Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer
Abstract Background Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods...
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| Format: | Article |
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BMC
2020-08-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-020-01251-0 |
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| author | Mitsuro Kanda Dai Shimizu Koichi Sawaki Shunsuke Nakamura Shinichi Umeda Takashi Miwa Haruyoshi Tanaka Chie Tanaka Masamichi Hayashi Yohei Iguchi Suguru Yamada Masahisa Katsuno Yasuhiro Kodera |
| author_facet | Mitsuro Kanda Dai Shimizu Koichi Sawaki Shunsuke Nakamura Shinichi Umeda Takashi Miwa Haruyoshi Tanaka Chie Tanaka Masamichi Hayashi Yohei Iguchi Suguru Yamada Masahisa Katsuno Yasuhiro Kodera |
| author_sort | Mitsuro Kanda |
| collection | DOAJ |
| description | Abstract Background Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr −/− mice, and assessed the clinical significance of NPTXR expression in GC specimens. Results NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K–AKT–mTOR, FAK–JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr −/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC. |
| first_indexed | 2024-12-19T17:48:34Z |
| format | Article |
| id | doaj.art-138724e245fd43dcabb4a4f01dc154ee |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-19T17:48:34Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-138724e245fd43dcabb4a4f01dc154ee2022-12-21T20:11:59ZengBMCMolecular Cancer1476-45982020-08-0119111410.1186/s12943-020-01251-0Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancerMitsuro Kanda0Dai Shimizu1Koichi Sawaki2Shunsuke Nakamura3Shinichi Umeda4Takashi Miwa5Haruyoshi Tanaka6Chie Tanaka7Masamichi Hayashi8Yohei Iguchi9Suguru Yamada10Masahisa Katsuno11Yasuhiro Kodera12Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of MedicineAbstract Background Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr −/− mice, and assessed the clinical significance of NPTXR expression in GC specimens. Results NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K–AKT–mTOR, FAK–JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr −/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.http://link.springer.com/article/10.1186/s12943-020-01251-0Gastric cancerNeuronal pentraxin receptorAntibodyKnockout mouse |
| spellingShingle | Mitsuro Kanda Dai Shimizu Koichi Sawaki Shunsuke Nakamura Shinichi Umeda Takashi Miwa Haruyoshi Tanaka Chie Tanaka Masamichi Hayashi Yohei Iguchi Suguru Yamada Masahisa Katsuno Yasuhiro Kodera Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer Molecular Cancer Gastric cancer Neuronal pentraxin receptor Antibody Knockout mouse |
| title | Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer |
| title_full | Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer |
| title_fullStr | Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer |
| title_full_unstemmed | Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer |
| title_short | Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer |
| title_sort | therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer |
| topic | Gastric cancer Neuronal pentraxin receptor Antibody Knockout mouse |
| url | http://link.springer.com/article/10.1186/s12943-020-01251-0 |
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