Abstract 4113: Characterization of a novel TIMP-2 deficient mouse model of experimental lung metastasis

Abstract

Abstract It is well known that the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteases (TIMPs) impacts tumor progression, thereby providing a novel avenue for cancer therapies. We have previously shown that forced TIMP-2 expression inhibits lung tumor growth independent of MMP inhibition via direct effects on tumor cells and modulation of the tumor microenvironment. The current study was undertaken to examine how reduced TIMP-2 expression impacts lung tumor growth using a novel TIMP-2 deficient (T2D) mouse model in a clean C57BL6 background. This is first time we fully developed and characterized TIMP2 deficient mice, validated by genotyping, histologic staining, protein and mRNA expression. The deletion of TIMP2 gene down regulated the expression TIMP2 mRNA and protein as demonstrated by quantitative RT-PCR and immunoblot experiments, respectively. Further, we investigated the impact of TIMP2 deletion on Lewis lung carcinoma model of metastasis. Lewis lung carcinoma cells transfected with luciferase (LL/2-Luc-M38, Caliper) were intratracheally instilled in the lungs into group's have heterozygous (T2D+/−), homozygous (T2D−/−), and wild type (WT) littermates. Tumor progression was monitored by IVIS imaging after 2nd week of intratracheal instillation and continued till 4th week, mice were sacrificed and lungs were perfused and harvested for further analysis. The IVIS analysis showed higher tumor burden in TIMP2 deficient and heterozygous mice as compared to wild type littermate, suggested that TIMP2 deficiency aggravates tumor development in deficient mice. The effects of recombinant TIMP2 on tumor microenvironment and microarray experiments are currently in progress. The molecular mechanism underlying the observed activities will be investigated. Collectively, these preliminary findings suggest that TIMP2 may be a novel target for lung cancer therapy. Citation Format: Sarvesh Kumar. Characterization of a novel TIMP-2 deficient mouse model of experimental lung metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4113. doi:10.1158/1538-7445.AM2015-4113