Changes in Hepatic Extracellular Matrix During the Development of Cancer-Cachexia in Mice

CHANGES IN HEPATIC EXTRACELLULAR MATRIX DURING THE DEVELOPMENT OF CANCER-CACHEXIA IN MICE Turner K.W.1, Rosa-Caldwell M.E.1, Brown J.L.1, Lee D.E.1, Perry R.A.1, Haynie W.A.1 Washington T.A.1, Wiggs M.P.2, Greene N.P.1: 1University of Arkansas, Fayetteville, Arkansas; 2Univeristy of Texas at Tyler, Tyler, Texas BACKGROUND: Cancer is one of the most widespread and deadly diseases in recent history. Cancer-cachexia is a systemic, metabolic disorder that greatly disrupts the patient’s energy balance, causing uncontrollable weight and, specifically, skeletal muscle loss. This cancer-induced cachexia is one of the major causes of cancer-related death. As a 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 examine hepatic extracellular matrix (ECM) changes during the development 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 age-matched with 4 wks animals, creating five groups (CON, 1, 2, 3 or 4 wks cancer progression, n=10-16/group). Livers were collected and ~9-10 samples/group were analyzed for collagen deposition via Sirius Red Staining. Liver mRNA was isolated, converted to cDNA, and quantified with Real Time Polymerase Chain Reaction (RT-PCR) for content of Collagen I, Collagen III, and MMP-9. Collagen I:III ratio was also calculated based on RT-PCR. Results were analyzed by one-way ANOVA as well as regression analysis. When significant F ratios were found, a Tukey-Kramer post hoc test was used to determine differences among means, significance was determined at pRESULTS: Liver weights normalized to tibia length were ~30% larger in 4 wks animals compared to all other groups (p2=0.78), with 4 wks having statistically greater collagen deposition than all other groups (p0.05). CONCLUSION: The liver is clearly affected by the progression of cancer-cachexia, becoming much larger and more fibrotic. Between 3 and 4 wks of cancer progression, the hepatic ECM undergoes rapid change as mRNA content for Collagen I, Collagen III, MMP-9, and actual collagen deposition are significantly higher than all other groups, likely resulting in decreased liver function and negatively affecting the health of the organism. Therefore, more thorough examinations are needed understand the mechanisms triggering hepatic ECM changes and their functional role during cancer cachexia progression. This study was supported by The Arkansas Bioscience Institute and National Institutes of Health R15AR069913