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      Loganetin and 5‐fluorouracil synergistically inhibit the carcinogenesis of gastric cancer cells via down‐regulation of the Wnt/β‐catenin pathway

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          Abstract

          Although most gastrointestinal tumours are sensitive to 5‐fluorouracil (5FU), drug resistance is commonly occurred after 5FU therapy in gastric cancer (GC). Loganetin is the primary active compound in Cornus officinali. However, the synergetic effects of loganetin and 5FU on GC remain unknown. Here, we investigated the synergetic effects and the underlying mechanism of loganetin and 5FU on proliferation, stem‐like properties, migration, and invasion of GC both in vitro and in vivo. We found that loganetin alone inhibited the proliferation, stem‐like properties, migration and invasion of GC cells in vitro. Importantly, the loganetin remarkably enhanced the anti‐cancer effect of 5FU on GC cells and the Wnt/β‐catenin pathway might be involved in this process. Animal experiments further confirmed the synergistic effects of 5FU and loganetin on inhibiting cell growth and metastasis of GC. These results suggested that loganetin could synergistically increase the effect of 5FU against GC, which sheds light on effective combinational drug strategies for GC treatment.

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          Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

          Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy.
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            Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors

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              Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

              Breast cancer cells disseminate through TIE2/MENA Calc /MENA INV -dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENA INV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.
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                Author and article information

                Contributors
                yaojingchun@yeah.net
                dshuang@zju.edu.cn
                yangliu@hmc.edu.cn , yangliuqq2003@163.com
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                24 October 2020
                December 2020
                : 24
                : 23 ( doiID: 10.1111/jcmm.v24.23 )
                : 13715-13726
                Affiliations
                [ 1 ] Department of Medical Oncology Zhejiang Provincial People’s Hospital People’s Hospital of Hangzhou Medical College Hangzhou China
                [ 2 ] Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province Zhejiang Provincial People’s Hospital People’s Hospital of Hangzhou Medical College Hangzhou China
                [ 3 ] State Key Laboratory of Genetics Manufacture Technology of Chinese Traditional Medicine Lunan Pharmaceutical Group Co., Ltd Linyi China
                [ 4 ] Department of Internal Medicine Clinic of August First Film Studio Beijing China
                Author notes
                [*] [* ] Correspondence

                Liu Yang, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.

                Emails: yangliu@ 123456hmc.edu.cn , yangliuqq2003@ 123456163.com

                Jingchun Yao, State Key Laboratory of Genetics Manufacture Technology of Chinese Traditional Medicine, China.

                Email: yaojingchun@ 123456yeah.net

                Dongsheng Huang, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.

                Email : dshuang@ 123456zju.edu.cn

                Author information
                https://orcid.org/0000-0001-7587-312X
                Article
                JCMM15932
                10.1111/jcmm.15932
                7754039
                33098378
                152ee086-43e8-44a4-ad5c-5cfd0867bcd9
                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 April 2020
                : 01 September 2020
                : 11 September 2020
                Page count
                Figures: 6, Tables: 0, Pages: 11, Words: 6027
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81772575
                Award ID: 81972455
                Funded by: Health Bureau of Zhejiang Province
                Award ID: 2018274734
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                December 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:22.12.2020

                Molecular medicine
                emt,gastric carcinoma,loganetin,stem‐like properties,β‐catenin
                Molecular medicine
                emt, gastric carcinoma, loganetin, stem‐like properties, β‐catenin

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