| First Author | Hernando E | Year | 2007 |
| Journal | Nat Med | Volume | 13 |
| Issue | 6 | Pages | 748-53 |
| PubMed ID | 17496901 | Mgi Jnum | J:121901 |
| Mgi Id | MGI:3712611 | Doi | 10.1038/nm1560 |
| Citation | Hernando E, et al. (2007) The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13(6):748-753 |
| abstractText | 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.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. |
