Molecular dissection of multi-stage tumorigenesis in transgenic mice

The epidemiology of cancer in humans and in animal models suggests that multiple genetic events are responsible for the genesis of malignant tumors. During development of many tumors, distinctive changes can be recognized: normal unaffected tissue, hyperplasia with a high incidence of proliferating cells, induction of tumor angiogenesis with the new growth of capillaries, solid tumors (neoplasia), and finally metastasis. The molecular analysis of tumorigenesis is often hampered by the unavailability of tissue specimens from the multiple stages. For this reason, the genetic reproducibility and the accessibility of tissue specimens have made transgenic mice a valuable tool to study the molecular events that are involved in the stepwise progression to the tumor phenotype. Many transgenic mouse models of human cancer, for example mammary epithelia, skin and liver, exhibit similar patterns of stepwise tumor development. In this review we discuss possible strategies to investigate the molecular events that are involved in multi-stage tumor development. Then we present in some detail the molecular dissection of tumor development in two transgenic models of fibrosarcomas of the skin, and a third transgenic mouse line that develops tumors of the beta cells in the islets of Langerhans (insulinomas). In particular, approaches to the molecular characterization of tumor cell proliferation and tumor angiogenesis are discussed.