Host and tumor derived MMP13 regulate extravasation and establishment of colorectal metastases in the liver.

BACKGROUND: Non alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the United States and worldwide. Our studies have previously shown an increase in metastatic burden in steatotic vs. normal livers using a mouse model of diet induced steatosis. In the present study we aim to identify and evaluate the molecular factors responsible for this increase in tumor burden. METHODS: We assessed changes in expression of a panel of matrix metalloproteinases (MMPs) using qRT-PCR between normal and steatotic livers and validated them with western blot analysis of protein levels. To evaluate the role of MMP13 on tumor development, we utilized a splenic injection model of liver metastasis in Wildtype and Mmp13 deficient mice, using either parental or stable Mmp13 knockdown cell lines. Further, to evaluate changes in the ability of tumor cells to extravasate we utilized whole organ confocal microscopy to identify individual tumor cells relative to the vasculature. MTT, migration and invasion assays were performed to evaluate the role of tumor derived MMP13 on hallmarks of cancer in vitro. RESULTS: We found that MMP13 was significantly upregulated in the steatotic liver both in mice as well as human patients with NAFLD. We showed a decrease in metastatic tumor burden in Mmp13-/- mice compared to wildtype mice, explained in part by a reduction in the number of tumor cells extravasating from the hepatic vasculature in the Mmp13-/- mice compared to wildtype mice. Additionally, loss of tumor derived MMP13 through stable knockdown in tumor cell lines lead to decreased migratory and invasive properties in vitro and metastatic burden in vivo. CONCLUSIONS: This study demonstrates that stromal as well as tumor derived MMP13 contribute to tumor cell extravasation and establishment of metastases in the liver microenvironment.

Importance of conserving middle hepatic vein distal branches for homogeneous regeneration of the left liver after right hepatectomy.

BACKGROUND: Liver regeneration enables repeat surgical procedures to achieve a potential cure in liver cancer patients. However, data regarding segmental regeneration and liver anatomy after liver resection are scarce. This study examined left liver regeneration after right hepatectomy and the impact of hepatic venous drainage on the regeneration of the paramedian sector (Couinaud's segment IV). METHODS: Twenty patients in whom right hepatectomy with conservation of the middle hepatic vein (MHV) on healthy liver had been performed were analysed for segmental volumes and vascular anatomy. Volumetric analysis of left liver segments and three-dimensional MHV reconstruction were conducted using pre- and postoperative computed tomography. The volumetric proportions represented by each segment within the left liver were compared and MHV anatomy was analysed to determine its potential role in the regeneration of left liver segments. RESULTS: After right hepatectomy, the proportion represented by segment IV within the left liver decreases by 13%, whereas the proportion represented by segments II and III increases by 15%. This heterogeneous regeneration is particularly observed in patients in whom a venous branch for segment IVb is sacrificed, leading to an altered outflow similar to that observed in MHV deprivation. The risk for venous branch deprivation in IVb is correlated to the depth of the bifurcation of the MHV in liver parenchyma. CONCLUSIONS: It is crucial to conserve the MHV in its distal part if homogeneous left liver regeneration after right hepatectomy that will allow potential repeat liver resection is to be achieved.

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.