Published ahead of print on August 2, 2007, doi:10.1165/rcmb.2007-0071OC
© 2008 American Thoracic Society DOI: 10.1165/rcmb.2007-0071OC Collagen I Promotes Epithelial-to-Mesenchymal Transition in Lung Cancer Cells via Transforming Growth Factor–β SignalingDepartments of 1 Oral Biology, 2 Biochemistry and Molecular Biology, 3 Genetics, Cell Biology and Anatomy; 4 Eppley Institute for Research in Cancer and Allied Diseases, and 5 Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska Correspondence and requests for reprints should be addressed to Margaret J. Wheelock, 987696 Nebraska Medical Center, Omaha, NE 68198-7696. E-mail: mwheelock{at}unmc.edu Epithelial-to-mesenchymal transition (EMT) is a fundamental biological process whereby epithelial cells lose their polarity and undergo a transition to a mesenchymal phenotype. When cancer cells invade adjacent tissues, they use a mechanism akin to EMT, and understanding the molecular mechanisms that drive this transition will facilitate studies into new targets for prevention of metastasis. Extracellular stimuli, such as growth factors, and their cytosolic effectors cooperate to promote EMT. In highly fibrotic cancers like lung cancer, it is thought that extracellular matrix molecules, including collagen, can initiate signals that promote EMT. Here, we present data showing that collagen I induces EMT in non–small cell lung cancer cell lines, which is prevented by blocking transforming growth factor (TGF)-β3 signaling. In addition, we show that collagen I–induced EMT is prevented by inhibitors of phosphoinositide 3-kinase and extracellular signal-related kinase signaling, which promotes transcription of TGF-β3 mRNA in these cells. Thus, our data are consistent with the hypothesis that collagen I induces EMT in lung cancer cells by activating autocrine TGF-β3 signaling. Epidermal growth factor also seems to initiate EMT via a TGF-dependent mechanism.
Key Words: non–small cell lung cancer • epithelial-to-mesenchymal transition • cadherin switching • collagen I • transforming growth factor–β
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