Endocrine Abstracts

Cancers arise through accumulation of mutations that compromise control of cell proliferation, differentiation, adhesion, invasion, angiogenesis and apoptosis. To identify targets for effective therapy, it is important to determine which lesions are needed for maintenance of the tumor. We have constructed genetically manipulated transgenic and knock-in mice to directly explore the roles of activated Myc and inactivated p53 in the genesis, progression and maintenance of neoplasia.
In one mouse model we have targeted a switchable Myc to pancreatic b cells. Consistent with Myc's known pro-apoptotic capability, acute Myc activation triggers ubiquitous b cell apoptosis leading to rapid onset of diabetes. Either over-expression of the apoptosis suppressor Bcl-xL or loss of the ARF or p53 tumour suppressor pathway, suppresses Myc induced b cell apoptosis, transforming Myc from a net growth suppressor to potent tumour inducer, triggering synchronous and ubiquitous progression of b cells into invasive, angiogenic tumors. Thus, when apoptosis is suppressed, Myc appears to possess the capacity not only to drive cell proliferation but also the capacity of those cells to elicit nurturing vasculature and excavate somatic space. Consistent with this, de-activation of Myc triggers rapid vascular collapse, accompanied by complete tumor regression.
To explore the role of p53 loss in tumourigenesis and tumour maintenance, we have replaced the endogenous p53 gene with one encoding an ectopically switchable form of p53. In the absence of p53 function, mice develop lymphoma and their cells are refractory to DNA damage-induced apoptosis or growth arrest or replicative senescence and rapidly acquire genome instability. Restoration of p53 function reverses all these phenotypes, including aberrant chromosome copy number. Thus, restoration of p53 function in p53-deficient tumour cells activates occult checkpoints with profound anti-neoplastic potential.