Hernando, E., Charytonowicz, E., Dudas, M. E., Menendez, S., Matushansky, I., Mills, J., Socci, N. D., Behrendt, N., Ma, L., Maki, R. G., Pandolfi, P. P., Cordon-Cardo, C. (June 2007) The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med, 13 (6). pp. 748-53. ISSN 1078-8956 (Print)1078-8956 (Linking)
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 Pten(loxP/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 (approximately 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/Pten(loxP/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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Cell Transformation, Neoplastic/genetics/metabolism/pathology Female Humans Hyperplasia Leiomyosarcoma/*enzymology/*etiology/pathology Male Mice Mice, Knockout Mice, Transgenic Muscle, Smooth/enzymology/pathology PTEN Phosphohydrolase/deficiency/genetics Phosphatidylinositol 3-Kinases/physiology Protein Kinases/*physiology Proto-Oncogene Proteins c-akt/*physiology Sarcoma/enzymology/etiology/pathology Signal Transduction/genetics/*physiology TOR Serine-Threonine Kinases |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN diseases & disorders > cancer > cancer types > sarcoma |
| CSHL Authors: | |
| Communities: | CSHL labs > Maki lab |
| Depositing User: | Matt Covey |
| Date: | June 2007 |
| Date Deposited: | 26 Oct 2016 19:20 |
| Last Modified: | 26 Oct 2016 19:20 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33674 |
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