title: In vitro engineering of human 3D chondrosarcoma: a preclinical model relevant for investigations of radiation quality impact.
abstract: BACKGROUND
  The benefit of better ballistic and higher efficiency of carbon ions for cancer treatment (hadron-therapy) is asserted since decades, especially for unresectable or resistant tumors like sarcomas. However, hadron-therapy with carbon ions stays underused and raises some concerns about potential side effects for patients. Chondrosarcoma is a cartilaginous tumor, chemo- and radiation-resistant, that lacks reference models for basic and pre-clinical studies in radiation-biology. Most studies about cellular effects of ionizing radiation, including hadrons, were performed under growth conditions dramatically different from human homeostasis. Tridimensional in vitro models are a fair alternative to animal models to approach tissue and tumors microenvironment.
  
  
  METHODS
  By using a collagen matrix, standardized culture conditions, physiological oxygen tension and a well defined chondrosarcoma cell line, we developed a pertinent in vitro 3D model for hadron-biology studies. Low- and high-Linear Energy Transfer (LET) ionizing radiations from GANIL facilities of ~1 keV/μm and 103 ± 4 keV/μm were used respectively, at 2 Gy single dose. The impact of radiation quality on chondrosarcoma cells cultivated in 3D was analyzed on cell death, cell proliferation and DNA repair.
  
  
  RESULTS
  A fair distribution of chondrosarcoma cells was observed in the whole 3D scaffold. Moreover, LET distribution in depth, for ions, was calculated and found acceptable for radiation-biology studies using this kind of scaffold. No difference in cell toxicity was observed between low- and high-LET radiations but a higher rate of proliferation was displayed following high-LET irradiation. Furthermore, 3D models presented a higher and longer induction of H2AX phosphorylation after 2 Gy of high-LET compared to low-LET radiations.
  
  
  CONCLUSIONS
  The presented results show the feasibility and usefulness of our 3D chondrosarcoma model in the study of the impact of radiation quality on cell fate. The observed changes in our tissue-like model after ionizing radiation exposure may explain some discrepancies between radiation-biology studies and clinical data.
authors.affiliation: LARIA-IRCM-DSV-Commissariat à l'Energie Atomique et aux Energies Alternatives, CIMAP, GANIL, Bd Henri Becquerel, BP 55027, 14076, Caen, cedex 05, France. hamdi@ganil.fr.
authors.forename: Dounia Houria
authors.initials: DH
authors.lastname: Hamdi
authors.affiliation: LARIA-IRCM-DSV-Commissariat à l'Energie Atomique et aux Energies Alternatives, CIMAP, GANIL, Bd Henri Becquerel, BP 55027, 14076, Caen, cedex 05, France. sofia.barbieri01@universitadipavia.it.|Università degli Studi di Pavia, Pavia, Italy. sofia.barbieri01@universitadipavia.it.
authors.forename: Sofia
authors.initials: S
authors.lastname: Barbieri
authors.affiliation: LARIA-IRCM-DSV-Commissariat à l'Energie Atomique et aux Energies Alternatives, CIMAP, GANIL, Bd Henri Becquerel, BP 55027, 14076, Caen, cedex 05, France. chevalier@ganil.fr.
authors.forename: François
authors.initials: F
authors.lastname: Chevalier
authors.affiliation: UMR6249-Université de Franche-Comté, Besançon, France. jegroetz@univ-fcomte.fr.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Groetz
authors.affiliation: EA4652-Normandie Université, Caen, France. florence.legendre@unicaen.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Legendre
authors.affiliation: EA4652-Normandie Université, Caen, France. magali.demoor@unicaen.fr.
authors.forename: Magali
authors.initials: M
authors.lastname: Demoor
authors.affiliation: EA4652-Normandie Université, Caen, France. philippe.galera@unicaen.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Galera
authors.affiliation: LARIA-IRCM-DSV-Commissariat à l'Energie Atomique et aux Energies Alternatives, CIMAP, GANIL, Bd Henri Becquerel, BP 55027, 14076, Caen, cedex 05, France. lefaix@ganil.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Lefaix
authors.affiliation: LARIA-IRCM-DSV-Commissariat à l'Energie Atomique et aux Energies Alternatives, CIMAP, GANIL, Bd Henri Becquerel, BP 55027, 14076, Caen, cedex 05, France. yannick.saintigny@cea.fr.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Saintigny
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002813:Chondrosarcoma / Q000473:pathology* / Q000532:radiotherapy; D004260:DNA Repair; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D011829:Radiation Dosage; D011839:Radiation, Ionizing; D011878:Radiotherapy / Q000379:methods / Q000592:standards
chemical_list: D006657:Histones