A mouse model of soft tissue sarcomas with conditional p53 and K-Ras mutations faithfully replicates key facets of the human disease and may prove to be an excellent model to study the pathogenesis of sarcoma.
Soft tissue sarcomas (STS) can be grouped into those with chromosomal translocations and a relatively simple karyotype, and those with a complex karyotype involving p53 pathway inactivation. The precise mechanism by which inactivation of p53 causes sarcomagenesis is unclear, although it is known that additional oncogenic mutations are required. David Kirsch et al. have now generated a temporally and spatially restricted mouse model of STS with conditional mutations in the endogenous Kras and Trp53 genes to study this further.
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The authors injected an adenovirus expressing Cre recombinase (Ad-Cre) into the muscles of the extremities of mice to induce the expression of conditional mutations in KrasG12D and Trp53. More than 90% of the mice developed STS when both mutant genes were expressed (confirmed by PCR). However, if the mice were infected with Ad-GFP (green fluorescent protein), or carried one wild-type Trp53 allele, no sarcomas developed. Moreover, of 53 mice with mutant Trp53 but wild-type Kras, only one developed STS. Therefore, cooperation between Kras and mutated Trp53 was necessary for efficient sarcomagenesis.
So, how do expression of KrasG12D and inactivation of Trp53 cooperate in this mouse model? Aberrant oncogene expression can induce the expression of ARF, which sequesters MDM2, a negative regulator of p53, thereby allowing p53 to function as a tumour suppressor. In line with this, David Kirsch et al. found that the proteins encoded by the Cdkn2a locus — INK4a and ARF — are upregulated in the STS found in their mouse model, but not in normal skeletal muscle from the same mouse. These results indicate that the Cdkn2a locus can respond to oncogenic KRAS in mesenchymal tissues to suppress sarcomagenesis through p53. Consistent with this hypothesis, the authors showed that deletion of Cdkn2a, but not key components of the intrinsic pathway of apoptosis downstream of p53 — Bak1 or Bax — could substitute for the mutation of p53. This suggests that sarcoma suppression by p53 in this model occurs by cell-cycle arrest or senescence and not by apoptosis.
This mouse model of STS has physiological expression levels of mutant Kras and Trp53, temporally and spatially controlled tumours, and importantly about 20% of mice with large extremity sarcomas developed metastases in the lungs but no evidence of metastases in the lymph nodes — all of which mimics human sarcomas. This will therefore be a useful model for further studies of the molecular pathogenesis of sarcoma and for testing new therapies.
Ezzie Hutchinson
References
Kirsch, D. G. et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nature Medicine13, 992–997 (2007) | Article | PubMed |
