title: Mass Spectrometry Imaging of the Hypoxia Marker Pimonidazole in a Breast Tumor Model.
abstract: Although tumor hypoxia is associated with tumor aggressiveness and resistance to cancer treatment, many details of hypoxia-induced changes in tumors remain to be elucidated. Mass spectrometry imaging (MSI) is a technique that is well suited to study the biomolecular composition of specific tissue regions, such as hypoxic tumor regions. Here, we investigate the use of pimonidazole as an exogenous hypoxia marker for matrix-assisted laser desorption/ionization (MALDI) MSI. In hypoxic cells, pimonidazole is reduced and forms reactive products that bind to thiol groups in proteins, peptides, and amino acids. We show that a reductively activated pimonidazole metabolite can be imaged by MALDI-MSI in a breast tumor xenograft model. Immunohistochemical detection of pimonidazole adducts on adjacent tissue sections confirmed that this metabolite is localized to hypoxic tissue regions. We used this metabolite to image hypoxic tissue regions and their associated lipid and small molecule distributions with MALDI-MSI. We identified a heterogeneous distribution of 1-methylnicotinamide and acetylcarnitine, which mostly colocalized with hypoxic tumor regions. As pimonidazole is a widely used immunohistochemical marker of tissue hypoxia, it is likely that the presented direct MALDI-MSI approach is also applicable to other tissues from pimonidazole-injected animals or humans.
authors.affiliation: FOM Institute AMOLF , 1098 XG Amsterdam, The Netherlands.
authors.forename: Nadine E
authors.initials: NE
authors.lastname: Mascini
authors.affiliation: The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Menglin
authors.initials: M
authors.lastname: Cheng
authors.affiliation: The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Asif
authors.initials: A
authors.lastname: Rizwan
authors.affiliation: Thermo Fisher Scientific , Stafford House, 1 Boundary Park, Hemel Hempstead HP2 7GE, Herts, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Podmore
authors.affiliation: TransMIT GmbH · TransMIT Center for Mass Spectrometric Developments , Schubertstrasse 60, 35392 Giessen, Germany.
authors.forename: Dhaka R
authors.initials: DR
authors.lastname: Bhandari
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen , Schubertstrasse 60, 35392 Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Römpp
authors.affiliation: The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
authors.affiliation: FOM Institute AMOLF , 1098 XG Amsterdam, The Netherlands.|The Maastricht Multimodal Molecular Imaging institute (M4I) , 6229 ER Maastricht, The Netherlands.
authors.forename: Ron M A
authors.initials: RM
authors.lastname: Heeren
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D009593:Nitroimidazoles / Q000032:analysis*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor; D009593:Nitroimidazoles; C033815:pimonidazole