Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling.
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)-beta3 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-beta3 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-beta3 signaling. Epidermal growth factor also seems to initiate EMT via a TGF-dependent mechanism.
Department of Oral Biology, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Yasushi
Y
Shintani
Masato
M
Maeda
Nina
N
Chaika
Keith R
KR
Johnson
Margaret J
MJ
Wheelock
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D053782:Transforming Growth Factor beta3 / Q000096:biosynthesis*
D024042:Collagen Type I; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D053782:Transforming Growth Factor beta3; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases