The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas.
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.
Hernando
Eva
E
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Charytonowicz
Elizabeth
E
Dudas
Maria E
ME
Menendez
Silvia
S
Matushansky
Igor
I
Mills
Joslyn
J
Socci
Nicholas D
ND
Behrendt
Nille
N
Ma
Li
L
Maki
Robert G
RG
Pandolfi
Pier Paolo
PP
Cordon-Cardo
Carlos
C
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
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