Tumor endothelial marker 1 (Tem1; endosialin) is the prototypical member of a family of genes expressed in the stroma of tumors. To assess the functional role of Tem1, we disrupted the Tem1 gene in mice by targeted homologous recombination. Tem1 ؊/؊ mice were healthy, their wound healing was normal, and tumors grew normally when implanted in s.c. sites. However, there was a striking reduction in tumor growth, invasiveness, and metastasis after transplantation of tumors to abdominal sites in mice without functional Tem1 genes. These data indicate that the stroma can control tumor aggressiveness and that this control varies with anatomic site. Therefore, they have significant implications for the mechanisms underlying tumor invasiveness and for models that evaluate this process.endosialin ͉ metastasis ͉ stroma ͉ tumor invasiveness ͉ angiogenesis
Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5′-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the LieberDeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5′-nucleotidase or adenosine A 1 or A 2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A 1 or A 2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A 1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A 2B receptors. In vitro studies supported roles for adenosine A 1 receptors in promoting fatty acid synthesis and for A 2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A 1 and A 2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver.
IntroductionFatty liver is the most common and earliest response of the liver to heavy alcohol consumption and may develop into alcoholic hepatitis and fibrosis. Although fatty liver is a very common medical problem and the molecular events involved in the pathogenesis of fatty liver are well understood, the connection between ethanol ingestion and metabolism and the activation of the events involved in the development of hepatic steatosis is not well understood.
In previous studies, we have demonstrated that adenosine and its receptors play a role in hepatic fibrosis. Here, we review evidence that toxin-induced increases in hepatic adenosine concentrations are generated from adenine nucleotides by the action of ecto-5'nucleotidase and thus that adenosine-mediated, toxin-induced hepatic fibrosis depends on extracellular conversion of adenine nucleotides to adenosine.
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