Abstract
BackgroundNon 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.MethodsWe 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.ResultsWe 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.ConclusionsThis study demonstrates that stromal as well as tumor derived MMP13 contribute to tumor cell extravasation and establishment of metastases in the liver microenvironment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-014-0282-0) contains supplementary material, which is available to authorized users.
Highlights
The obesity epidemic has been closely linked with an increased incidence of non alcoholic fatty liver disease (NAFLD) [1]
With the increasing recognition of Non alcoholic fatty liver disease (NAFLD) as a significant liver disease, it is highly relevant to understand which matrix metalloproteinases (MMPs) are altered in the steatotic microenvironment and whether these MMPs contribute to the increased metastasis
We found that Mmp12 (P < 0.001) and Mmp13 (P < 0.05) were significantly upregulated in the liver of mice with steatosis compared to normal livers using 2-way ANOVA followed by the Bonferroni post-test (Figure 1a)
Summary
The obesity epidemic has been closely linked with an increased incidence of non alcoholic fatty liver disease (NAFLD) [1]. The changes in the tissue microenvironment can affect cell-cell interactions and influence the development of both primary and metastatic tumors. Epidemiological studies show that NAFLD has been linked to an increase in the risk for development of primary liver cancer [4,5] but very little is known about the effect of steatosis on tumor metastasis to the liver. Obesity is an independent risk factor for the development of these tumor types among others [6]. 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
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