Gender Differences in a Mouse Model of Hepatocellular Carcinoma Revealed Using Multi-Modal Imaging
Author:
Engel Brian J.1, Paolillo Vincenzo2, Uddin Md. Nasir1, Gonzales Kristyn A.3, McGinnis Kathryn M.3, Sutton Margie N.1ORCID, Patnana Madhavi4, Grindel Brian J.1, Gores Gregory J.5ORCID, Piwnica-Worms David1ORCID, Beretta Laura3ORCID, Pisaneschi Federica16ORCID, Gammon Seth T.1ORCID, Millward Steven W.1ORCID
Affiliation:
1. Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA 2. Cyclotron Radiochemistry Facility, UT MD Anderson Cancer Center, Houston, TX 77030, USA 3. Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA 4. Department of Abdominal Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA 5. College of Medicine, The Mayo Clinic, Rochester, MN 55905, USA 6. Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM) at the University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Abstract
The worldwide incidence of hepatocellular carcinoma (HCC) continues to rise, in part due to poor diet, limited exercise, and alcohol abuse. Numerous studies have suggested that the loss or mutation of PTEN plays a critical role in HCC tumorigenesis through the activation of the PI3K/Akt signaling axis. The homozygous knockout of PTEN in the livers of mice results in the accumulation of fat (steatosis), inflammation, fibrosis, and eventually progression to HCC. This phenotype bears a striking similarity to non-alcoholic steatohepatitis (NASH) which is thought to occupy an intermediate stage between non-alcoholic fatty liver disease (NAFLD), fibrosis, and HCC. The molecular and physiological phenotypes that manifest during the transition to HCC suggest that molecular imaging could provide a non-invasive screening platform to identify the hallmarks of HCC initiation prior to the presentation of clinical disease. We have carried out longitudinal imaging studies on the liver-specific PTEN knockout mouse model using CT, MRI, and multi-tracer PET to interrogate liver size, steatosis, inflammation, and apoptosis. In male PTEN knockout mice, significant steatosis was observed as early as 3 months using both magnetic resonance spectroscopy (MRS) and computed tomography (CT). Enhanced uptake of the apoptosis tracer 18F-TBD was also observed in the livers of male PTEN homozygous knockout mice between 3 and 4 months of age relative to heterozygous knockout controls. Liver uptake of the inflammation tracer [18F]4FN remained relatively low and constant over 7 months in male PTEN homozygous knockout mice, suggesting the suppression of high-energy ROS/RNS with PTEN deletion relative to heterozygous males where the [18F]4FN liver uptake was elevated at early and late time points. All male PTEN homozygous mice developed HCC lesions by month 10. In contrast to the male cohort, only 20% (2 out of 10) of female PTEN homozygous knockout mice developed HCC lesions by month 10. Steatosis was significantly less pronounced in the female PTEN homozygous knockout mice relative to males and could not accurately predict the eventual occurrence of HCC. As with the males, the [18F]4FN uptake in female PTEN homozygous knockout mice was low and constant throughout the time course. The liver uptake of 18F-TBD at 3 and 4.5 months was higher in the two female PTEN knockout mice that would eventually develop HCC and was the most predictive imaging biomarker for HCC in the female cohort. These studies demonstrate the diagnostic and prognostic role of multi-modal imaging in HCC mouse models and provide compelling evidence that disease progression in the PTEN knockout model is highly dependent on gender.
Funder
National Cancer Institute MD Anderson Center for Advanced Biomedical Imaging MD Anderson Quantitative Image Analysis Core Pilot National Eye Institute National Institute of Biomedical Imaging and Bioengineering NCI Cancer Center Support
Subject
Cancer Research,Oncology
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