Insulin-like Growth Factor II Is Focally Up-regulated and Functionally Involved as a Second Signal for Oncogene-induced Tumorigenesis

The histopathology and epidemiology of human and animal cancers have clearly implicated a developmental process by which a normal cell is converted into a malignant tumor through a series of steps manifested in distinguishable histological and temporal stages (Foulds 1969; Henson and Albores-Saavedra 1993). The advanced stages have in some cases proved accessible to analysis, resulting in theories of tumorigenesis based on genetic change (Knudson 1986; Klein 1987; Fearon and Vogelstein 1990), involving activation of oncogenes, inactivation of tumor suppressor genes, and altered expression of cell surface molecules. Yet the early stages of tumorigenesis have remained largely inaccessible and the critical determinants undefined. A powerful system to investigate the process of tumorigenesis has resulted from the ability to manipulate the mouse germ line, both through the introduction of new genetic information (Hanahan 1989) and through the disruption of existing genes by homologous recombination (Capecchi 1988; Zimmer 1992). Lines of transgenic...