[CELL 109, 335-346, May 3, 2002]

Summary

p53 andINK4a/ARF mutations promote tumorogenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lympomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16INK4a. Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone - respond poorly to cyclophosphamide therapy in vivo. Morover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16INK4a, and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.

Figure 1. Contribution of p53 and Bcl2 to Treatment Responses

Mice harboring ctrl.-MSCV, p53 null-MSCV, and ctrl.-bcl2 lymphomas were treated at comparable tumor burdens (day 0) with a single dose of cyclophosphamide (CTX) and monitored by whole-body fluorescence imaging. Representative examples are shown.

[CANCER CELL 1, 289-298 April 2002]

Whole body fluorescence imaging of lymphoma progression in live mice. The cover shows the temporal and spatial progression of Em-myc lymphoma cells tagged with green fluorescent protein in a live mouse (with time progression from top to bottom). Note that the lymphomas first expand within the lympoid compartments and bone. In the absence of p53 or following Bcl-2 overexpression, these lympomas readily disseminate into nonlympoid compartments. For details see Schmitt et al. (pp. 289-298) in this issue.

Summary

 Although the p53 tumor supressor acts in plethora of processes that influence cellular proliferation and survival, it remains unclear which p53 functions are essential for tumor suppression and, as a consequence, are selected against during tumor development. Using a mouse model harbouring primary, genetically modified myc-driven lympomas, we show that disruption of apoptosis downstream of p53 by Bcl2 or a dominant-negative caspase 9 confers-like p53 loss-a selective advantage, and completely alleviates pressure to inactivate p53 during lymphomagenesis. Despite their p53-null-like aggressive phenotype, apoptosis-defective lymphomas that retain intact p53 genes do not display the checkpoint defects and gross aneuploidy that are charcteristic of p53 mutant tumors. Therefore, apoptosis is the only p53 function selected against during lymphoma development, whereas defective cell-cycle checkpoints and aneuploidy are mere byproducts of p53 loss.

Figure 4. Whole body fluorescence imaging allows visualisation of lymphoma dissemination.

Lymphomas with indicated genotypes and transduced with a GFP-coexpressing retrovirus were transplanted into recipients to monitor lymphoma dissemination in whole viable animals by GFP fluorescence.