title: Targeting CD146 with a 64Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas.
abstract: Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. (64)Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼ 2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ(2) = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.
authors.affiliation: Department of Radiology, University of Wisconsin-Madison, Madison, WI 53705; Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038;
authors.forename: Yunan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Reinier
authors.initials: R
authors.lastname: Hernandez
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038;
authors.forename: Jun
authors.initials: J
authors.lastname: Rao
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038;
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038;
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038;
authors.forename: Jinrong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Christopher G
authors.initials: CG
authors.lastname: England
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Graves
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lewis
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038;
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Mary E
authors.initials: ME
authors.lastname: Meyerand
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nickles
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China 400038; wcai@uwhealth.org bianxiuwu@263.net.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Department of Radiology, University of Wisconsin-Madison, Madison, WI 53705; Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705; University of Wisconsin Carbone Cancer Center, Madison, WI 53705 wcai@uwhealth.org bianxiuwu@263.net.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000917:Antibody Formation / Q000187:drug effects; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000276:immunology* / Q000473:pathology; D051929:CD146 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D002999:Clone Cells; D003301:Copper Radioisotopes; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000000981:diagnostic imaging* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008819:Mice, Nude; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D049268:Positron-Emission Tomography; D014176:Protein Biosynthesis / Q000187:drug effects; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014057:Tomography, X-Ray Computed; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D051929:CD146 Antigen; D003301:Copper Radioisotopes
keywords: CD146; cancer stem cells; epithelial-mesenchymal transition; glioblastoma multiforme; positron emission tomography