Oncogene-dependent tumor suppression: using the dark side of the force for cancer therapy.
Cancers arise by an evolutionary process that involves the protracted acquisition by somatic cells of suites of interlocking mutations that uncouple proliferation, survival, migration, and damage responses from the mechanisms (selective pressures) that normally restrain or restrict them in time and space. The relative rareness of cancer cells within the soma, in the face of huge numbers of available cell targets, substantial rates of mutation, and an abundance of proto-oncogenes and tumor suppressor gene targets, indicates that the evolutionary space available to incipient tumor cells is highly restricted. The principal way in which this is achieved is through intrinsic tumor suppression pathways-innate growth arrest and apoptotic programs that fulfill an essentially analogous functional role to checkpoints in the cell cycle machinery by antagonizing the tumorigenic potential of oncogenic mutations. Using switchable transgenic and knockin mouse models, it is possible to identify these various tumor suppressor programs and establish where, when, how, and why they act to forestall neoplasia in each tissue type and, consequently, how and why their failure leads to cancer.
Evan
G I
GI
Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143-0875, USA.
Christophorou
M
M
Lawlor
E A
EA
Ringshausen
I
I
Prescott
J
J
Dansen
T
T
Finch
A
A
Martins
C
C
Murphy
D
D
D000818:Animals; D003043:Cocarcinogenesis; D020869:Gene Expression Profiling; D016259:Genes, myc; D016158:Genes, p53; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53