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.
| Original language | English |
|---|---|
| Article number | e1007380 |
| Journal | PLoS Genetics |
| Volume | 14 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2018 |
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ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
Cite this
Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage. / Collino, Agnese; Termanini, Alberto; Nicoli, Paola; Diaferia, Giuseppe; Polletti, Sara; Recordati, Camilla; Castiglioni, Vittoria; Caruso, Donatella; Mitro, Nico; Natoli, Gioacchino; Ghisletti, Serena.
In: PLoS Genetics, Vol. 14, No. 5, e1007380, 01.05.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage
AU - Collino, Agnese
AU - Termanini, Alberto
AU - Nicoli, Paola
AU - Diaferia, Giuseppe
AU - Polletti, Sara
AU - Recordati, Camilla
AU - Castiglioni, Vittoria
AU - Caruso, Donatella
AU - Mitro, Nico
AU - Natoli, Gioacchino
AU - Ghisletti, Serena
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048229189&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048229189&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1007380
DO - 10.1371/journal.pgen.1007380
M3 - Article
C2 - 29734330
AN - SCOPUS:85048229189
VL - 14
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 5
M1 - e1007380
ER -