title: Histopathological analyses of the antitumor activity of anti-glypican-3 antibody (GC33) in human liver cancer xenograft models: The contribution of macrophages.
abstract: Previously, we demonstrated the antitumor efficacy of the anti-glypican-3 (GPC3) antibody GC33 in several human liver cancer xenograft models and the important role of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor mechanism of GC33. Involvement of other mechanisms such as modulation of the functions of GPC3 in antitumor activity remains to be elucidated. In this study, we investigated histopathologically time-course changes in xenografts in mice following a single administration of GC33 to clarify the morphological changes contributing to the tumor growth inhibition of GC33, including the changes in GPC3-related factors/components [proliferation, extracellular matrices (ECMs) and macrophage]. Histopathological changes peaked 3-5 d after GC33 administration and included increased tumor cell death, tumor cells with round morphology, multinucleated tumor cells and small spindle/round-like cells (mostly F4/80-positive macrophages). No direct effects of GC33 on proliferation activity of tumor cells were observed. Meanwhile, alteration of ECM structures and a remarkable increase in macrophages was noted in the GC33-treated group. Increase in macrophages was observed mainly in the outer layer of tumor nodules; the area of the increase approximately included the area where the change in tumor cells and ECMs were observed. Interestingly, depletion of macrophages in the xenograft models resulted in a marked reduction of the antitumor activity of GC33. In the in vitro ADCC assay, ADCC was only slightly induced by mouse peritoneal macrophages. These data suggest that macrophages play an important role in the antitumor activity of GC33, which is not likely to be direct ADCC by macrophages themselves.
authors.affiliation: Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. takaihrt@chugai-pharm.co.jp
authors.forename: Hirotake
authors.initials: H
authors.lastname: Takai
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kato
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishiguro
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Takai
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Ohtani
authors.forename: Masamichi
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D053673:Glypicans / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D053673:Glypicans