Anlotinib suppresses lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma through a process potentially involving VEGFR-3 signaling
Copyright: © 2020, Cancer Biology & Medicine..
Objective: Lymphatic metastasis is one of the leading causes of malignancy dispersion in various types of cancer. However, few anti-lymphangiogenic drugs have been approved for clinical use to date. Therefore, new therapies to block lymphangiogenesis are urgently required. Methods: Immunohistochemistry, immunofluorescence, Western blot, migration assays, and lymphangiogenesis and lymphatic metastasis assays were used. Results: Anlotinib, a receptor tyrosine kinase inhibitor, suppressed the rate of new metastatic lesions (31.82% in the placebo arm and 18.18% in the anlotinib arm) in patients with advanced lung adenocarcinoma who were enrolled in our ALTER-0303 study. D2-40+-lymphatic vessel density was strongly correlated with disease stage, metastasis, and poor prognosis in 144 Chinese patients with lung adenocarcinoma. In mice bearing A549EGFP tumors, tumor lymphatic vessel density, tumor cell migration to lymph nodes, and the number of distant metastatic lesions were lower in the anlotinib group than in the controls. Anlotinib inhibited the growth and migration of human lymphatic endothelial cells (hLECs) and lymphangiogenesis in vitro and in vivo. Treatment of hLECs with anlotinib downregulated phosphorylated vascular endothelial growth factor receptor 3 (VEGFR-3). Conclusions: Anlotinib inhibits lymphangiogenesis and lymphatic metastasis, probably through inactivating VEGFR-3 phosphorylation. The results indicate that anlotinib may be beneficial for treatment in avoiding lymphangiogenesis and distant lymphatic metastasis in lung adenocarcinoma. (Trial registration: ALTER0303; NCT02388919; March 17, 2015.).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Cancer biology & medicine - 17(2020), 3 vom: 15. Aug., Seite 753-767 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qin, Tingting [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.11.2021 Date Revised 29.11.2021 published: Print ClinicalTrials.gov: NCT02388919 Citation Status MEDLINE |
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| doi: |
10.20892/j.issn.2095-3941.2020.0024 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315158867 |
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| 100 | 1 | |a Qin, Tingting |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Anlotinib suppresses lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma through a process potentially involving VEGFR-3 signaling |
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| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT02388919 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright: © 2020, Cancer Biology & Medicine. | ||
| 520 | |a Objective: Lymphatic metastasis is one of the leading causes of malignancy dispersion in various types of cancer. However, few anti-lymphangiogenic drugs have been approved for clinical use to date. Therefore, new therapies to block lymphangiogenesis are urgently required. Methods: Immunohistochemistry, immunofluorescence, Western blot, migration assays, and lymphangiogenesis and lymphatic metastasis assays were used. Results: Anlotinib, a receptor tyrosine kinase inhibitor, suppressed the rate of new metastatic lesions (31.82% in the placebo arm and 18.18% in the anlotinib arm) in patients with advanced lung adenocarcinoma who were enrolled in our ALTER-0303 study. D2-40+-lymphatic vessel density was strongly correlated with disease stage, metastasis, and poor prognosis in 144 Chinese patients with lung adenocarcinoma. In mice bearing A549EGFP tumors, tumor lymphatic vessel density, tumor cell migration to lymph nodes, and the number of distant metastatic lesions were lower in the anlotinib group than in the controls. Anlotinib inhibited the growth and migration of human lymphatic endothelial cells (hLECs) and lymphangiogenesis in vitro and in vivo. Treatment of hLECs with anlotinib downregulated phosphorylated vascular endothelial growth factor receptor 3 (VEGFR-3). Conclusions: Anlotinib inhibits lymphangiogenesis and lymphatic metastasis, probably through inactivating VEGFR-3 phosphorylation. The results indicate that anlotinib may be beneficial for treatment in avoiding lymphangiogenesis and distant lymphatic metastasis in lung adenocarcinoma. (Trial registration: ALTER0303; NCT02388919; March 17, 2015.) | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a lymph node metastasis | |
| 650 | 4 | |a Anlotinib | |
| 650 | 4 | |a VEGFR-3 dephosphorylation | |
| 650 | 4 | |a lung adenocarcinoma | |
| 650 | 4 | |a lymphangiogenesis | |
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| 650 | 7 | |a Quinolines |2 NLM | |
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| 700 | 1 | |a Liu, Zhujun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Junling |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shaochuan |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Yanan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Hailin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kai |e verfasserin |4 aut | |
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