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. 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 up-regulated 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.
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 LSL-KrasG12D/+ 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 to 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 only known inhibitor of vimentin is withaferin A, a steroidal lactone that causes disassembly of the vimentin 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.