Promote Liver Carcinogenesis Research Articles

High-Fat Diet Delays Liver Fibrosis Recovery and Promotes Hepatocarcinogenesis in Rat Liver Cirrhosis Model.

More effective treatments for hepatitis viral infections have led to a reduction in the incidence of liver cirrhosis. A high-fat diet can lead to chronic hepatitis and liver fibrosis, but the effects of lipid intake on liver disease status, including hepatitis C virus and alcohol, after elimination of the cause are unclear. To investigate the effects, we used a rat cirrhosis model and a high-fat diet in this study. Male Wistar rats were administered carbon tetrachloride for 5 weeks. At 12 weeks of age, one group was sacrificed. The remaining rats were divided into four groups according to whether or not they were administered carbon tetrachloride for 5 weeks, and whether they were fed a high-fat diet or control diet. At 12 weeks of age, liver fibrosis became apparent and then improved in the groups where carbon tetrachloride was discontinued, while it worsened in the groups where carbon tetrachloride was continued. Liver fibrosis was notable in both the carbon tetrachloride discontinuation and continuation groups due to the administration of a high-fat diet. In addition, liver precancerous lesions were observed in all groups, and tumor size and multiplicity were higher in the high-fat diet-fed groups. The expression of genes related to inflammation and lipogenesis were upregulated in rats fed a high-fat diet compared to their controls. The results suggest that a high-fat diet worsens liver fibrosis and promotes liver carcinogenesis, presumably through enhanced inflammation and lipogenesis, even after eliminating the underlying cause of liver cirrhosis.

ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism.

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.

SAT-225 - Fibroblast growth factor 19 cooperates with Myc to promote liver carcinogenesis

SAT-225 - Fibroblast growth factor 19 cooperates with Myc to promote liver carcinogenesis

Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment.

Bile acids (BAs) are physiological detergents that can not only promote the digestion and absorption of lipids, but also may be a potential carcinogen. The accumulation of BAs in the body can lead to cholestatic liver cirrhosis and even liver cancer. Recently, studies demonstrated that BAs are highly accumulated in metastatic lymph nodes, but not in normal healthy lymph nodes or primary tumors. Lymph node metastasis is second only to hematogenous metastasis in liver cancer metastasis, and the survival and prognosis of hepatocellular carcinoma (HCC) patients with lymph node metastasis are significantly worse than those without lymph node metastasis. Meanwhile, component of BAs was found to significantly enhance the invasive potential of HCC cells. However, it is still poorly understood how deregulated BAs fuel the metastasis process of liver cancer. The tumor microenvironment is a complex cellular ecosystem that evolves with and supports tumor cells during their malignant transformation and metastasis progression. Aberrant BAs metabolism were found to modulate tumor immune microenvironment by preventing natural killer T (NKT) cells recruitment and increasing M2-like tumor-associated macrophages (TAMs) polarization, thus facilitate tumor immune escape and HCC development. Based on these available evidence, we hypothesize that a combination of genetic and epigenetic factors in cancerous liver tissue inhibits the uptake and stimulates the synthesis of BAs by the liver, and excess BAs further promote liver carcinogenesis and HCC metastasis by inducing immunosuppressive microenvironment.

Impact of Cyanotoxin Ingestion on Liver Cancer Development Using an At-Risk Two-Staged Model of Mouse Hepatocarcinogenesis.

Exposure to cyanobacterial hepatotoxins has been linked to the promotion and increased incidence of liver cancer in pre-clinical and epidemiologic studies. The family of hepatotoxins, microcystins (MCs), are produced by over 40 cyanobacterial species found in harmful algal blooms (HABs) worldwide, with MC-LR being the most common and potent MC congener. In the current study, we hypothesized that the low-dose chronic ingestion of Microcystis cyanotoxins via drinking water would promote liver carcinogenesis in pre-initiated mice. Four groups of C3H/HeJ mice received one intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) at 4 weeks of age. Three weeks later, the mice were administered ad libitum drinking water containing one of the following: (1) reverse osmosis, deionized water; (2) water containing 500 mg/L phenobarbital (PB500); (3) water with purified MC-LR (10 µg/L) added; or (4) water containing lysed Microcystis aeruginosa (lysate; 10 µg/L total MCs). The exposure concentrations were based on environmentally relevant concentrations and previously established Ohio EPA recreational water MC guidelines. Throughout the 30-week exposure, mouse weights, food consumption, and water consumption were not significantly impacted by toxin ingestion. We found no significant differences in the number of gross and histopathologic liver lesion counts across the treatment groups, but we did note that the PB500 group developed lesion densities too numerous to count. Additionally, the proportion of lesions classified as hepatocellular carcinomas in the MC-LR group (44.5%; p < 0.05) and lysate group (55%; p < 0.01) was significantly higher compared to the control group (14.9%). Over the course of the study, the mice ingesting the lysate also had a significantly lower survival probability (64.4%; p < 0.001) compared to water (96.8%), PB500 (95.0%), and MC-LR (95.7%) exposures. Using cyanotoxin levels at common recreational water concentration levels, we demonstrate the cancer-promoting effects of a single cyanotoxin MC congener (MC-LR). Furthermore, we show enhanced hepatocarcinogenesis and significant mortality associated with combinatorial exposure to the multiple MCs and bioactive compounds present in lysed cyanobacterial cells—a scenario representative of the ingestion exposure route, such as HAB-contaminated water and food.

Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non-Cell Autonomous Liver Carcinogenesis.

This study reveals that activation of p53 in hepatocytes promotes liver carcinogenesis derived from HPCs, which elucidates a paradoxical aspect of a tumor suppressor p53 and novel mechanism of liver carcinogenesis. See related commentary by Barton and Lozano, p. 2824.

E. faecalis promotes liver carcinogenesis.

E. faecalis promotes liver carcinogenesis.

Low concentrations of 4-ABP promote liver carcinogenesis in human liver cells and a zebrafish model

4-Aminobiphenyl (4-ABP) is a human bladder cancer carcinogen found in the manufacture of azo dyes and the composition of cigarette smoke in the environment. To determine whether low concentrations of 4-ABP induced or promote liver carcinogenesis and investigate the underlying mechanism, we have established the liver cell carcinogenesis model in human liver cell lines and zebrafish to evaluate liver cancer development associated with long-term exposure to low concentrations of 4-ABP. Results show that repeated 4-ABP exposure promoted cellular proliferation and migration via the involvement of ROS in Ras/MEK/ERK pathway in vitro. Also, 4-ABP (1, 10, and 100 nM) induces hepatocellular carcinoma (HCC) formation in HBx, Src (p53-/-) transgenic zebrafish at four months of age and in wild-type zebrafish at seven months of age. In addition, we observed a correlation between the Ras-ERK pathway and 4-ABP-induced HCC in vitro and in vivo. Our finding suggests low concentrations of 4-ABP repeated exposure is a potential risk factor for liver cancer. To our knowledge, this is the first report on the promotion of liver carcinogenesis in human liver cells and zebrafish following 4-ABP exposure.

Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes-Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans.

Mothers against decapentaplegic homolog (SMAD) 7 is an antagonist of TGF-β signaling. In the present investigation, we sought to determine the relevance of SMAD7 in liver carcinogenesis using in vitro and in vivo approaches. We found that SMAD7 is up-regulated in a subset of human HCC samples with poor prognosis. Gene set enrichment analysis revealed that SMAD7 expression correlates with activated yes-associated protein (YAP)/NOTCH pathway and cholangiocellular signature genes in HCCs. These findings were substantiated in human HCC cell lines. In vivo, overexpression of Smad7 alone was unable to initiate HCC development, but it significantly accelerated c-Myc/myeloid cell leukemia 1 (MCL1)-induced mouse HCC formation. Consistent with human HCC data, c-Myc/MCL1/Smad7 liver tumors exhibited an increased cholangiocellular gene expression along with Yap/Notch activation and epithelial-mesenchymal transition (EMT). Intriguingly, blocking of the Notch signaling did not affect c-Myc/MCL1/Smad7-induced hepatocarcinogenesis while preventing cholangiocellular signature expression and EMT, whereas ablation of Yap abolished c-Myc/MCL1/Smad7-driven HCC formation. In mice overexpressing a myristoylated/activated form of AKT, coexpression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly up-regulated, especially in the most aggressive tumors, and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers. The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and inducing a cholangiocellular and EMT signature.

Dietary fructose promotes liver carcinogenesis by inducing the malignant transformation of hepatic progenitor cells

Abstract The incidence of nonalcoholic fatty liver disease (NAFLD)-associated liver cancer is rising particularly in western societies. Dietary fructose has been increasingly reported as a significant contributor for the onset of NAFLD. However, the association between a high-fructose diet and liver cancer incidence is not fully understood. In this study, we investigated the effect of dietary fructose on liver tumorigenesis. In a mouse model of diethylnitrosamine (DEN)-induced liver tumor initiation, high-fructose diet was found to significantly increased hepatic lipid deposition and expression of inflammatory cytokines in mouse livers. Besides, DEN administration induced the malignant transformation of hepatic progenitor cells (HPCs) into malignant tumor initiating cells, while DEN + Fructose mice had significantly enriched HPCs with enhanced proliferation, invasion, chemoresistance, and tumorigenic capabilities. This study for the first time demonstrates that fructose promotes liver carcinogenesis via increasing tumorigenic HPCs and inflammatory microenvironment, which warrants precautionary control of the excessive intake of dietary fructose.

RNA-binding motif protein 43 (RBM43) suppresses hepatocellular carcinoma progression through modulation of cyclin B1 expression.

RNA-binding proteins play key roles in the posttranscriptional regulation of mRNA during cancer progression. Here, we show that RNA-binding motif protein 43 (RBM43) is significantly downregulated in human tumors, and its low expression is correlated with poor prognosis in patients with HCC. Overexpression of RBM43 suppressed cell proliferation in culture and resulted in the growth arrest of tumor xenografts, whereas downregulating RBM43 played an opposite role. We have also demonstrated that overexpression or knockdown of RBM43 affects the cell-cycle progression of liver cancer cells. Mechanistically, RBM43 directly associated with the 3'UTR of Cyclin B1 mRNA and regulated its expression. Moreover, loss of Rbm43 in mice promoted liver carcinogenesis and HCC development after diethylnitrosamine (DEN)-carbon tetrachloride (CCl4) treatment. Taken together, our data indicate that RBM43 is a tumor suppressor that controls the cell cycle through modulation of Cyclin B1 expression, providing evidence that RBM43 is particularly important in HCC.

Investigation of the Effects of Octreotide Agent on Oxidative Stress, 8-Hydroxy Deoxyguanosine in Experimental Hepatic Carcinogenesis Rat Model.

2-AAF and DEN are well-known liver toxicants commonly used to stimulate tumors in laboratory animals. The aim of this study was to investigate the effect of octreotide on DEN-induced and 2-AAF-supplemented hepatocarcinogenesis in Wistar albino rats. In this study, 64 Wistar albino rats were divided into 8 groups. DEN (175 mg/kg) initiated and 2-AAF (20 mg/kg) promoted liver carcinogenesis in rats. The tumor growth inhibitor octreotide (300 μg/kg) was used. Rats were sacrificed at the end of experiment and their liver tissues were taken for the study. SOD, GSH-Px, CAT activities, NO and MDA levels were measured spectrophotometrically. Also, Hsp70 and 8-OHdG was measured by the ELISA method. In group 7, MDA, 8-OHdG, and Hsp70 levels were significantly increased. In addition, SOD, GSH-Px activity was significantly reduced in this group. MDA, 8-OHdG and Hsp70 levels were significantly reduced in Group 8, which received octreotide for treatment. DEN and 2-AAF cause very serious liver damage. Octreotide protects the liver from carcinogenesis, increases the activity of cellular antioxidant enzymes and helps reduce DNA damage. Therefore, octreotide may be an inhibitor in tumor cells and may reduce oxidative stress.

Intrahepatic immune changes after hepatitis c virus eradication by direct-acting antiviral therapy.

The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth. This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy. Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non-tumoral tissues and analysed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry. Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients. In conclusion, removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA-induced SVR.

Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis.

Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

BackgroundBesides its neurotransmitter and vasoconstriction functions, serotonin is an important mediator of numerous biological processes in peripheral tissues including cell proliferation, steatosis, and fibrogenesis. Recent reports indicate that serotonin may promote tumor growth in liver cancer, however, the molecular mechanisms remain elusive. n this study, we investigated the role and molecular signaling mechanisms mediated by serotonin in liver cancer cell survival, drug resistance, and steatosis.MethodsEffect of serotonin on modulation of cell survival/proliferation was determined by MTT/WST1 assay. Effect of serotonin on the regulation of autophagy biomarkers and lipid/fatty acid proteins expression, AKT/mTOR and Notch signaling was evaluated by immunoblotting. The role of serotonin in normal human hepatocytes and liver cancer cell steatosis was analyzed by Oil Red O staining. The mRNA expression levels of lipid/fatty acid proteins and serotonin receptors were validated by qRT-PCR. The important roles of autophagy, Notch signaling, serotonin receptors and serotonin re-uptake proteins on serotonin-mediated cell steatosis were investigated by using selective inhibitors or antagonists. The association of peripheral serotonin, autophagy, and hepatic steatosis was also investigated using chronic EtOH fed mouse model.ResultsExposure of liver cancer cells to serotonin induced Notch signaling and autophagy, independent of AKT/mTOR pathway. Also, serotonin enhanced cancer cell proliferation/survival and drug resistance. Furthermore, serotonin treatment up-regulated the expression of lipogenic proteins and increased steatosis in liver cancer cells. Inhibition of autophagy or Notch signaling reduced serotonin-mediated cell steatosis. Treatment with serotonin receptor antagonists 5-HTr1B and 5-HTr2B reduced serotonin-mediated cell steatosis; in contrast, treatment with selective serotonin reuptake inhibitors (SSRIs) increased steatosis. In addition, mice fed with chronic EtOH resulted in increased serum serotonin levels which were associated with the induction of hepatic steatosis and autophagy.ConclusionsSerotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy.

Imbalanced expression pattern of steroid receptor coactivator-1 and -3 in liver cancer compared with normal liver: An immunohistochemical study with tissue microarray.

Steroids affect normal and pathological functions of the liver through receptors, which require coactivators for their transcriptional activation. Steroid receptor coactivator (SRC)-1 and SRC-3 have been demonstrated to be regulated in numerous cancers; however, their expression profiles in liver cancer including hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) remain unclear. Using tissue microarray immunohistochemistry, normal liver tissue and HCC tissue exhibited immunoreactivity of SRC-1, which were predominantly localized within extranuclear components; in CCC, they were detected within the cell nuclei; SRC-3 was also detected in the cell nuclei. Furthermore, no altered expression of SRC-1 and SRC-3 was observed in liver cancer compared with normal liver tissue; however, in CCC, the expression of SRC-3 was significantly increased compared with that detected in HCC. Importantly, although expression of SRC-1 and SRC-3 did not reveal any significant differences (30 vs. 40%) in normal liver tissue, HCC and CCC expression of SRC-1 was significantly decreased compared with that of SRC-3 (9.3 vs. 36%, and 6.7 vs. 67.7% for HCC and CCC, respectively). Further comparative analysis revealed that this discrepancy was detected in males with liver cancer, across all ages of HCC cases, younger CCC cases and all stages of liver cancer. The results suggested the presence of an imbalanced expression pattern of SRC-1 and SRC-3 from normal liver tissue to liver cancer (decreased SRC-1 and increased SRC-3), which may affect hepatic function and therefore promote liver carcinogenesis.

Abstract 3477: Metabolic pathway analyses identify proline biosynthesis as a promoter of liver carcinogenesis

Abstract Cancer cells undergo dramatic metabolic reprogramming, largely to meet the requirements of sustained proliferation. These metabolic pathways are tightly regulated by various oncogenes, such as Myc and Ras. However, it has been difficult to directly and effectively inhibit these oncogenic signaling cascades with pharmacological compounds. Therefore, focusing on the downstream metabolic pathways that enable indefinite growth may provide a therapeutic opportunity. To identify metabolic enzymes required for hepatocellular carcinoma (HCC) tumorigenesis, we compared gene expression profiles of normal liver tissue to the Morris Hepatoma and DEN (Diethylnitrosamine)-induced HCC models as well as a liver regeneration model. PYCR1 (Pyrroline-5-Carboxylate Reductase 1), an enzyme in the proline biosynthesis pathway, was identified as one of the top up-regulated genes in the HCC models. An increase in PYCR1 protein levels in tumor samples versus normal liver tissue was confirmed by Western blot. shRNA-mediated knockdown of PYCR1 in HCC cell lines (Huh-7, Hep3B, HepG2 SNU-398, and MH3924a) potently reduced cell proliferation in vitro and tumor growth in vivo. Conversely, overexpression of PYCR1 enhanced the proliferation of Hep3B and AML12 cells. Importantly, PYCR1 expression was not elevated in regenerating tissues, and knockdown in a non-tumorigenic cell line did not influence proliferation. Additional enzymes in the proline biosynthesis pathway were also altered in tumors. For instance, ALDH18A1 was up-regulated and knockdown by shRNA decreased proliferation of human HCC cell lines. Metabolomic analyses suggested that the metabolism of glucose was disrupted in PYCR1 knockdown cells, with reduced fluxes through glycolytic and pentose phosphate pathways. Clinical data demonstrated that PYCR1 expression was increased in HCC, and expression levels correlated with increasing tumor grades and were independent predictors of clinical outcome. Overall, our data suggest that enhanced expression of proline biosynthetic enzymes promotes cell proliferation, and that inhibiting PYCR1 or ALDH18A1 may be a novel therapeutic strategy to target HCC. Citation Format: Zhaobing Ding, Russell E. Ericksen, Michael Steckel, Andrea Haegebarth, Sylvia Gruenewald, Weiping Han. Metabolic pathway analyses identify proline biosynthesis as a promoter of liver carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3477.

Abstract 5446: Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival

Abstract The hormone serotonin is known as 5-hydroxytryptamine. It is a precursor of melatonin, derived from the amino acid tryptophan. Serotonin acts as a neurotransmitter and modulates several key functions in the human body, such as appetite, mood and sleep. Apart from its important roles in the central nervous system (CNS), serotonin regulates various extra-neuronal pathophysiological functions. Serotonin is synthesized by Enterochromaffin cells of the gut, mostly stored in platelets and about 2% of free serotonin released in the blood. The role of peripheral serotonin in adipocytes, pancreatic cells, macrophages and liver cells is not fully understood. In the current study, we investigated the role of serotonin in liver cancer cell signaling and liver cancer cell growth. Treatment of serotonin in liver cancer cells HepG2 and SK-Hep1 induced autophagy markers and effectors such as LC3 I/II, phospho-4EBP1, ATG3 and Beclin1, and, increased cell proliferation and cell survival. AKT/mTOR pathway controls cellular autophagy and our results demonstrated that exposure of serotonin to liver cancer cells inactivates AKT/mTOR signaling and induced autophagy. Also, we demonstrate that serotonin also activates Notch signaling pathway as evident by induction of Notch target gene Hes1. Notch inhibitors Avagacestat 2 and FLI-06 inhibited serotonin-mediated Notch signaling and cellular autophagy. Furthermore, by the activation of Notch signaling, serotonin-induced oleic acid-mediated cell steatosis in both HepG2 and SK-Hep1 liver cancer cells. In addition, treatment of serotonin also induced autophagy modulator proteins such as SIRT1 and Tumor Necrosis Factor Alpha Inducing Protein 8 (TNFAIP8) which participate in the modulation of cellular autophagy and cell survival. Taken together our data suggested that peripheral serotonin regulates liver cancer cell steatosis, cells survival and may promote liver carcinogenesis by the modulation of AKT/mTOR and Notch signaling pathways. Citation Format: Suresh Niture, Deepak Kumar. Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5446.

Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage.

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.

From the Editor’s desk....: May 2018

From the Editor’s desk....: May 2018