TIMP-1 Overexpression in Lung Carcinoma Enhances Tumor Kinetics and Angiogenesis in Brain Metastasis

Tissue inhibitors of matrix metalloproteinase (TIMP) orchestrate many biologic activities, including inhibition of matrix metalloproteinase activity, activation of pro-matrix metalloproteinases, and regulation of cell proliferation, angiogenesis, and apoptosis induction. Tissue inhibitors of matrix metalloproteinase can play a protective role during tumor invasion and metastasis, but elevated TIMP messenger RNA levels have also been associated with aggressive cancers and poor clinical outcome. We examined the potential roles of TIMP-1 in H2009 lung adenocarcinoma cells and in cells transfected with a human TIMP-1-overexpressing vector (HB-6 and HB-1). Tumors resulting from the implantation of parental cell lines and transfected HB-1 cells into the brains of nude mice had a typical carcinoma profile, but human TIMP-1-overexpressing tumors showed enhanced tumor kinetics and focally more infiltrative features; vessel density assessed with anti-CD31 immunohistochemistry was also greater within HB-1 tumor implants. Similar effects on HB-6 and HB-1 cells versus parental cell lines and empty vector clones were observed in endothelial cell assays. Anchorage-independent growth and invasion through Matrigel were also increased in TIMP-1-overexpressing cells. Together, these results indicate tumor-promoting functions of TIMP-1 through alterations in angiogenesis, increased tumorigenicity, and invasive behavior. Although matrix metalloproteinase inhibition has been the traditionally identified function of TIMP-1, matrix metalloproteinase-independent interactions may contribute to the growth of metastatic carcinomas in the brain.