Aberrant hyperactivation of akt and Mammalian target of rapamycin complex 1 signaling in sporadic chordomas.
OBJECTIVE
Chordomas are rare, malignant bone neoplasms in which the pathogenic mechanisms remain unknown. Interestingly, tuberous sclerosis complex (TSC) is the only syndrome in which the incidence of chordomas has been described. We previously reported the pathogenic role of the TSC genes in TSC-associated chordomas. In this study, we investigated whether aberrant TSC/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is associated with sporadic chordomas.


METHODS
We assessed the status of mTORC1 signaling in primary tumors/cell lines of sacral chordomas and further examined upstream of mTORC1 signaling, including the PTEN (phosphatase and tensin homologue deleted on chromosome ten) tumor suppressor. We also tested the efficacy of the mTOR inhibitor rapamycin on signaling and growth of chordoma cell lines.


RESULTS
Sporadic sacral chordoma tumors and cell lines examined commonly displayed hyperactivated Akt and mTORC1 signaling. Strikingly, expression of PTEN, a negative regulator of mTORC1 signaling, was not detected or significantly reduced in chordoma-derived cell lines and primary tumors. Furthermore, rapamycin inhibited mTORC1 activation and suppressed proliferation of chordoma-derived cell line.


CONCLUSIONS
Our results suggest that loss of PTEN as well as other genetic alterations that result in constitutive activation of Akt/mTORC1 signaling may contribute to the development of sporadic chordomas. More importantly, a combination of Akt and mTORC1 inhibition may provide clinical benefits to chordoma patients.
Han
Sangyeul
S
Center for Human Genetic Research, Massachusetts General Hospital, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. syhan@partners.org
Polizzano
Carolyn
C
Nielsen
Gunnlaugur P
GP
Hornicek
Francis J
FJ
Rosenberg
Andrew E
AE
Ramesh
Vijaya
V
D049109:Cell Proliferation / Q000187:drug effects; D002817:Chordoma / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000502:physiology; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology
D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus