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 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.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Charytonowicz
authors.forename: Maria E
authors.initials: ME
authors.lastname: Dudas
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Igor
authors.initials: I
authors.lastname: Matushansky
authors.forename: Joslyn
authors.initials: J
authors.lastname: Mills
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Nille
authors.initials: N
authors.lastname: Behrendt
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007890:Leiomyosarcoma / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000201:enzymology / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012509:Sarcoma / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse