis [7,8]. Moreover, NF-B induces the expression of COX-2, IL-6 and TNF-.…”

Multiscale Modeling of Inflammation and Inflammatory Diseases

“…It is now well recognized that although precise mechanisms are not yet fully understood, inflammation and cancer are closely correlated [6][7][8][9]. The link between inflammation and cancer development is particularly strong in patients with lung cancer, as the lungs are constantly exposed to environmental insults that may cause chronic inflammatory injuries and infection [10,11]. Currently, lung cancer is the leading cause of cancer-related deaths worldwide with 5-year survival rates averaging around only 15-18% [11,12].…”