Abstract
Introduction: Obesity and newer chemotherapeutic agents used to treat metastatic colorectal carcinoma are associated with hepatic steatosis and Toll-like receptor-4 (TLR4) is increased in fatty liver. TLR4 is known to have pro-neoplastic effects in primary malignancies; however, the effect of hepatic TLR4 on metastatic liver tumor engraftment is unknown. The aim of this study was to determine if reduced TLR4 expression would alter the rate of metastatic tumor engraftment in steatotic liver. Methods: TLR4 deficient and corresponding wild-type C57Bl/10 mice were fed a diet of 60% fat or control diet to generate 4 groups of animals: Group 1 TLR4 intact/lean; Group 2 TLR4 deleted/lean; Group 3 TLR4 intact/obese; Group 4, TLR4 deleted/obese. Following 5 weeks of diet manipulation the mice underwent laparotomy and intrasplenic injection of 100,000 MC38 mouse colon adenocarcinoma cells. The diets were maintained for 28 days following operation at which time the mice were sacrificed and total liver tumor number and volume were measured. Liver steatosis was determined on H&E and Oil Red-O sections. Serum and tissue levels of IL-6 and TNF-a were measured by enzyme-linked immunosorbent assay. Differences between groups were measured using one-way ANOVA with the LSD procedure, all numbers reported as mean +/− standard deviation. Results: 1) Mice fed a high fat diet were consistently larger and had marked steatosis histologically compared to mice fed control diet. 2) Mean tumor number and volume was similar for all groups (number: Group 1 7.0+/−3.4; Group 2 10.8+/−12.0; Group 3 6.8+/−8.3; Group 4 4.3+/−5.3: p > 0.05 for all comparisons and volume: Group 1 272.1+/−465.6mm3; Group 2 595.5+/−917.3 mm3; Group 3 738.5+/−980.4 mm3; Group 4 1357.1+/−3280.6 mm3: p > 0.05 for all comparisons). 3) Serum levels of IL-6 and TNF-a were not markedly elevated and did not significantly differ. 4) Liver tissue levels of IL-6 and TNF-a were generally higher than serum, but were not significantly different among the groups. Conclusions: These findings indicate that in the setting of hepatic steatosis,TLR4 does not play a significant role in metastatic tumor engraftment.
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