Abstract
Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.
Highlights
The microenvironment of chronically inflamed tissues is a source of multiple mediators that trigger and sustain cellular transformation and tumorigenesis [1,2,3,4]
We found that while chronic liver inflammation was associated with the induction of a stressresponse characterized by the induction of metalloproteinases and collagen genes among the others, Hepatocellular Carcinoma (HCC) development was characterized by the downregulation of these inflammatory programs and instead a robust transcriptional activation of genes encoding enzymes involved in the two phases of metabolic transformations and detoxification, namely Phase I and Phase II transformations, as well as efflux transporters involved in the extrusion of transformed metabolites from cells
The 48 hours clodronate treatment resulted in a significant macrophage depletion from both inflamed livers and cancer nodules of Mdr2-/- mice, as shown in S1A and S1B Fig. An RNAseq analysis carried out in livers of untreated and clodronate treated mice revealed that genes differentially expressed by clodronate treatment were significantly enriched for ontology terms associated to macrophage and lymphocyte function (S1C Fig, S1 Table)
Summary
The microenvironment of chronically inflamed tissues is a source of multiple mediators that trigger and sustain cellular transformation and tumorigenesis [1,2,3,4]. A straightforward logical assumption is that for cells to emerge, thrive and eventually develop cancers in such contexts, they must acquire early in tumorigenesis the ability either to efficiently cope with the damage exerted by toxic agents or to promote their detoxification. To directly test this hypothesis, we used a well-characterized model of liver cancer, in which the absence of ABCB4, a transporter for phosphatidylcholine expressed selectively in hepatocytes and encoded by the Mdr gene, results in defective emulsification of bile acids and their precipitation on the bile canalicular surface of hepatocytes, leading to membrane damage, cell death and chronic inflammation. These cancers are etiologically and genetically similar to those occurring in pediatric patients with type 2 Progressive Familial Intrahepatic Cholestasis (PFIC), in which mutations in the same family of hepatocyte transporters results in liver cancer by the age of five [10,11]
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