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CHANGES IN LIVER FIBROSIS DURING THE PROGRESSION OF CANCER-CACHEXIA IN MICE

Abstract

Kyle W. Turner*1, Megan E. Rosa-CaldwellƗ1, Jacob L. BrownƗ1, David E. LeeƗ1, Richard A. PerryƗ1, Wesley A. HaynieƗ1, Tyrone A. Washingtonǂ1, Michael P. Wiggsǂ2, Nicholas P. Greeneǂ1 1University of Arkansas, Fayetteville, Arkansas; 2Univeristy of Texas at Tyler, Tyler, Texas

Cancer is one of the most widespread and deadly diseases in recent history. Cancer-cachexia is a systematic, metabolic disorder that greatly disrupts the patient’s energy balance, causing uncontrollable weight and skeletal muscle loss. This cancer-induced cachexia is one of the major causes of cancer-related death. As the primary metabolic organ controlling energy balance, the liver is likely involved with the progression of cancer-cachexia. However, very little research has investigated the liver’s involvement in the progression of cancer-cachexia. PURPOSE: The purpose of this study was to observe changes in liver fibrosis during the progression of cancer-cachexia. METHODS: C57BL/6J mice were injected with 1X106 lewis lung carcinoma cells in the hind flank and cancer was allowed to progress for 1,2, 3, or 4 wks. Control animals were injected with sterile phosphate buffered saline solution (PBS) and harvested with 4 wks animals, creating five groups (CON, 1, 2, 3 or 4wks cancer progression, n=10-16/group). Livers were harvested and ~8 samples/group were analyzed for collagen deposition and measures of mitochondrial content. Results were analyzed by one-way ANOVA as well as regression analysis. When differences were found, a Tukey-Kramer post hoc was used to determine differences among means, significance was determined at p<0.05. RESULTS: Liver weights normalized to tibia length were ~30% larger in 4wks animals compared to all other groups (p<0.05). Sirius red staining for collagen indicated that collagen area increased over time in an exponential fashion (r2=0.78), with 4wks having statistically greater collagen deposition than all other groups. Preliminary analysis (n=4/group) of COX-IV content in the liver suggested no change in mitochondrial content. CONCLUSION: The liver is clearly affected by the progression of cancer-cachexia, becoming much larger and more fibrotic. It can be inferred that this fibrotic damage may also exacerbate the energy balance problems caused by cancer-cachexia. Therefore, further research needs to be conducted in this area to more thoroughly understand the liver’s role in this pathology.

This study was supported by The Arkansas Bioscience Institute and National Institutes of Health R15AR069913.

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