Technical Report abstract
Nature Medicine 13, 748 - 753 (2007)
Published online: 13 May 2007 | Corrected online: 21 May 2007 | doi:10.1038/nm1560
The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas
Eva Hernando1,5, Elizabeth Charytonowicz1, Maria E Dudas1, Silvia Menendez1, Igor Matushansky2, Joslyn Mills1, Nicholas D Socci3, Nille Behrendt1, Li Ma4, Robert G Maki2, Pier Paolo Pandolfi1,4 & Carlos Cordon-Cardo1,5
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.
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
- Computational Biology Center, New York, New York 10021, USA.
- Departments of Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
- Present addresses: Department of Pathology, Experimental Pathology Program, New York University School of Medicine, New York, New York 10016, USA (E.H.) and Department of Pathology, Columbia University, New York, New York 10032, USA (C.C.-C.).
Correspondence to: Pier Paolo Pandolfi1,4 e-mail: p-pandolfi@ski.mskcc.org
Correspondence to: Carlos Cordon-Cardo1,5 e-mail: cc2791@columbia.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomasNature Medicine Technical Report
Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancerNature Medicine Article (01 Jan 2005)
Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapyModern Pathology Original Article
Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapyModern Pathology Original Article
See all 13 matches for Research
