Wnt and Hedgehog Are Critical Mediators of Cigarette Smoke-Induced Lung Cancer

Abstract

BackgroundLung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood.Methodology/Principal FindingsHere, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype.Conclusions/SignificanceThese experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.

Cigarette Smoke Induces Epidermal Growth Factor Receptor-Dependent Redistribution of Apical MUC1 and Junctional β-Catenin in Polarized Human Airway Epithelial Cells

“…Accordingly, in preliminary studies using SYBR Green-based quantitative PCR, we found that CS upregulated two established nuclear targets of Wnt/␤-catenin/Lef-1 signaling pathway, WISP1 (WNT1 inducible signaling pathway protein1, 5.86-fold-increase) and FGF4 (fibroblast growth factor 4, 19.45-fold-increase) (unpublished data). 35,36 Although the activation of canonical Wnt signaling has been reported in previous publications using HBE cell monolayers, 10,23 to the best of our knowledge this study is the first to demonstrate CS-induced activation of Wnt signaling in a fully differentiated pseudostratified model of the human airway epithelium that compromises three heterogeneous cell populations (ciliated columnar cells, goblet cells, and undifferentiated basal cells). Moreover, we established a pathological link between upstream EGFR and downstream canonical Wnt signaling in response to CS exposure.…”

“…18 -20 Moreover, in company with the redistribution of EGFR and ␤-catenin, short-term exposure of HBE cell monolayers to CS has been shown to initiate signaling events that include aberrant activation of both EGFR and canonical Wnt/␤-catenin signaling. [21][22][23] While EGFR and Wnt are known mediators of CS-induced airway diseases, the specific events that coordinate cytoarchitectural damage and aberrant activation of protumor signaling are unclear.…”

The Gli code: an information nexus regulating cell fate, stemness and cancer

“…In mice, approximately 20 days of treatment with cyclopamine are sufficient to abolish the tumors and prevent recurrence and metastasis [48], suggesting that limited treatments will be efficacious. Finally, the finding that oncogenic RAS requires positive GLI activity in several contexts [48] and that HH-GLI is also activated by other cancer-inducing agents, such as tobacco smoke [82], suggests that the GLI code participates in a vast number of human cancers. The dependence of many human tumors on high positive GLI activity thus represents an unexpected common target.…”

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

“…The Wnt pathway has been associated with normal lung development and homeostasis as well as chronic lung diseases such as fibrosis and asthma (Konigshoff et al, 2010;Van et al, 2008). However, there are contradictory findings indicating that the Wnt pathway is activated or down-regulated by cigarette smoke in bronchial epithelial cells (Lemjabbar-Alaoui et al, 2006;Wang et al, 2011). Wnt inhibitory factor 1 (Wif1), an extracellular antagonist that acts by binding to Wnt ligands, is a frequent target for epigenetic silencing in various human cancers (Ying et al, 2009).…”