Development of a methodology for in vivo follow-up of hepatocellular carcinoma in hepatocyte specific Trim24-null mice treated with myo-inositol trispyrophosphate - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Journal of experimental & clinical cancer research Année : 2016

Development of a methodology for in vivo follow-up of hepatocellular carcinoma in hepatocyte specific Trim24-null mice treated with myo-inositol trispyrophosphate

Mihaela Ignat
  • Fonction : Auteur
Cherif Akladios
  • Fonction : Auteur
  • PersonId : 1114552
Veronique Lindner
  • Fonction : Auteur
  • PersonId : 1065503
Konstantin Khetchoumian
  • Fonction : Auteur
Pierre Marc Aprahamian
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  • PersonId : 1134659
Jacques Marescaux
  • Fonction : Auteur

Résumé

BACKGROUND: Genetically induced hepatocellular carcinoma (HCC) models are generally used to investigate carcinogenesis pathways, but very few attempts were made to valorize them for pharmacological testing. This study describes a micro-computed tomography (micro-CT) - based methodology for the diagnostic and lifelong follow-up of HCC in the hepatocyte-specific Trim24-null mouse line. Myo-inositol trispyrophosphate (ITPP) was tested as anti-cancer drug. METHODS: Partial hepatectomy was performed in 2 months-old Trim24-null mice, in order to accelerate the carcinogenesis process. HCC diagnosis was obtained by micro-CT scan with double contrast agent: 10 mul/g Fenestra LC was injected intraperitoneally 6 h prior to imaging and 10 mul/g Fenestra VC was injected intravenously 15 min prior to imaging. Twenty three hepatocyte-specific Trim24-null mice were considered for ITPP testing (3 mg/g/week intraperitoneally during 10 months in 12 mice, versus 11 controls). Lifelong follow-up was performed using micro-CT. Comparative analysis was performed using unpaired t test with Welch correction and survival curves were compared by log-rank test. Gene expression analysis was performed using the RT q-PCR technique. RESULTS: Double contrast micro-CT scan allowed HCC diagnosis as hypodense, isodense or hyperdense nodules. Positive predictive value was 81.3 %. Negative predictive value was 83.3 %. Tumor growth could be objectified by micro-CT scan before the ITPP treatment was started, and at 3 and 9 months follow-up. Significant progression of tumor volume was demonstrated in the both groups, with no difference between groups (p > 0.05). In the ITPP group, a mild decrease in tumor doubling time was first observed (31.9 +/- 12 days, p > 0.05) followed by a significant increase (59.8 +/- 18.3 days, p = 0.008). However, tumor doubling time was not different between groups (p > 0.05). Median survival after treatment initiation was 223 days (controls) versus 296 days (ITPP group, p = 0.0027). HIF1alpha, VEGF, glutamine synthase, osteopontin expression levels were not significantly modified at the end of follow-up. In the ITPP group, the p53 expression profile was inversed as compared to the control group, higher in non-tumor livers than in tumors. CONCLUSION: ITPP treatment allowed for a two-month survival improvement, with better tolerance of tumor burden and apoptosis increase in non-tumor, pathological livers.

Dates et versions

hal-03680459 , version 1 (27-05-2022)

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Mihaela Ignat, Cherif Akladios, Veronique Lindner, Konstantin Khetchoumian, Marius Teletin, et al.. Development of a methodology for in vivo follow-up of hepatocellular carcinoma in hepatocyte specific Trim24-null mice treated with myo-inositol trispyrophosphate. Journal of experimental & clinical cancer research, 2016, 35 (1), ⟨10.1186/s13046-016-0434-8⟩. ⟨hal-03680459⟩
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