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Jiang YK, Li W, Qiu YY, Yue M. Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer. World J Gastrointest Oncol 2024; 16:2318-2334. [PMID: 38994153 PMCID: PMC11236256 DOI: 10.4251/wjgo.v16.i6.2318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/04/2024] [Accepted: 04/18/2024] [Indexed: 06/13/2024] Open
Abstract
Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.
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Affiliation(s)
- Ya-Kun Jiang
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Wei Li
- Health Management Center, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Meng Yue
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
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2
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Qi C, Lei L, Hu J, Wang G, Liu J, Ou S. Identification of a five-gene signature deriving from the vacuolar ATPase (V-ATPase) sub-classifies gliomas and decides prognoses and immune microenvironment alterations. Cell Cycle 2022; 21:1294-1315. [PMID: 35266851 PMCID: PMC9132400 DOI: 10.1080/15384101.2022.2049157] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aberrant expression of coding genes of the V-ATPase subunits has been reported in glioma patients that can activate oncogenic pathways and result in worse prognosis. However, the predictive effect of a single gene is not specific or sensitive enough. In this study, by using a series of bioinformatics analyses, we identified five coding genes (ATP6V1C2, ATP6V1G2, TCIRG1, ATP6AP1 and ATP6AP2) of the V-ATPase that were related to glioma patient prognosis. Based on the expression of these genes, glioma patients were sub-classified into different prognosis clusters, of which C1 cluster performed better prognosis; however, C2 cluster showed more malignant phenotypes with oncogenic and immune-related pathway activation. The single-cell RNA-seq data revealed that ATP6AP1, ATP6AP2, ATP6V1G2 and TCIRG1 might be cell-type potential markers. Copy number variation and DNA promoter methylation potentially regulate these five gene expressions. A risk score model consisted of these five genes effectively predicted glioma prognosis and was fully validated by six independent datasets. The risk scores also showed a positive correlation with immune checkpoint expression. Importantly, glioma patients with high-risk scores presented resistance to traditional treatment. We also revealed that more inhibitory immune cells infiltration and higher rates of “non-response” to immune checkpoint blockade (ICB) treatment in the high-risk score group. In conclusion, our study identified a five-gene signature from the V-ATPase that could sub-classify gliomas into different phenotypes and their abnormal expression was regulated by distinct mechanisms and accompanied with immune microenvironment alterations potentially act as a biomarker for ICB treatment.
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Affiliation(s)
- Chunxiao Qi
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.,Department of Neurosurgery, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Lei Lei
- Department of Rheumatology and Immunology, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, China
| | - Jinqu Hu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Gang Wang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jiyuan Liu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shaowu Ou
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
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Shi M, Gu Y, Jin K, Fang H, Chen Y, Cao Y, Liu X, Lv K, He X, Lin C, Liu H, Li H, He H, Qin J, Li R, Zhang H, Zhang W. CD47 expression in gastric cancer clinical correlates and association with macrophage infiltration. Cancer Immunol Immunother 2021; 70:1831-1840. [PMID: 33389016 PMCID: PMC10992211 DOI: 10.1007/s00262-020-02806-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/21/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND CD47 has been identified as an innate immune checkpoint and found to be associated with inferior survival in various types of cancer. However, the critical role of CD47 in gastric cancer and its association with tumor associated macrophages remain unclear. METHODS Tumor tissues of gastric cancer from Zhongshan Hospital and data from GSE62254, GSE84437 and TCGA datasets were analyzed. Immunohistochemistry was performed to detect the expression of CD47, CD11c, CD163 and CD68 in gastric cancer tissues. Kaplan-Meier curves and Cox model were used for comparing the clinical outcomes of patients belonging to different subgroups. RESULTS Gastric cancer patients with high CD47 expression exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (ACT). A positive correlation was found between M1-polarized macrophage infiltration and CD47 expression in gastric cancer; however, the prognostic value of M1-polarized macrophages was attenuated in CD47-high gastric cancer patients. Moreover, we found that CD47 mRNA level was enriched in microsatellite-instable (MSI) subtype of gastric cancer and associated with ARID1A mutation and FGFR2 signaling pathway activation. CONCLUSIONS Aberrant CD47 expression represented an independent predictor for adverse survival outcome and ACT resistance in gastric cancer. Targeting CD47 might be a promising strategy for gastric cancer patients.
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Affiliation(s)
- Mingsu Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yun Gu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Kaifeng Jin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hanji Fang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yifan Chen
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Yifan Cao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Kunpeng Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xudong He
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chao Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hao Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - He Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hongyong He
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ruochen Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Heng Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Weijuan Zhang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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Kumble LD, Silver E, Oh A, Abrams JA, Sonett JR, Hur C. Treatment of early stage (T1) esophageal adenocarcinoma: Personalizing the best therapy choice. World J Meta-Anal 2019; 7:406-417. [DOI: 10.13105/wjma.v7.i9.406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/03/2019] [Accepted: 10/19/2019] [Indexed: 02/06/2023] Open
Abstract
Esophagectomy is considered the primary form of management for esophageal adenocarcinoma (EAC); however, the surgery is associated with high rates of morbidity and mortality. For patients with early-stage EAC, endoscopic resection (ER) presents a potential curative treatment option that is less invasive and carries fewer risks procedure related risks, but it is associated with higher rates of cancer recurrence following the procedure. For some patients, age and comorbidities may prevent them from having esophagectomy as a treatment option, while other patients may be operative candidates but do not wish to undergo esophagectomy for a variety of reasons related to their values and preferences. Furthermore, while anxiety of cancer recurrence following ER may significantly diminish a patient’s quality of life (QOL), so might the morbidity surrounding esophagectomy. In addition to considering health status, patient preferences, and impacts on QOL, physicians and patients must also consider what treatments would be both beneficial and available to the patient, considering esophagectomy methods-minimally invasive vs open-or the use of chemoradiotherapy in addition to ER. Our article reviews and summarizes available treatment options for patients with early EAC and their potential effects on the health and wellbeing of patients based on the current data. We conclude with a request for more research of available options for early EAC patients, the conditions that determine when each option should be employed, and their effects not only on patient health but also QOL.
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Affiliation(s)
| | - Elisabeth Silver
- General Medicine, Columbia University Medical Center, New York, NY 10032, United States
| | - Aaron Oh
- General Medicine, Columbia University Medical Center, New York, NY 10032, United States
| | - Julian A Abrams
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States
| | - Joshua R Sonett
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States
| | - Chin Hur
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States
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Setia N, Ahn S, Han HS, Park DY, Lauwers GY. Predictive value of WHO classification for PD-L1 and Her2/Neu expression and distinct associations with protein expression based classification in gastric carcinoma. Hum Pathol 2019; 94:64-70. [PMID: 31676362 DOI: 10.1016/j.humpath.2019.10.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/13/2019] [Accepted: 10/20/2019] [Indexed: 12/12/2022]
Abstract
The Cancer Genome Atlas data on gastric carcinoma has identified four biologic pathways as potential drivers of gastric carcinogenesis and suggested targeted therapies based on the genomic alterations underscoring each subset. The correlation between morphology, biologic groups and their corresponding biomarkers has been eluded in several previous studies; however, a comprehensive analysis in consideration of the recent advancements has not been performed. In this study we explored the predictive value of morphology for biomarker expression and its association with protein expression based classification of gastric carcinoma. Four hundred eighty six gastric carcinomas which had been classified into protein expression-based groups formed the case cohort. Upon analysis, we found a low positive predictive value of an individual morphologic pattern for biomarker-expression, indicating that an individual morphologic pattern alone cannot predict PD-L1, Her2/neu expression and EBV- or MSI-gastric cancer. A combination approach targeting the test in certain WHO patterns can be employed for maximizing the positive predictive values. These include, PD-L1 testing in tubular, carcinoma with lymphoid stroma, undifferentiated and poorly cohesive patterns and Her2/neu testing in tubular, mixed, papillary, mucinous and solid patterns. The predictive values and morphologic associations presented here have the potential to select patients for personalized therapy.
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Affiliation(s)
- Namrata Setia
- Department of Pathology, University of Chicago, IL, USA 60637.
| | - Sangjeong Ahn
- Department of Pathology, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Republic of Korea 22711.
| | - Hye S Han
- Konkuk University School of Medicine, Seoul, South Korea 501-600.
| | - Do Youn Park
- Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Busan, Republic of Korea 602-739.
| | - Gregory Y Lauwers
- Department of Pathology, H Lee Moffitt Cancer Center and Research Institute, Departments of Oncological Sciences, Pathology and Cell Biology, University of South Florida, Tampa, Florida, USA 33612.
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Kosovec JE, Zaidi AH, Pounardjian TS, Jobe BA. The Potential Clinical Utility of Circulating Tumor DNA in Esophageal Adenocarcinoma: From Early Detection to Therapy. Front Oncol 2018; 8:610. [PMID: 30619750 PMCID: PMC6297385 DOI: 10.3389/fonc.2018.00610] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/28/2018] [Indexed: 12/11/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) is a lethal cancer requiring improved screening strategies and treatment options due to poor detection methods, aggressive progression, and therapeutic resistance. Emerging circulating tumor DNA (ctDNA) technologies may offer a unique non-invasive strategy to better characterize the highly heterogeneous cancer and more clearly establish the genetic modulations leading to disease progression. The presented review describes the potential advantages of ctDNA methodologies as compared to current clinical strategies to improve clinical detection, enhance disease surveillance, evaluate prognosis, and personalize treatment. Specifically, we describe the ctDNA-targetable genetic markers of prognostic significance to stratify patients into risk of progression from benign to malignant disease and potentially offer cost-effective screening of established cancer. We also describe the application of ctDNA to more effectively characterize the heterogeneity and particular mutagenic resistance mechanisms in real-time to improve prognosis and therapeutic monitoring strategies. Lastly, we discuss the inconsistent clinical responses to currently approved therapies for EAC and the role of ctDNA to explore the dynamic regulation of novel targeted and immunotherapies to personalize therapy and improve patient outcomes. Although there are clear limitations of ctDNA technologies for immediate clinical deployment, this review presents the prospective role of such applications to potentially overcome many of the notable hurdles to treating EAC patients. A deeper understanding of complex EAC tumor biology may result in the progress toward improved clinical outcomes.
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Affiliation(s)
- Juliann E Kosovec
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Ali H Zaidi
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Tamar S Pounardjian
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Blair A Jobe
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, United States
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Human Epidermal Growth Factor Receptor 2 Over-Expression in Patients with Esophageal Squamous Cell Carcinoma; Correlation with Response to Neo-Adjuvant Chemoradiation and Survival. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2018. [DOI: 10.5812/ijcm.8466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Bonotto M, Garattini SK, Basile D, Ongaro E, Fanotto V, Cattaneo M, Cortiula F, Iacono D, Cardellino GG, Pella N, Fasola G, Antonuzzo L, Silvestris N, Aprile G. Immunotherapy for gastric cancers: emerging role and future perspectives. Expert Rev Clin Pharmacol 2017; 10:609-619. [PMID: 28349740 DOI: 10.1080/17512433.2017.1313113] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The broad use of immunotherapy is revolutionizing the treatment paradigms of many solid tumors. Although chemotherapy remains the treatment backbone for advanced gastric cancer, improvements in its molecular characterization and progresses in understanding its underpinning biology have supported clinical development of novel immunotherapies. However, the results of recent trials testing these new agents raise the question on how to identify the patients that could greatly benefit. Areas covered: This article summarizes the current understanding on the biology and the mechanisms underlying different clinical features of gastric cancers. Particularly, after a comprehensive literature search, we speculate whether specific molecular subsets of patients could derive more benefit from immunotherapy. Expert commentary: Most cancers may evade the immune response, which is normally regulated by a delicate balance between activating and inhibitory signals. For example, both CTLA-4 and PD-1, once linked to PD-L1/2, may inhibit T-cell signaling. The use of agent to harness the power of the immune system appears to be the ultimate frontier in gastric cancer treatment. While anti-CTLA-4 antibodies are minimally active, there is growing evidence for the efficacy of PD1/-L1 inhibitors. The search of predictive factors for immunotherapy will provide key hints towards the optimal use of these agents.
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Affiliation(s)
- Marta Bonotto
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Silvio Ken Garattini
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Debora Basile
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Elena Ongaro
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Valentina Fanotto
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Monica Cattaneo
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Francesco Cortiula
- a Department Oncology , University Hospital of Udine , Udine , Italy.,b Department of Medical Area , University of Udine , Udine , Italy
| | - Donatella Iacono
- a Department Oncology , University Hospital of Udine , Udine , Italy
| | | | - Nicoletta Pella
- a Department Oncology , University Hospital of Udine , Udine , Italy
| | - Gianpiero Fasola
- a Department Oncology , University Hospital of Udine , Udine , Italy
| | | | - Nicola Silvestris
- d Medical Oncology Unit , National Cancer Institute IRCCS "Giovanni Paolo II" , Bari , Italy
| | - Giuseppe Aprile
- a Department Oncology , University Hospital of Udine , Udine , Italy.,e Department of Oncology , General Hospital San Bortolo, ULSS8 Berica , Vicenza , Italy
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Liu X, Meltzer SJ. Gastric Cancer in the Era of Precision Medicine. Cell Mol Gastroenterol Hepatol 2017; 3:348-358. [PMID: 28462377 PMCID: PMC5404028 DOI: 10.1016/j.jcmgh.2017.02.003] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/13/2017] [Indexed: 12/14/2022]
Abstract
Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine.
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Key Words
- CIMP, CpG island methylator phenotype
- CIN, chromosomally unstable/chromosomal instability
- Cancer Genomics
- EBV, Epstein-Barr virus
- GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach
- GC, gastric cancer
- GTPase, guanosine triphosphatase
- Gastric Cancer
- HDGC, hereditary diffuse gastric cancer
- LOH, loss of heterozygosity
- MSI, microsatellite unstable/instability
- MSI-H, high microsatellite instability
- MSS/EMT, microsatellite stable with epithelial-to-mesenchymal transition features
- Molecular Classification
- NGS, next-generation sequencing
- PDX, patient-derived tumor xenografts
- Preclinical Models
- TCGA, The Cancer Genome Atlas
- TGF, transforming growth factor
- hPSC, human pluripotent stem cell
- lncRNA, long noncoding RNA
- miRNA, microRNA
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Affiliation(s)
- Xi Liu
- Department of Pathology, First Affiliated Hospital of Xi’ an Jiaotong University, Xi’ an, Shaanxi, China,Division of Gastroenterology, Department of Medicine, and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland
| | - Stephen J. Meltzer
- Division of Gastroenterology, Department of Medicine, and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland,Correspondence Address correspondence to: Stephen J. Meltzer, MD, Johns Hopkins University School of Medicine, 1503 East Jefferson Street, Room 112, Baltimore, Maryland 21287. fax: (410) 502-1329.Johns Hopkins University School of Medicine1503 East Jefferson Street, Room 112BaltimoreMaryland21287
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Li L, Niu H, Sun B, Xiao Y, Li W, Yuan H, Lou H. Riccardin D-N induces lysosomal membrane permeabilization by inhibiting acid sphingomyelinase and interfering with sphingomyelin metabolism in vivo. Toxicol Appl Pharmacol 2016; 310:175-184. [PMID: 27660101 DOI: 10.1016/j.taap.2016.09.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 09/03/2016] [Accepted: 09/16/2016] [Indexed: 12/14/2022]
Abstract
Lysosomes are important targets for anticancer drug discovery. Our previous study showed that Riccardin D-N (RD-N), a natural macrocylic bisbibenzyl derivative produced by Mannich reaction, induced cell death by accumulating in lysosomes. Experiments were performed on human lung squamous cell carcinoma tissue from left inferior lobar bronchus of patient xenografts and H460 cells. RD-N was administrated for 25days. The specimens of xenografts in Balb/c athymic (nu+/nu+) male mice were removed for immunohistochemistry, subcellular fractionation, enzyme activities and Western blotting analysis. mRFP-GFP-LC3 reporter was used to examine autophagy in H460 cells. Sphingomyelin assay was evaluated by thin-layer chromatography and assay kit. Lysosomal membrane permeabilization (LMP) caused by acid sphingomyelinase (ASM) inhibition and subsequent changes of sphingomyelin (SM) metabolism selectively destabilized the cancer cell lysosomes in RD-N-treated H460 cells in vitro and tumor xenograft model in vivo. The destabilized lysosomes induced the release of cathepsins from the lysosomes into the cytosol and further triggered cell death. These results explain the underlying mechanism of RD-N induced LMP. It can be concluded that a more lysosomotropic derivative was synthesized by introduction of an amine group, which could have more potential applications in cancer therapy.
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Affiliation(s)
- Lin Li
- Department of Natural Product Chemistry, Key Lab of Chemical Biology of MOE (Ministry of Education), Shandong University, Jinan 250012, China
| | - Huanmin Niu
- Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan 250012, China
| | - Bin Sun
- Department of Natural Product Chemistry, Key Lab of Chemical Biology of MOE (Ministry of Education), Shandong University, Jinan 250012, China
| | - Yanan Xiao
- School of Pharmaceutical Science, Shandong University, Jinan 250012, China
| | - Wei Li
- Department of Natural Product Chemistry, Key Lab of Chemical Biology of MOE (Ministry of Education), Shandong University, Jinan 250012, China
| | - Huiqing Yuan
- Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan 250012, China
| | - Hongxiang Lou
- Department of Natural Product Chemistry, Key Lab of Chemical Biology of MOE (Ministry of Education), Shandong University, Jinan 250012, China.
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Genomics and the Prediction and Characterization of Cancer and Some Observations About Pancreatic Cancer. Clin Ther 2016; 38:1543-5. [DOI: 10.1016/j.clinthera.2016.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 06/03/2016] [Indexed: 11/22/2022]
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12
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Cancer Genomics: Targeting Inherited Risk and Somatic Mutations in Precision Oncology. Clin Ther 2016; 38:1548-50. [DOI: 10.1016/j.clinthera.2016.03.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 03/16/2016] [Accepted: 03/28/2016] [Indexed: 01/02/2023]
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