Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas

This article has been updated

Abstract

We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding PtenloxP/loxP mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/PtenloxP/loxP mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.

Note: In the version of this article initially published online, the name of the fifth author was misspelled. The correct name is Matushansky. The error has been corrected for all versions of the article.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The PI3K/AKT pathway is markedly upregulated in leiomyosarcomas and MFH/HGUPS.
Figure 2: PTEN deletion in smooth muscle cells predisposes mice to hyperplasia.
Figure 3: Tagln-cre/PtenloxP/loxP mice develop abdominal and retroperitoneal leiomyosarcomas.
Figure 4: Progression from smooth muscle hyperplasia to sarcoma in Tagln-cre/PtenloxP/loxP mice is strongly associated with sequential mTOR activation and upregulation of p19Arf and Mdm2.
Figure 5: Rapamycin treatment decelerates tumor growth and markedly prolongs the survival of Tagln-cre/PtenloxP/loxP mice compared to untreated mice.

Similar content being viewed by others

Change history

  • 21 May 2007

    Note: In the version of this article initially published online, the name of the fifth author was misspelled. The correct name is Matushansky. The error has been corrected for all versions of the article.

References

  1. Helman, L.J. & Meltzer, P. Mechanisms of sarcoma development. Nat. Rev. Cancer 3, 685–694 (2003).

    Article  CAS  Google Scholar 

  2. Vivanco, I. & Sawyers, C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  3. Sun, Y. et al. IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Oncogene 25, 1042–1052 (2006).

    Article  CAS  Google Scholar 

  4. Xiao, G.H. et al. Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc. Natl. Acad. Sci. USA 98, 247–252 (2001).

    Article  CAS  Google Scholar 

  5. Hu, J. et al. Loss of DNA copy number of 10q is associated with aggressive behavior of leiomyosarcomas: a comparative genomic hybridization study. Cancer Genet. Cytogenet. 161, 20–27 (2005).

    Article  CAS  Google Scholar 

  6. Segal, N.H. et al. Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am. J. Pathol. 163, 691–700 (2003).

    Article  CAS  Google Scholar 

  7. Trotman, L.C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).

    Article  Google Scholar 

  8. Lepore, J.J. et al. High-efficiency somatic mutagenesis in smooth muscle cells and cardiac myocytes in SM22α-Cre transgenic mice. Genesis 41, 179–184 (2005).

    Article  CAS  Google Scholar 

  9. Hornick, J.L. & Fletcher, C.D. Criteria for malignancy in nonvisceral smooth muscle tumors. Ann. Diagn. Pathol. 7, 60–66 (2003).

    Article  Google Scholar 

  10. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P.P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).

    Article  CAS  Google Scholar 

  11. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  Google Scholar 

  12. Zhou, B.P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat. Cell Biol. 3, 973–982 (2001).

    Article  CAS  Google Scholar 

  13. Bjornsti, M.A. & Houghton, P.J. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer 4, 335–348 (2004).

    Article  CAS  Google Scholar 

  14. Majumder, P.K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med. 10, 594–601 (2004).

    Article  CAS  Google Scholar 

  15. Xie, Y., Skytting, B., Nilsson, G., Brodin, B. & Larsson, O. Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype. Cancer Res. 59, 3588–3591 (1999).

    CAS  PubMed  Google Scholar 

  16. Carsillo, T., Astrinidis, A. & Henske, E.P. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc. Natl. Acad. Sci. USA 97, 6085–6090 (2000).

    Article  CAS  Google Scholar 

  17. Yeung, R.S. et al. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc. Natl. Acad. Sci. USA 91, 11413–11416 (1994).

    Article  CAS  Google Scholar 

  18. Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    Article  CAS  Google Scholar 

  19. Radany, E.H., Hong, K., Kesharvarzi, S., Lander, E.S. & Bishop, J.M. Mouse mammary tumor virus/v-Ha-ras transgene-induced mammary tumors exhibit strain-specific allelic loss on mouse chromosome 4. Proc. Natl. Acad. Sci. USA 94, 8664–8669 (1997).

    Article  CAS  Google Scholar 

  20. Politi, K. et al. A mouse model of uterine leiomyosarcoma. Am. J. Pathol. 164, 325–336 (2004).

    Article  CAS  Google Scholar 

  21. Holtwick, R. et al. Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc. Natl. Acad. Sci. USA 99, 7142–7147 (2002).

    Article  CAS  Google Scholar 

  22. Li, L., Miano, J.M., Cserjesi, P. & Olson, E.N. SM22 alpha, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis. Circ. Res. 78, 188–195 (1996).

    Article  CAS  Google Scholar 

  23. Wijesekara, N. et al. Muscle-specific Pten deletion protects against insulin resistance and diabetes. Mol. Cell. Biol. 25, 1135–1145 (2005).

    Article  CAS  Google Scholar 

  24. Di Cristofano, A. et al. Impaired Fas response and autoimmunity in Pten+/− mice. Science 285, 2122–2125 (1999).

    Article  CAS  Google Scholar 

  25. Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    Article  CAS  Google Scholar 

  26. Sarbassov, D.D., Guertin, D.A., Ali, S.M. & Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  Google Scholar 

  27. Dei Tos, A.P. et al. Tumor suppressor genes and related molecules in leiomyosarcoma. Am. J. Pathol. 148, 1037–1045 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Florenes, V.A. et al. MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. J. Natl. Cancer Inst. 86, 1297–1302 (1994).

    Article  CAS  Google Scholar 

  29. Rieske, P. et al. A comparative study of P53/MDM2 genes alterations and P53/MDM2 proteins immunoreactivity in soft-tissue sarcomas. J. Exp. Clin. Cancer Res. 18, 403–416 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C. Matei, C. Le and M. Lupu for help with the MRI analysis; W. Golden, T. Matos and M.S. Jiao for technical assistance; and E. Diaz-Rodriguez, R. Sotillo and members of the C.C.-C. and P.P.P. laboratories (T.-H. Shen, M. Drobnjak, A. Alimonti, L. Trotman) for discussion, editorial advice and critical reading of the manuscript. We thank R. Parsons (Columbia University) for the IRS2 antibody; A.J. Levine (University of Medicine and Dentistry of New Jersey (UMDNJ)) for the MDM2 antibody; and S.W. Lowe (Cold Spring Harbor Laboratory (CSHL)) for the PML antibody. This work was partially supported by philantropic funds from the R.O. Perelman foundation. C.C.-C. and P.P.P. are supported by grants from the US National Institutes of Health (NIH/NCI PO1 CA47179).

Author information

Authors and Affiliations

Authors

Contributions

E.H. designed and performed experiments and wrote the manuscript. E.C. and S.M. performed animal studies, dissections, genotyping and western blot analyses. E.C. carried out DNA, RNA and protein extraction and sequencing. M.E.D. performed IHC analyses. J.M. assisted in tissue culture and western blot analyses. I.M. assisted with interpretation of the data and editing of the manuscript. N.D.S. performed the statistical analyses on human data. N.B. assisted on laser capture microdissection (data not shown). L.M. designed and characterized the pTSC2 antibody. R.G.M. contributed to assembling the human clinical databases and edited the manuscript. C.C.-C. interpreted the mouse histopathology, quantified the expression levels of IHC markers in human samples and assisted in the graphical illustration of the results. E.H., P.P.P. and C.C.-C. designed and conceptualized the study, analyzed and interpreted all data and edited the manuscript.

Corresponding authors

Correspondence to Pier Paolo Pandolfi or Carlos Cordon-Cardo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Schematic representation of the AKT-mTOR pathway and upstream signaling cascades impacting directly on indirectly on Akt activation, some of which are reported as deregulated in human STS. (PDF 181 kb)

Supplementary Fig. 2

SM22αcre/PtenloxP/loxP mice also develop non-sarcomatous tumors. (PDF 2375 kb)

Supplementary Fig. 3

Western blots analyses of PTEN, p-Akt and p-S6 on total lysates of normal and tumor samples from SM22αcre/PtenloxP/loxP mice. (PDF 159 kb)

Supplementary Fig. 4

Increasing levels of p-4E-BP1 and β-catenin in the progression from SM hyperplasia to leiomyosarcoma. (PDF 1021 kb)

Supplementary Table 1

Relative mRNA expression levels of components of the AKT-mTOR pathway and upstream membrane receptors assesed by microarray analysis of different STS subtypes.6 (PDF 103 kb)

Supplementary Table 2

Evaluation of expression levels of PI3K-AKT components in various soft tissue sarcomas. (PDF 122 kb)

Supplementary Table 3

Criteria for scoring IHC stainings. (PDF 136 kb)

Supplementary Table 4

Tumor incidence in SM22αcre/Ptenlox/lox mice (n=18). (PDF 49 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hernando, E., Charytonowicz, E., Dudas, M. et al. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13, 748–753 (2007). https://doi.org/10.1038/nm1560

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1560

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing