Highlights
- •Chondrosarcoma stem cells (ChSCs) are radioresistant and are suppressed by miR-34.
- •mTOR inhibition by Rapamycin targets ChSCs via FOXO3 and miR-34.
- •Combination of carbon-ion therapy with mTOR inhibitors effectively controls ChSCs.
Abstract
Background and purpose
High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors
of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently
needed.
Material and methods
Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with
miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem
cells, stemness-associated phenotype, radioresistance and tumor-initiating properties
were evaluated.
Results
We show that high-grade chondrosarcoma cells contain a population of radioresistant
cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34
mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression.
mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression.
Conclusion
Our results show that particle therapy combined with molecular treatments effectively
controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.
Abbreviations:
ALDH (aldehyde dehydrogenase), CFE (colony forming efficiency), CS (chondrosarcoma), CSC (cancer stem cell), LET (linear energy transfer), mTOR (mammalian target of rapamycin), NTCP (normal tissue complication probability), OER (oxygen enhancement ratio), PARP (poly ADP ribose polymerase), RBE (relative biological effectiveness), TCP (tumor control probability)Keywords
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Article info
Publication history
Published online: July 24, 2020
Accepted:
July 20,
2020
Received in revised form:
July 20,
2020
Received:
January 29,
2020
Identification
Copyright
© 2020 Elsevier B.V. All rights reserved.
