Suppression of Myc-Induced Apoptosis in β Cells Exposes Multiple Oncogenic Properties of Myc and Triggers Carcinogenic Progression

To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic β cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature β cells induces uniform β cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes β cell mass. Thus, the oncogenic potential of c-Myc in β cells is masked by apoptosis. Upon suppression of c-Myc-induced β cell apoptosis by coexpression of Bcl-xL, c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and β cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.