INHIBITION OF SV40 T-ANTIGEN-INDUCED HEPATOCELLULAR-CARCINOMA IN TIMP-1 TRANSGENIC MICE

The potential of tissue inhibitors of metalloproteinases (TIMPs) to in hibit neoplastic progression has been postulated from studies of genet ically manipulated cells. To investigate whether the TIMP-1 expressed in a host tissue suppresses cancer in vivo and to identify the affecte d stages, we developed transgenic mice with constitutive overexpressio n or reduction of TIMP-1 in the liver. In double transgenic experiment s, the TIMP-1 lines were crossed with a second transgenic line which e xpresses the Simian Virus 40 t/T antigen (TAg). This viral oncogene le ads to heritable development of hepatocellular carcinomas with a 100% incidence. Effects of TIMP-1 coexpression on the TAg-induced neoplasms were determined at the tissue and cellular level. Here, we report tha t overexpression of hepatic TIMP-1 blocked the development of TAg-indu ced hepatocellular carcinomas. High TIMP-1 levels inhibited not only t he later stages in tumor development (growth and angiogenesis), but al so events associated with tumor initiation (altered hepatocyte cytolog y and tissue architecture). We further show that an antisense-mediated reduction of TIMP-1 resulted in a more rapid tumor initiation and pro gression. These data demonstrate that intrinsic TIMP-1 levels contribu te to a tissue's susceptibility to viral oncogene-induced tumorigenesi s.