High fat diet induced hepatic steatosis establishes a permissive microenvironment for colorectal metastases and promotes primary dysplasia in a murine model.
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.
VanSaun
Michael Nathan
MN
Departments of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37212, USA.
Lee
In Kyu
IK
Washington
Mary Kay
MK
Matrisian
Lynn
L
Gorden
David Lee
DL
D000230:Adenocarcinoma / Q000556:secondary*; D000818:Animals; D015179:Colorectal Neoplasms / Q000473:pathology*; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000473:pathology*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000150:complications / Q000473:pathology
D004041:Dietary Fats