High Fat Diet Induced Hepatic Steatosis Establishes a Permissive Microenvironment for Colorectal Metastases and Promotes Primary Dysplasia in a Murine Model

Abstract

Non-alcoholic fatty liver disease (NAFLD), which includes steatosis and its progression to non-alcoholic steatohepatitis, is a liver disorder of increasing clinical significance. Here we characterize a murine model of high fat diet-induced NAFLD with progression from liver steatosis to histological features compatible with steatohepatitis and more advanced stages of NAFLD in humans, including chronic portal inflammation, pericellular and bridging fibrosis, Mallory body formation, and bile ductular reaction. Chronic changes induced by the prolonged consumption of a high-fat diet alone culminate in the development of primary liver dysplasias. Importantly, we extend these studies to demonstrate that even the early stages of uncomplicated steatosis provide a permissive microenvironment for the growth of colon cancer cells that are metastatic to the liver. High fat diet-induced steatosis, coupled with a splenic injection model of experimental liver metastasis using syngeneic MC38 colon cancer cells, resulted in an increased number of secondary tumor nodules and metastatic burden in steatotic livers. Metastatic nodules were associated with focal peritumoral areas of infiltrating inflammatory cells and associated apoptotic cell populations. These results suggest that the modulation of specific host factors in the steatotic liver contributes to tumor progression in the microenvironment of NAFLD.

A Preclinical Model of Chronic Alcohol Consumption Reveals Increased Metastatic Seeding of Colon Cancer Cells in the Liver

“…Because liver metastasis is the primary determinant of colorectal cancer patient survival, identifying the associated risk factors is necessary in the clinical field. Previous studies have presented the liver metastasis-enhancing effect of a high-fat diet and endotoxins on colorectal cancer (11,14); however, regarding alcohol consumption and liver metastasis in colorectal cancer, no experimental study has been conducted, and their relationship is only based on clinical observation (10) To investigate the effect of alcohol intake on the two main stages of cancer metastasis to the liver (survival and adhesion vs. metastatic colonization), we established a splenic injection model with MC38 cells under four different conditions of alcohol intake (control, prealcohol, postalcohol, or thorough alcohol consumption). Alcohol consumption significantly increased liver metastasis of colorectal cancer as evidenced by metastatic nodule numbers under naked view, histologic findings, as well as liver weights (Fig.…”

“…Liver metastasis was generated using a previously described splenic injection model (11). Briefly, the mice were anesthetized using a ketamine/xylazine mixture, and the spleen was exteriorized via a 5 mm incision in the left upper abdomen.…”

Recent Advances in Colorectal Cancer Research: The Microenvironment Impact

“…Most interestingly, it has been reported that a high fat diet induces an hepatic steatosis, which establishes a permissive microenvironment for colorectal metastases [19]. Notably, signals including those elicited by TGFβ are initiated from steatotic host microenvironment and they set the proper conditions for tumor development even in the initial stage.…”

Targeting liver inflammatory myeloid cells with immunomodulatory liposomes improves nonalcoholic steatohepatitis in mice

“…Imaging of mice identified DiR signal in the 79 liver and spleen at both time points (Figure 4-3, A and B In contrast to a high-fat diet, where the only source of calories is fat, the DIO model described in this chapter uses a 60% fat diet combined with excess sugar in water (55% fructose and 45% sucrose). In female C57BL/6J mice, 14 weeks of feeding with fat and fructose induces stage-3 liver fibrosis, which generally takes up to 14 months if mice are fed only a fat rich diet (307). The combination of both fat and sugar may be more relevant for human NAFLD, where fructose, a major source of sweetness in sugary beverages, is strongly associated with steatohepatitis and liver fibrosis in obese and type 2 diabetes patients (303).…”

“…Rodent models fed a high fat diet alone develop obesity and insulin resistance within 2- 4 72 weeks, but take about 9-14 months to develop severe steatohepatitis (307 …”