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

Authors: 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.
Article Title: The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas
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. © 2007 Nature Publishing Group.
Keywords: signal transduction; protein kinase b; controlled study; gene deletion; pathogenesis; nonhuman; antineoplastic agent; mouse; animals; mice; mice, knockout; allele; mus; smooth muscle fiber; protein kinases; protein depletion; animal experiment; animal model; phosphatidylinositol 3 kinase; carcinogenesis; cell lineage; animalia; mice, transgenic; cell transformation, neoplastic; sarcoma; hyperplasia; mammalian target of rapamycin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; tumor growth; leiomyosarcoma; everolimus; cell hyperplasia; muscle, smooth; lifespan; abdominal cancer; insulin receptor substrate 2
Journal Title: Nature Medicine
Volume: 13
Issue: 6
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2007-06-01
Start Page: 748
End Page: 753
Language: English
DOI: 10.1038/nm1560
PUBMED: 17496901
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 75" - "Export Date: 17 November 2011" - "CODEN: NAMEF" - "Source: Scopus"
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