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Tobacco smoke causes chronic inflammation in the lungs. The proteins that are involved in the process of inflammation can also lead to initiation of lung cancer and progression to metastasis. How this process occurs has not been fully defined. One of the proteins known to be involved in this process, Snail, is also known to be present in human non-small cell lung cancer tissues, and, when it is present, lung cancer patients have a worse prognosis. We have shown experimentally that the injury to and inflammation of the lungs caused by cigarette smoke can induce the presence of Snail, which in turn induces the presence of another protein, SPARC. These proteins subsequently initiate tumor formation and a process known as epithelial-to-mesenchymal transition (EMT). In EMT, normal epithelial cells acquire the ability to detach from the cells surrounding them, degrade their surrounding tissues, and move to another location. We have shown Snail-dependent tumor growth and metastasis in both a cell-based model as well as in mice. Our observation of Snail-dependent tumor growth and metastasis of otherwise normal lung epithelial cells in mice offers strong support for the role of Snail as a novel inducer of lung cancer. Furthermore, our preliminary data lead us to hypothesize that SPARC is an important determinant of Snail-dependent initiation.
In the proposed studies, we will investigate how Snail is able to mediate lung cancer initiation and progression by evaluating the ability of Snail and the molecules associated with it, SPARC, HSP27, miR-29b, and MEK/ERK. We hypothesize that inflammation-induced Snail drives tumor initiation and parallel progression to metastasis by induction of the protein SPARC. A more complete understanding of how lung cancer develops will provide new targets for early treatment of the disease.
In Aim 1 of this proposal, we will use cell lines derived from normal lung tissue that we have engineered to produce Snail. Into these cell lines, we will introduce modifications of the genes for SPARC, HSP27, miR-29b, and MEK/ERK. By evaluating the levels of each gene and protein before and after modification, we will determine the relationship between each. Furthermore, we will use these cell lines in three cell-based experiments designed to model tumor initiation and EMT.
In Aim 2 of this proposal, we will introduce the cell lines developed in Aim 1 into an animal model designed to mimic lung cancer. In this model, we will inject cells directly into the trachea of a mouse, where the mouse inhales them and they implant into the lungs. Normal cells will not form tumors, but we hypothesize that our cells, with production of Snail and its associated molecules, will not only form tumors but will, in a parallel manner, form metastases. Any loss of the associated molecules will disrupt and possibly completely abolish this process.
In summary, we have uniquely identified the likelihood that Snail and SPARC work together to initiate lung cancer and simultaneously drive progression to metastasis. The overall objective of the proposed studies is to outline how Snail leads to cancer initiation and progression, especially the role of SPARC, HSP29, miR-29b, and MEK/ERK. We anticipate these findings to help in identification of new targets for early lung cancer detection and disease prevention. |
