title: Combined PET Imaging of the Inflammatory Tumor Microenvironment Identifies Margins of Unique Radiotracer Uptake.
abstract: The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages.Cancer Res; 77(8); 1831-41. ©2017 AACR.
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany. zinnhardt@wwu.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Zinnhardt
authors.affiliation: Imagerie Moléculaire In Vivo, Inserm, CEA, Univ. Paris Sud, CNRS, Université Paris Saclay, CEA - Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Hayet
authors.initials: H
authors.lastname: Pigeon
authors.affiliation: Imagerie Moléculaire In Vivo, Inserm, CEA, Univ. Paris Sud, CNRS, Université Paris Saclay, CEA - Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Thézé
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.|PARCC INSERM-U970, Université Paris Descartes, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Viel
authors.affiliation: Department of Clinical Radiology, University Hospital Münster, Münster, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Wachsmuth
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Inga B
authors.initials: IB
authors.lastname: Fricke
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schelhaas
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Honold
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schwegmann
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.affiliation: Department of Clinical Radiology, University Hospital Münster, Münster, Germany.|DFG EXC 1003 Cluster of Excellence 'Cells in Motion', University of Münster, Münster, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Faber
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kuhlmann
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.|DFG EXC 1003 Cluster of Excellence 'Cells in Motion', University of Münster, Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.|Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.|DFG EXC 1003 Cluster of Excellence 'Cells in Motion', University of Münster, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: Imagerie Moléculaire In Vivo, Inserm, CEA, Univ. Paris Sud, CNRS, Université Paris Saclay, CEA - Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Winkeler
authors.affiliation: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-University Münster, Münster, Germany.|DFG EXC 1003 Cluster of Excellence 'Cells in Motion', University of Münster, Münster, Germany.|Department of Geriatrics, Johanniter Hospital, Evangelische Kliniken, Bonn, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005462:Fluorine Radioisotopes; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D017628:Microglia / Q000473:pathology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D018079:Receptors, GABA / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: C463819:Bzrp protein, mouse; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; D020782:Matrix Metalloproteinases