Recent advances in cancer research: mouse models of tumorigenesis.
Over the past 20 years, cancer research has gained major insights into the complexity of tumor development, in particular into the molecular mechanisms that underlie the progressive transformation of normal cells into highly malignant derivatives. It is estimated that the transformation of a normal cell to a malignant tumor cell is dependent upon a small number of genetic alterations, estimated to be within the range of four to seven rate-limiting events. Critical events in the evolution of neoplastic disease include the loss of proliferative control, the failure to undergo programmed cell death (apoptosis), the onset of neoangiogenesis, tissue remodeling, invasion of tumor cells into surrounding tissue and, finally, metastatic dissemination of tumor cells to distant organs. In patients, the molecular analysis of these multiple steps is hampered by the unavailability of tumor biopsies from all tumor stages. In contrast, mouse models of tumorigenesis allow the reproducible isolation of all tumor stages, including normal tissue, which are then amenable to pathological, genetic and biochemical analyses and, hence, have been instrumental in investigating cancer-related genes and their role in carcinogenesis. In this review, we discuss mouse tumor models that have contributed substantially to the identification and characterization of novel tumor pathways. In particular, we focus on transgenic and knockout mouse models that closely mimic human cancer and thus can be used as model systems for cancer research.