An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents
Moeini, Agrin (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Torrecilla, Sara (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Tovar, Victoria (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Montironi, Carla (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica))
Andreu-Oller, Carmen (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Peix, Judit (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Higuera, Mónica (Hospital Universitari Vall d'Hebron)
Pfister, Dominik (German Cancer Research Center (DKFZ))
Ramadori, Pierluigi (German Cancer Research Center (DKFZ))
Pinyol, Roser (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Solé, Manel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Heikenwälder, Mathias (German Cancer Research Center (DKFZ))
Friedman, Scott L. (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica))
Sia, Daniela (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica))
Llovet, Josep M. (Institució Catalana de Recerca i Estudis Avançats)

Data:	2019
Resum:	Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods: We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2. 41; 95% confidence interval, 1. 21-4. 80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis.
Ajuts:	European Commission 667273 Ministerio de Ciencia e Innovación SAF2016-76390
Nota:	Program (HEPCAR, reference no. 667273-2); US Department of Defense(CA150272P3); an Accelerator Award (CRUCK, AECC, AIRC) (HUNTER,reference no. C9380/A26813), NCI Cancer Center Support Grant, National Cancer Institute; Tisch Cancer Institute (P30-CA196521); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute (SAF2016-76390); and the Generalitat de Catalunya/AGAUR (SGR-1358). Agrin Moeini is supported by Spanish National Health Institute. Sara Torrecilla and Judit Peix are funded by Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd-ISCIII). Carla Montironi is a recipient of Josep Font grant. Carmen Andreu-Oller is supported by "la Caixa" INPhINIT Fellowship Grant (LCF/BQ/IN17/11620024). Roser Pinyol is supported by HEPCAR and AECC. Daniela Sia is supported by the Gilead Sciences Research Scholar Program in Liver Disease. Scott L. Friedman is supported by the National Institutes of Health Research project grant (R01,DK5662) and US Department of Defense (CA150272P3). Mathias Heikenwälder was supported by an ERC Consolidator grant (HepatoMetaboPath), the SFBTR 209, 1335 and SFBTR179.
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Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer ; Microenvironment ; Cytokines ; Lymphocytes
Publicat a:	Gastroenterology, Vol. 157 Núm. 5 (november 2019) , p. 1383-1397.e11, ISSN 1528-0012

DOI: 10.1053/j.gastro.2019.07.028
PMID: 31344396

26 p, 7.8 MB

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