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Gastroenterology. 2019 Sep;157(3):807-822. doi: 10.1053/j.gastro.2019.05.069. Epub 2019 Jun 10.

Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin Require Choline and Can Be Detected by Positron Emission Tomography.

Author information

1
Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
2
Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
3
Assistance Publique-Hôpitaux de Paris, Département de Pathologie, Hôpital Universitaire Henri Mondor, Créteil, France; Institut National de la Santé et de la Recherche Médicale U955, Team 18, Institut Mondor de Recherche Biomédicale; Université Paris Est Créteil, Créteil, France.
4
Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Hôpital St-Antoine, Sorbonne Université, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France.
5
Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France; Assistance Publique-Hôpitaux de Paris, Anatomie Pathologique, Hôpital St-Antoine, Sorbonne Université, Paris, France.
6
Assistance Publique-Hôpitaux de Paris, Médecine Nucléaire, Hôpital Tenon, Sorbonne Université, Paris, France; Laboratoire d'Imagerie Moléculaire Photonique, UMS28, Phénotypage du Petit Animal, Sorbonne Université, Paris, France.
7
Laboratoire d'Imagerie Moléculaire Photonique, UMS28, Phénotypage du Petit Animal, Sorbonne Université, Paris, France.
8
Assistance Publique-Hôpitaux de Paris, Médecine Nucléaire, Hôpital Universitaire Henri Mondor, Créteil, France.
9
Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherché 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France.
10
Institut National de la Santé et de la Recherche Médicale U1174, Université Paris Sud, Orsay, France.
11
Assistance Publique-Hôpitaux de Paris, Médecine Interne, Hôpital Universitaire Henri Mondor, Créteil, France.
12
Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France. Electronic address: Sabine.colnot@inserm.fr.

Abstract

BACKGROUND & AIMS:

In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate β-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically.

METHODS:

We studied mice with activation of β-catenin in liver (Apcko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose, followed by 18F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet.

RESULTS:

Livers and tumors from Apcko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated β-catenin were positive in 18F-fluorocholine PET, but not 18F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apcko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apcko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors.

CONCLUSIONS:

In mice and humans, HCCs with mutations that activate β-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress β-catenin.

KEYWORDS:

CTNNB1; Liver Cancer; OCT3; Wnt Pathway

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