Cancer Models

Abstract

Among the variety of functions regulated by TGF-β pathways and their involvement in disease pathogenesis, it is perhaps their role in the suppression of malignant transformation and tumorigenesis that has gained the most attention. There are now several connections between the disruption of the cellular components of this pathway and human cancer. Mutations in the type II TGF-β receptor gene were the first to be described, and occur frequently in hereditary forms of nonpolyposis colorectal cancer with a phenotype of microsatellite instability (1,2). The downstream effectors of TGF-β signals are now also recognized as frequent molecular targets. Mutations in the Smad4 gene are common in familial juvenile polyposis and in pancreatic carcinomas, and are also found in other forms of epithelial cancers, while novel cytoplasmic oncoproteins that directly interact with and inhibit receptor-activated Smad proteins have been found in leukemias (2–7). In addition, many studies of cultured primary-tumor cells, cell lines, and established in vivo tumor models have described the now prototypical alterations in cancer-cell production and responsiveness to TGF-β that are widely recognized as important events. The recently established mouse models that explore these features and probe their relationship to the pathogenesis of human malignancy are of great significance, and represent the focus of this chapter.