Lung cancer is the leading cause of cancer deaths in the United States . Non–small cell lung cancer (NSCLC) represents 80% of all lung cancers . At the time of NSCLC diagnosis, 40–50% of patients already have stage 4 disease and a 5-year survival rate of <1%. Up to one-half of the remaining patients who undergo curative surgery will have recurrence with metastatic disease [1,3]. At present, there are no treatments that target the process of metastatic spread.
Vimentin, a type 3 intermediate filament, is involved in multiple steps of the metastatic cascade, including epithelial-to mesenchymal transition (EMT), breach of the basement membrane, dissociation of cells from the original tumor, invasion into new tissue, and establishment at a secondary site . Vimentin expression is upregulated in NSCLC and is used as a diagnostic marker to distinguish between the initial progression of localized epithelial cells and the invasive spread of metastatic tumor cells [4,5].
Multiple gene abnormalities contribute to the development of NSCLC. Two of the most common mutations are to the oncogene Kras and to the tumor suppressor gene p53 . To investigate the role of vimentin in the development and progression of NSCLC, we use a mouse model in which lung adenocarcinomas are induced by Cre recombinase–mediated expression of a mutant Kras allele. We crossed these mice with mice harboring floxed alleles of Tp53 to create a model of metastatic lung cancer.
We then crossed the resultant mice with vimentin-null mice. Compared with wild-type mice with induced lung adenocarcinoma, the vimentin-null mice had prolonged survival, decreased tumor burden, and decreased lymph node involvement, suggesting a reduction in the spread of metastatic cancer cells.
The compound withaferin A is a steroidal lactone that binds to vimentin and causes disassembly of the network. Withaferin A has been shown to inhibit cancer cell migration in vitro . When wild-type mice with induced lung adenocarcinoma were treated with withaferin A, they showed evidence of slower tumor progression than did untreated mice. These findings shine a hopeful light on the treatment of NSCLC in the future.
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