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mTOR Inhibition Mitigates Enhanced mRNA Translation Associated with the Metastatic Phenotype of Osteosarcoma Cells In Vivo
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 22(24)
- Publication Year :
- 2016
-
Abstract
- Purpose: To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention. Experimental Design: We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an antimetastatic therapeutic strategy through pharmacokinetic studies and preclinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis. Results: Metastatic osteosarcoma cells translate mRNA more efficiently than nonmetastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the MTDs defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents. Conclusions: Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression, and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo. Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression. Clin Cancer Res; 22(24); 6129–41. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Proteomics
Cancer Research
Mice, Nude
Apoptosis
Mice, SCID
Article
Metastasis
03 medical and health sciences
Mice
0302 clinical medicine
In vivo
Cell Line, Tumor
medicine
Animals
Humans
RNA, Messenger
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Cell Proliferation
Sirolimus
Mice, Inbred BALB C
Osteosarcoma
business.industry
TOR Serine-Threonine Kinases
Cancer
Translation (biology)
medicine.disease
Phenotype
Xenograft Model Antitumor Assays
030104 developmental biology
Oncology
Cell culture
030220 oncology & carcinogenesis
Immunology
Cancer research
Female
business
Signal Transduction
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 22
- Issue :
- 24
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....c605986e8c5c13019d367d3ee72e547c