title: Natural variations of copper and sulfur stable isotopes in blood of hepatocellular carcinoma patients.
abstract: The widespread hypoxic conditions of the tumor microenvironment can impair the metabolism of bioessential elements such as copper and sulfur, notably by changing their redox state and, as a consequence, their ability to bind specific molecules. Because competing redox state is known to drive isotopic fractionation, we have used here the stable isotope compositions of copper ((65)Cu/(63)Cu) and sulfur ((34)S/(32)S) in the blood of patients with hepatocellular carcinoma (HCC) as a tool to explore the cancer-driven copper and sulfur imbalances. We report that copper is (63)Cu-enriched by ∼0.4‰ and sulfur is (32)S-enriched by ∼1.5‰ in the blood of patients compared with that of control subjects. As expected, HCC patients have more copper in red blood cells and serum compared with control subjects. However, the isotopic signature of this blood extra copper burden is not in favor of a dietary origin but rather suggests a reallocation in the body of copper bound to cysteine-rich proteins such as metallothioneins. The magnitude of the sulfur isotope effect is similar in red blood cells and serum of HCC patients, implying that sulfur fractionation is systemic. The (32)S-enrichment of sulfur in the blood of HCC patients is compatible with the notion that sulfur partly originates from tumor-derived sulfides. The measurement of natural variations of stable isotope compositions, using techniques developed in the field of Earth sciences, can provide new means to detect and quantify cancer metabolic changes and provide insights into underlying mechanisms.
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France; vincent.balter@ens-lyon.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Balter
authors.affiliation: Mechanistic Toxicology & Molecular Pathology Department of Non-Clinical Development, UCB BioPharma, SPRL Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium;
authors.forename: Andre
authors.initials: A
authors.lastname: Nogueira da Costa
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France;
authors.forename: Victor Paky
authors.initials: VP
authors.lastname: Bondanese
authors.affiliation: Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Klervia
authors.initials: K
authors.lastname: Jaouen
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France;
authors.forename: Aline
authors.initials: A
authors.lastname: Lamboux
authors.affiliation: National Cancer Institute, Bangkok 10400, Thailand;
authors.forename: Suleeporn
authors.initials: S
authors.lastname: Sangrajrang
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vincent
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France;
authors.forename: François
authors.initials: F
authors.lastname: Fourel
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Télouk
authors.affiliation: Unité 785, Pathogénèse et Traitement de l'Hépatite Fulminante et du Cancer du Foie, INSERM, Université Paris-Sud, 94800 Villejuif, France;
authors.forename: Michelle
authors.initials: M
authors.lastname: Gigou
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France; Institut Universitaire de France, 75005 Paris, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Lécuyer
authors.affiliation: National Cancer Institute, Bangkok 10400, Thailand;
authors.forename: Petcharin
authors.initials: P
authors.lastname: Srivatanakul
authors.affiliation: Unité 785, Pathogénèse et Traitement de l'Hépatite Fulminante et du Cancer du Foie, INSERM, Université Paris-Sud, 94800 Villejuif, France; Institut Pasteur, 75015 Paris, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
authors.affiliation: UMR 5276, Laboratoire de Géologie de Lyon, École Normale Supérieure de Lyon, CNRS, Université de Lyon 1, BP 7000 Lyon, France;
authors.forename: Francis
authors.initials: F
authors.lastname: Albarède
authors.affiliation: Unité 823, Ontogenèse et Oncogenèse Moléculaire, Institut Albert Bonniot, INSERM, Université Joseph Fourier, 38706 Grenoble, France; and Strathclyde Institute of Global Public Health, International Prevention Research Institute, 69006 Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000097:blood*; D003300:Copper / Q000097:blood*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood*; D008297:Male; D008875:Middle Aged; D013455:Sulfur / Q000097:blood*; D013460:Sulfur Isotopes / Q000097:blood; D059016:Tumor Microenvironment
chemical_list: D013460:Sulfur Isotopes; D013455:Sulfur; D003300:Copper
keywords: cancer; copper; liver; stable isotopes; sulfur