peritoneal dissemination
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Author(s):  
Sheng-Mao Wu ◽  
Yee-Jee Jan ◽  
Shih-Chuan Tsai ◽  
Hung-Chuan Pan ◽  
Chin-Chang Shen ◽  
...  

Abstract Background and purpose Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. Experimental approach Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. Key results HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and implications Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Graphical abstract Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.


2021 ◽  
Vol 42 (1) ◽  
pp. 115-124
Author(s):  
SATOSHI HOSOYA ◽  
KAZU UEDA ◽  
SUGURU ODAJIMA ◽  
KOHEI OGAWA ◽  
HIROMI KOMAZAKI ◽  
...  

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Tomoya Takami ◽  
Koji Yasuda ◽  
Nozomi Uozumi ◽  
Yutaka Musiake ◽  
Hiroshi Shintani ◽  
...  

Abstract Background Recent advances in cancer immunotherapy have been remarkable, with many reports on the clinical effects of immune checkpoint inhibitors. Nivolumab has been covered by the national health insurance in Japan as a third-line agent for advanced and recurrent gastric cancer since September 2017. The objective response rate for nivolumab for gastric cancer is 11.2%. However, patients’ quality of life during this treatment has not been examined. Here, we report a case in which multidisciplinary treatment, including with nivolumab, resulted in long-term survival and improved quality of life. Case presentation A 70-year-old Asian woman was referred for surgery for gastric cancer. Postoperative pathological examination revealed peritoneal dissemination, and the patient was diagnosed with stage IV gastric cancer. Therefore, she was treated with S-1 and cisplatin based on negative immunohistochemical staining of resected specimens for human epidermal growth factor receptor 2. However, owing to instability and adverse events, treatment was subsequently changed to S-1 monotherapy. Two years after changing to S-1 monotherapy, she developed recurrence of peritoneal dissemination and was treated with docetaxel. Radiation therapy was also used because the recurrent lesions were local. However, 6 months later, new peritoneal dissemination and lymph node metastasis were observed and nivolumab was started. Subsequent abdominal computed tomography revealed a marked reduction in the disseminated nodules and lymphadenopathy. After 54 cycles of nivolumab, the lesions had disappeared completely. The patient has not developed side effects, including immune-responsive adverse events, has improved quality of life, and is returning to work. She is currently taking nivolumab, and there is no evidence of recurrence approximately 3 years after starting nivolumab. Conclusions Nivolumab may have beneficial effects in some patients with advanced or recurrent gastric cancer. Although the prognosis for gastric cancer and peritoneal dissemination is poor, multidisciplinary treatment that includes nivolumab may lead to long-term survival.


2021 ◽  
Vol 12 (11) ◽  
pp. 1083-1088
Author(s):  
Shinpei Ogino ◽  
Tatsuya Matsumoto ◽  
Yosuke Kamada ◽  
Noriaki Koizumi ◽  
Hiroshi Fujiki ◽  
...  

Author(s):  
Keisuke Matsusaki ◽  
Kuniaki Aridome ◽  
Shigenobu Emoto ◽  
Hiroaki Kajiyama ◽  
Nobumasa Takagaki ◽  
...  

AbstractPatients with peritoneal dissemination (PD) caused by abdominal malignancies are often associated with massive ascites, which shows extremely dismal prognosis because of the discontinuation of systemic chemotherapy mostly due to poor performance status. Many treatment methods, such as simple drainage, peritoneovenous shunting (PVS) and cell-free and concentrated reinfusion therapy (CART), have been used for symptom relief. However, the clinical efficacies of these methods have not been fully investigated yet. Recently, we developed the Clinical Practice Guideline for PD caused by various malignancies according to "Minds Clinical Practice Guideline Development Guide 2017". In this guideline, we systematically reviewed information on clinical diagnosis and treatments for PD using PubMed databases (2000 – 2020), and clarified the degree of recommendation for clinical questions (CQ). The evidence level was divided into groups by study design and quality. The literature level and a body of evidence were evaluated in reference to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Based on the results of systematic review, the strength of the recommendations was evaluated at a consensus meeting of the Guideline Committee. This is the English synopsis of the part of treatment of malignant ascites in Clinical Practice Guideline for PD, 2021 in Japanese. The guidelines summarize the general aspect of the treatment of malignant ascites and statements with recommendation strengths, evidence levels, agreement rates and future perspective for four raised clinical questions.


Author(s):  
Mr Faris Soliman ◽  
Dr Lin Ye ◽  
Dr Wenguo Jiang ◽  
Miss Rachel Hargest

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