Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.
Your institute does not have access to this article
Open Access articles citing this article.
Inflammation and Regeneration Open Access 07 February 2022
Journal of Hematology & Oncology Open Access 22 July 2021
Cell Communication and Signaling Open Access 04 June 2021
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Borden, E.C. et al. Soft tissue sarcomas of adults: state of the translational science. Clin. Cancer Res. 9, 1941–1956 (2003).
Symonds, H. et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78, 703–711 (1994).
Yin, C., Knudson, C.M., Korsmeyer, S.J. & Dyke, T.V. Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385, 637–640 (1997).
Toledo, F. et al. A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network. Cancer Cell 9, 273–285 (2006).
Liu, G. et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat. Genet. 36, 63–68 (2004).
Chien, Y.-H. et al. Heteroduplex analysis of the sequence relationships between the genomes of Kirsten and Harvey sarcoma viruses, their respective parental leukemia viruses, and the rat endogenous 30S RNA. J. Virol. 31, 752–760 (1979).
Hong, H.H. et al. Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years. Toxicol. Pathol. 28, 529–534 (2000).
Weihrauch, M. et al. Mutation analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride. Environ. Mol. Mutagen. 40, 36–40 (2002).
Garcia, J.M. et al. Mutational status of K-ras and TP53 genes in primary sarcomas of the heart. Br. J. Cancer 82, 1183–1185 (2000).
Hill, M.A. et al. Detection of K-ras mutations in resected primary leiomyosarcoma. Cancer Epidemiol. Biomarkers Prev. 6, 1095–1100 (1997).
Sakamoto, A. et al. H-, K-, and N-ras gene mutation in atypical fibroxanthoma and malignant fibrous histiocytoma. Hum. Pathol. 32, 1225–1231 (2001).
Tuveson, D.A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
Olive, K.P. et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119, 847–860 (2004).
Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000).
White, L.M. et al. Histologic assessment of peritumoral edema in soft tissue sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 61, 1439–1445 (2005).
Weissleder, R. & Ntziachristos, V. Shedding light onto live molecular targets. Nat. Med. 9, 123–128 (2003).
Grimm, J. et al. Use of gene expression profiling to direct in vivo molecular imaging of lung cancer. Proc. Natl. Acad. Sci. USA 102, 14404–14409 (2005).
Clark, M.A.C.F., Judson, I. & Thomas, J.M. Medical progress: soft-tissue sarcomas in adults. N. Engl. J. Med. 353, 701–711 (2005).
Jackson, E.L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005).
Zhang, Y., Xiong, Y. & Yarbrough, W.G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92, 725–734 (1998).
Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).
Sherr, C.J. The INK4a/ARF network in tumour suppression. Nat. Rev. Mol. Cell Biol. 2, 731–737 (2001).
Matushansky, I. & Maki, R.G. Mechanisms of Sarcomagenesis. Hematol. Oncol. Clin. North Am. 19, 427–449 (2005).
Zong, W.X., Lindsten, T., Ross, A.J., MacGregor, G.R. & Thompson, C.B. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 15, 1481–1486 (2001).
Wei, M.C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 624–626 (2001).
Tsumura, H., Yoshida, T., Saito, H., Imanaka-Yoshida, K. & Suzuki, N. Cooperation of oncogenic K-ras and p53 deficiency in pleomorphic rhabdomyosarcoma development in adult mice. Oncogene 25, 7673–7679 (2006).
Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).
Jackson, E.L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).
Takeuchi, O. et al. Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease. Proc. Natl. Acad. Sci. USA 102, 11272–11277 (2005).
Montet, X., Ntziachristos, V., Grimm, J. & Weissleder, R. Tomographic fluorescence mapping of tumor targets. Cancer Res. 65, 6330–6336 (2005).
We thank A. Berns (Netherlands Cancer Institute) for providing the Trp53Fl mice and R. Depinho (Dana Farber Cancer Institute) for the Cdkn2afFl mice. We thank W. Strob and S. Schmidt from Siemens AG - Medical Solutions, Erlangen, for providing the prototype handheld near-infrared imaging device. We also thank S. Rhee and P. Waterman for performing the MRI and FMT imaging, K. Reilly for suggestions on immunohistochemistry, K. Mercer for performing necropsies, and members of the Jacks lab for advice and critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute (T.J.), partially by Cancer Center Support (core) grant P30-CA14051 from the US National Cancer Institute (to T.J.), R24 CA92782 (to R.W.), P50 CA86355 (to R.W.), U54 CA119349 (to R.W. and T.J.), KO8 CA 114176 (to D.G.K.), the Leaf fund (to D.G.K.), and the Burroughs Wellcome Fund (to D.M.D.). T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar.
Ralph Weissleder is a founder of and holds shares of stock in VisEn Medical, a company that is developing experimental imaging technologies.
Christian Schultz is employed by Siemens Medical Solutions USA, a company that is developing medical imaging equipment and technologies.
About this article
Cite this article
Kirsch, D., Dinulescu, D., Miller, J. et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med 13, 992–997 (2007). https://doi.org/10.1038/nm1602
Inflammation and Regeneration (2022)
Journal of Hematology & Oncology (2021)
Cell Communication and Signaling (2021)
Scientific Reports (2021)
Nature Communications (2020)