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Zheng Y, Meng L, Qu L, Zhao C, Wang L, Ma J, Liu C, Shou C. Co-targeting TMEM16A with a novel monoclonal antibody and EGFR with Cetuximab inhibits the growth and metastasis of esophageal squamous cell carcinoma. J Transl Med 2024; 22:1046. [PMID: 39563381 DOI: 10.1186/s12967-024-05830-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/30/2024] [Indexed: 11/21/2024] Open
Abstract
The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.
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Affiliation(s)
- Yutian Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
- Department of Pathology, National Center for Children's Health (NCCH), Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Lin Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Chuanke Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lixin Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jiayi Ma
- Beijing National Day School, Beijing, 100039, China
| | - Caiyun Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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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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3
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Li D, Ding L, Chen Y, Wang Z, Zeng Z, Ma X, Huang H, Li H, Qian X, Yang Z, Zhu H. Exploration of radionuclide labeling of a novel scFv-Fc fusion protein targeting CLDN18.2 for tumor diagnosis and treatment. Eur J Med Chem 2024; 266:116134. [PMID: 38266552 DOI: 10.1016/j.ejmech.2024.116134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/04/2024] [Accepted: 01/07/2024] [Indexed: 01/26/2024]
Abstract
PURPOSE Claudin 18.2 (CLDN18.2), due to its highly selective expression in tumor cells, has made breakthrough progress in clinical research and is expected to be integrated into routine tumor diagnosis and treatment. METHODS In this research, we obtained an scFv-Fc fusion protein (SF106) targeting CLDN18.2 through hybridoma technology. The scFv-Fc fusion protein was labeled with radioactive isotopes (124I and 177Lu) to generate the radio-probes. The targeting and specificity of the radio-probes were tested in cellular models, and its diagnostic and therapeutic potential was further evaluated in tumor-bearing models. RESULTS The molecular probes [124I]I-SF106 and [177Lu]Lu-DOTA-SF106 possess high radiochemical purity (RCP, 98.18 ± 0.93 % and 97.05 ± 1.1 %) and exhibit good stability in phosphate buffer saline and 5 % human serum albumin (92.44 ± 4.68 % and 91.03 ± 2.42 % at 120 h). [124I]I-SF106 uptake in cells expressing CLDN18.2 was well targeted and specific, and the dissociation constant was 17.74 nM [124I]I-SF106 micro-PET imaging showed that the maximum standardized uptake value (SUVmax) was significantly higher than CLDN18.2-negative tumors (1.83 ± 0.02 vs. 1.23 ± 0.04, p < 0.001). The maximum uptake was attained in tumors expressing CLDN18.2 at 48 h after injection. [124I]I-SF106 and [177Lu]Lu-DOTA-SF106 dosimetric study showed that the effective dose in humans complies with the medical safety standards required for their clinical application. The results of treatment experiments showed that 3 MBq of [177Lu]Lu-DOTA-SF106 in CLDN18.2-expressing tumor-bearing mice could significantly inhibit tumor growth. CONCLUSION These results indicate that radionuclide-labeled scFv-Fc molecular probes ([124I]I-SF106 and [177Lu]Lu-DOTA-SF106) provide a new possibility for the diagnosis and treatment of CLDN18.2-positive cancer patients in clinical practice.
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Affiliation(s)
- Dapeng Li
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lei Ding
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yan Chen
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zilei Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Ziqing Zeng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaopan Ma
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Haifeng Huang
- Department of Orthopedics, Guizhou Provincial People's Hospital, Guiyang, 550025, Guizhou, China
| | - Hongjun Li
- Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, 215000, China
| | - Xueming Qian
- Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, 215000, China.
| | - Zhi Yang
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Hua Zhu
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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4
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Wang Z, Zhao C, Ding J, Chen Y, Liu J, Hou X, Kong X, Dong B, Yang Z, Zhu H. Screening, Construction, and Preliminary Evaluation of CLDN18.2-Specific Peptides for Noninvasive Molecular Imaging. ACS Pharmacol Transl Sci 2023; 6:1829-1840. [PMID: 38093841 PMCID: PMC10714438 DOI: 10.1021/acsptsci.3c00165] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 10/08/2023] [Accepted: 11/07/2023] [Indexed: 04/23/2025]
Abstract
Recent global clinical trials have shown that CLDN18.2 is an ideal target for the treatment of gastric cancer and that patients with high CLDN18.2 expression can benefit from targeted therapy. Therefore, accurate and comprehensive detection of CLDN18.2 expression is important for patient screening and guidance in anti-CLDN18.2 therapy. Phage display technology was used to screen CLDN18.2-specific peptides from 100 billion libraries. 293TCLDN18.1 cells were used to exclude nonspecific binding and CLDN18.1 binding sequences, while 293TCLDN18.2 cells were used to screen CLDN18.2-specific binding peptides. The monoclonal clones obtained from phage screening were sequenced, and peptides were synthesized based on the sequencing results. Binding specificity and affinity were assessed with a fluorescein isothiocyanate (FITC)-conjugated peptide. A 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated peptide was also synthesized for 68Ga radiolabeling. The in vitro and in vivo stability, partition coefficients, in vivo molecular imaging, and biodistribution were also characterized. Overall, 54 monoclonal clones were selected after phage display screening. Subsequently, based on the cell ELISA results, CLDN18.2 preference monoclonal clones were selected for deoxyribonucleic acid (DNA) sequencing, and four 7-peptide sequences were obtained after sequence comparison; among them, a peptide named T37 was further validated in vitro and in vivo. The T37 peptide specifically recognized CLDN18.2 but not CLDN18.1 and bound strongly to CLDN18.2-positive cell membranes. The 68Ga-DOTA-T37 probe exhibits good in vitro properties and high stability as a hydrophilic probe; it has high biological safety, and positron emission tomography/computed tomography (PET/CT) studies have shown that it can specifically target CLDN18.2 protein and CLDN18.2-positive tumors in mice. 68Ga-DOTA-T37 demonstrated the superiority and feasibility of using a CLDN18.2-specific probe in PCT/CT imaging, which deserves further development and exploitation.
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Affiliation(s)
- Zilei Wang
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Chuanke Zhao
- Key
Laboratory of Carcinogenesis and Translational Research (Ministry
of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jin Ding
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Yan Chen
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Jiayue Liu
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Xingguo Hou
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - XiangXing Kong
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Bin Dong
- Central
Laboratory, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Zhi Yang
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
| | - Hua Zhu
- State
Key Laboratory of Holistic Integrative Management of Gastrointestinal
Cancers, Beijing Key Laboratory of Carcinogenesis and Translational
Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals
(National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital
& Institute, Beijing 100142, China
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5
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Aziz F, Shoaib N, Rehman A. Hub genes identification and association of key pathways with hypoxia in cancer cells: A bioinformatics analysis. Saudi J Biol Sci 2023; 30:103752. [PMID: 37593462 PMCID: PMC10428120 DOI: 10.1016/j.sjbs.2023.103752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/17/2023] [Accepted: 07/22/2023] [Indexed: 08/19/2023] Open
Abstract
Three human cancer cell lines (A549, HCT116, and HeLa) were used to investigate the molecular mechanisms and potential prognostic biomarkers associated with hypoxia. We obtained gene expression data from Gene Expression Omnibus (GEO) datasets GSE11704, GSE147384, and GSE38061, which included 5 hypoxic and 8 control samples. Using the GEO2R tool and Venn diagram software, we identified common differentially expressed genes (cDEGs). The cDEGs were then subjected to Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis by employing DAVID. The hub genes were identified from critical PPI subnetworks through CytoHuba plugin and these genes' prognostic significance and expression were verified using Kaplan-Meier analysis and Gene Expression Profiling Interactive Analysis (GEPIA), respectively. The research showed 676 common DEGs (cDEGs), with 207 upregulated and 469 downregulated genes. The STRING analysis showed 673 nodes and 1446 edges in the PPI network. We identified 4 significant modules and 19 downregulated hub genes. GO analysis revealed all of them were majorly involved in ribosomal large subunit assembly and biogenesis, rRNA processing, ribosome biogenesis, translation, RNA & protein binding frequently at the sites of nucleolus and nucleoplasm while 11 were significantly associated with a better prognosis of hypoxic tumors. Our research sheds light on the molecular mechanisms that underpin hypoxia in human cancer cell lines and identifies potential prognostic biomarkers for hypoxic tumors.
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Affiliation(s)
- Faiza Aziz
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, 54590 Lahore, Pakistan
| | - Naila Shoaib
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, 54590 Lahore, Pakistan
| | - Abdul Rehman
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, 54590 Lahore, Pakistan
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Xu W, Chen Y, Zhang Z, Jiang Y, Wang Z. Exosomal PIK3CB promotes PD-L1 expression and malignant transformation in esophageal squamous cell carcinoma. Med Oncol 2023; 40:221. [PMID: 37402056 DOI: 10.1007/s12032-023-02093-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/19/2023] [Indexed: 07/05/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC), which accounts for 90% of esophageal carcinomas, seriously endangers human health. Worse still, the 5-year overall survival of ESCC is approximately 20%. Elucidation of the potential mechanism and exploration of promising drugs for ESCC are urgently needed. In this study, a high level of exosomal PIK3CB protein was found in the plasma of ESCC patients, which might indicate a poor prognosis. Moreover, a significant Pearson's correlation was observed at the protein level between exosomal PIK3CB and exosomal PD-L1. Further study revealed that cancer cell-intrinsic and exosome-derived PIK3CB promoted the transcriptional activity of the PD-L1 promoter in ESCC cells. Moreover, treatment with exosomes with lower levels of exosomal PIK3CB decreased the protein level of the mesenchymal marker β-catenin while increasing that of the epithelial marker claudin-1, indicating the potential regulation of epithelial-mesenchymal transition. Consequently, the migratory ability and cancer stemness of ESCC cells and the growth of tumors formed by ESCC cells were decreased with the downregulation of exosomal PIK3CB. Therefore, exosomal PIK3CB plays an oncogenic role by promoting PD-L1 expression and malignant transformation in ESCC. This study may provide new insight into the inherent biological aggressiveness and the poor response to currently available therapies of ESCC. Exosomal PIK3CB may be a promising target for the diagnosis and therapy of ESCC in the future.
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Affiliation(s)
- Wei Xu
- Department of Thoracic Surgery, Chongqing University Cancer Hospital, Chongqing, China
| | - Yang Chen
- Department of Thoracic Surgery, Chongqing University Cancer Hospital, Chongqing, China
| | - Zhi Zhang
- Department of Thoracic Surgery, Chongqing University Cancer Hospital, Chongqing, China
| | - Yuequan Jiang
- Department of Thoracic Surgery, Chongqing University Cancer Hospital, Chongqing, China.
| | - Zhiqiang Wang
- Department of Thoracic Surgery, Chongqing University Cancer Hospital, Chongqing, China.
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7
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Yang L, Liu S, He W, Xiong Z, Xia L. Characterisation of tumor microenvironment and prevalence of CD274/PD-L1 genetic alterations difference in colorectal Cancer. BMC Cancer 2023; 23:221. [PMID: 36894899 PMCID: PMC9996909 DOI: 10.1186/s12885-023-10610-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 02/06/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Large-scale genomic alterations, especially CD274/PD-L1 gene amplification, have great impact on anti-PD-1 efficacy on cancers such as Hodgkin's lymphoma. However, the prevalence of PD-L1 genetic alterations in colorectal cancer (CRC) and its correlation with the tumor immune microenvironment and clinical implications remain unknown. MATERIALS AND METHODS PD-L1 genetic alterations were evaluated in 324 patients with newly diagnosed CRC including 160 mismatch repair-deficient (dMMR) patients and 164 mismatch repair-proficient (pMMR) patients using fluorescence in situ hybridization (FISH) method. The correlation between PD-L1 and the expression of the common immune markers was analyzed. RESULTS Totally 33 (10.2%) patients were identified with aberrant PD-L1 genetic alternations including deletion (2.2%), polysomy (4.9%), and amplification (3.1%); They had more aggressive features such as advanced stage (P = 0.02), shorter overall survival (OS) (P < 0.001) than patients with disomy. The aberrations correlated with positive lymph node (PLN) (p = 0.001), PD-L1 expression by immunohistochemistry (IHC) in tumor cells (TCs) or tumor-infiltrated immunocytes (ICs) (both p < 0.001), and pMMR (p = 0.029). When dMMR and pMMR were analyzed independently, the correlations of aberrant PD-L1 genetic alterations with PD-1 expression (p = 0.016), CD4 + T cells (p = 0.032), CD8 T + cells (p = 0.032) and CD68 + cells (p = 0.04) were only found in dMMR cohort. CONCLUSIONS The prevalence of PD-L1 genetic alterations was relatively low in CRC, but the aberrations usually correlate with aggressive nature. The correlation between PD-L1 genetic alterations and tumor immune features was only observed in dMMR CRC.
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Affiliation(s)
- Lin Yang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, 1838 Baiyun Avenue North, Guangzhou, 510515, China
| | - Shousheng Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.,Department of General Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China
| | - Wenzhuo He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.,Department of General Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China
| | - Zhenchong Xiong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China. .,Department of Breast Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.
| | - Liangping Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China. .,Department of General Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.
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8
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Ogden S, Ahmed I, Yang SH, Fullwood P, the OCCAMS consortium, Francavilla C, Sharrocks AD. Oncogenic ERRB2 signals through the AP-1 transcription factor to control mesenchymal-like properties of oesophageal adenocarcinoma. NAR Cancer 2023; 5:zcad001. [PMID: 36694726 PMCID: PMC9869078 DOI: 10.1093/narcan/zcad001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/08/2022] [Accepted: 01/06/2023] [Indexed: 01/25/2023] Open
Abstract
Oesophageal adenocarcinoma (OAC) is a deadly disease with poor survival statistics and few targeted therapies available. One of the most common molecular aberrations in OAC is amplification or activation of the gene encoding the receptor tyrosine kinase ERBB2, and ERBB2 is targeted in the clinic for this subset of patients. However, the downstream consequences of these ERBB2 activating events are not well understood. Here we used a combination of phosphoproteomics, open chromatin profiling and transcriptome analysis on cell line models and patient-derived datasets to interrogate the molecular pathways operating downstream from ERBB2. Integrated analysis of these data sets converge on a model where dysregulated ERBB2 signalling is mediated at the transcriptional level by the transcription factor AP-1. AP-1 in turn controls cell behaviour by acting on cohorts of genes that regulate cell migration and adhesion, features often associated with EMT. Our study therefore provides a valuable resource for the cancer cell signalling community and reveals novel molecular determinants underlying the dysregulated behaviour of OAC cells.
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Affiliation(s)
- Samuel Ogden
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
| | - Ibrahim Ahmed
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
| | - Shen-Hsi Yang
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
| | - Paul Fullwood
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
| | | | - Chiara Francavilla
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
- Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, Manchester M13 9PT, UK
| | - Andrew D Sharrocks
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
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9
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Ding YN, Xue M, Tang QS, Wang LJ, Ding HY, Li H, Gao CC, Yu WP. Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges. World J Gastroenterol 2022; 28:5403-5419. [PMID: 36312831 PMCID: PMC9611702 DOI: 10.3748/wjg.v28.i37.5403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/27/2022] [Accepted: 09/15/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.
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Affiliation(s)
- Yi-Nan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Ming Xue
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Qiu-Sha Tang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Li-Jun Wang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Hui-Yan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Han Li
- Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Cheng-Cheng Gao
- Department of Radiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Ping Yu
- Medical School, Southeast University, Nanjing 210009, Jiangsu Province, China
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10
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Zhao C, Rong Z, Ding J, Wang L, Wang B, Ding L, Meng L, Meng X, Wang F, Yang Z, Shou C, Zhu H. Targeting Claudin 18.2 Using a Highly Specific Antibody Enables Cancer Diagnosis and Guided Surgery. Mol Pharm 2022; 19:3530-3541. [PMID: 35344359 DOI: 10.1021/acs.molpharmaceut.1c00947] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Claudin 18.2 (CLDN18.2) is a new potential target for cancer therapy, especially for advanced gastric cancer (AGC). A molecular targeting probe is of importance for patient stratification and therapeutic guidance. Here, we explored an antibody-dependent molecular imaging strategy for specific detection and surgery guidance based on a CLDN18.2-specific antibody, 5C9. Two imaging probes, 124I-5C9 and Cy5.5-5C9, were synthesized. The specificity to CLDN18.2 being evidenced in the cellular experiments with control, the diagnostic utility was assessed by immunopositron emission tomography (immuno-PET) and fluorescence imaging using xenograft models. A near-infrared fluorescent II imaging probe FD1080-5C9 was designed to facilitate the comprehensive surgical removal of lesions. 124I-5C9 immuno-PET imaging clearly delineated subcutaneous CLDN18.2-positive tumors, with a peak uptake (maximum standardized uptake value; SUVmax) of 2.25 ± 0.30, whereas the highest values for the 124I-IgG and blocking groups were 0.70 ± 0.13 and 0.66 ± 0.12, respectively. Cy5.5-5C9 fluorescence imaging showed similar results. As proof of the diagnosis and guided surgery (DGS) concept, 124I-5C9 and FD1080-5C9 were simultaneously administered in orthotopic CLDN18.2-positive tumor models, facilitating the comprehensive resection of tumor tissue. Combined, 124I-5C9 and FD1080-5C9 are both promising DGS tools: the former reveals CLDN18.2 in lesions as a PET probe, and the latter can guide surgery. These results provide a utility molecular imaging strategy for specific detection and surgery guidance based on a CLDN18.2-specific antibody both in AGC and other cancers.
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Affiliation(s)
- Chuanke Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhuona Rong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jin Ding
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Lixin Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Bing Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Lei Ding
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Lin Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiangxi Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Feng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
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11
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Bai Z, Guo Z, Liu J, Chen YA, Lu Q, Zhang P, Hong L, Wang Y, Dong J. Lapatinib Suppresses HER2-Overexpressed Cholangiocarcinoma and Overcomes ABCB1- Mediated Gemcitabine Chemoresistance. Front Oncol 2022; 12:860339. [PMID: 35463361 PMCID: PMC9033256 DOI: 10.3389/fonc.2022.860339] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/22/2022] [Indexed: 11/29/2022] Open
Abstract
Background Recent breakthroughs in cholangiocarcinoma (CCA) genomics have led to the discovery of many unique identifying mutations, of which HER2 has been found to be overexpressed specifically in cases of extrahepatic CCA. However, whether or not lapatinib (an oral tyrosine kinase inhibitor selective for inhibition of HER2), or a combination of lapatinib and gemcitabine, exerts inhibitory effects on HER2-overexpressed CCA is still unclear. Methods The effect of lapatinib and a lapatinib-gemcitabine combination treatment on CCA was determined using organoid and cell line models. Cell cycle arrest, apoptosis and proteins involving HER2-dependent downstream signaling pathways were analyzed to assess the effect of lapatinib on HER2+ CCA. The synergistic effect of lapatinib and gemcitabine was interpreted by docking analysis, ABCB1-associated ATPase assay, rhodamine transport assay and LC-MS/MS analyses. Results dFdCTP, the active metabolite of gemcitabine, is proved to be the substrate of ABCB1 by docking analysis and ATPase assay. The upregulation of ABCB1 after gemcitabine treatment accounts for the resistance of gemcitabine. Lapatinib exerts a dual effect on HER2-overexpressed CCA, suppressing the growth of CCA cells by inhibiting HER2 and HER2-dependent downstream signaling pathways while inhibiting ABCB1 transporter function, allowing for the accumulation of active gemcitabine metabolites within cells. Conclusions Our data demonstrates that lapatinib can not only inhibit growth of CCA overexpressing HER2, but can also circumvent ABCB1-mediated chemoresistance after gemcitabine treatment. As such, this provides a preclinical rationale basis for further clinical investigation into the effectiveness of a combination treatment of lapatinib with gemcitabine in HER2-overexpressed CCA.
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Affiliation(s)
- Zhiqing Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Zhiying Guo
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jiaxing Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu-Ann Chen
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Qian Lu
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Lili Hong
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College (State Key Laboratory of Bioactive Substance and Function of Natural Medicines & NHC Key Laboratory of Biosynthesis of Natural Products), Beijing, China
| | - Yunfang Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China.,Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
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12
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Advances in the curative management of oesophageal cancer. Br J Cancer 2022; 126:706-717. [PMID: 34675397 PMCID: PMC8528946 DOI: 10.1038/s41416-021-01485-9] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/01/2021] [Accepted: 06/30/2021] [Indexed: 12/24/2022] Open
Abstract
The incidence of oesophageal cancer, in particular adenocarcinoma, has markedly increased over the last four decades with adenocarcinoma becoming the dominant subtype in the West, and mortality rates are high. Nevertheless, overall survival of patients with oesophageal cancer has doubled in the past 20 years, with earlier diagnosis and improved treatments benefiting those patients who can be treated with curative intent. Advances in endotherapy, surgical approaches, and multimodal and other combination therapies have been reported. New vistas have emerged in targeted therapies and immunotherapy, informed by new knowledge in genomics and molecular biology, which present opportunities for personalised cancer therapy and novel clinical trials. This review focuses exclusively on the curative intent treatment pathway, and highlights emerging advances.
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13
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Rosenbaum MW, Gonzalez RS. Immunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies. Semin Diagn Pathol 2021; 39:48-57. [PMID: 34740486 DOI: 10.1053/j.semdp.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/28/2021] [Indexed: 11/11/2022]
Abstract
Biomarkers play a key role in the comprehensive pathologic evaluation of gastrointestinal malignancies. These biomarkers can be predictive, indicating whether a tumor is likely to respond to a particular therapy, or prognostic, providing information about the likely course and outcome of a disease. This review article will discuss available immunohistochemical stains for assessing these markers, including staining rationale, scoring criteria, associated systemic therapies, and pictorial examples. PD-L1, HER2, and mismatch repair status can be evaluated via immunohistochemistry for esophageal, gastric, and colorectal carcinomas. Biomarkers currently play a more limited role in evaluation of pancreatic and small bowel malignancies. Immunohistochemistry can also be used to evaluate biomarker status in gastrointestinal stromal tumors, gastrointestinal malignancies with NTRK gene fusions, and undifferentiated carcinomas with switch-sucrose non-fermentable complex abnormalities.
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Affiliation(s)
- Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, United States
| | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, United States.
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14
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Jiang Q, Chen L, Chen H, Tang Z, Liu F, Sun Y. Integrated Analysis of Stemness-Related LncRNAs Helps Predict the Immunotherapy Responsiveness of Gastric Cancer Patients. Front Cell Dev Biol 2021; 9:739509. [PMID: 34589496 PMCID: PMC8473797 DOI: 10.3389/fcell.2021.739509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022] Open
Abstract
The immune microenvironment plays a critical role in tumor biology. As a critical feature of cancers, stemness is acknowledged as a contributor to the development of drug resistance in gastric cancers (GCs). Long non-coding RNAs (lncRNAs) have been revealed to participate in this process. In this study, we aimed to develop a stemness-related lncRNA signature (SRLncSig) with guiding significance for immunotherapy. Three cohorts (TCGA, Zhongshan, and IMvigor210) were enrolled for analysis. A list of stemness-related lncRNAs (SRlncRNAs) was collected by co-expression strategy under the threshold of coefficient value >0.35 and p-value < 0.05. Cox and Lasso regression analysis was further applied to find out the SRlncRNAs with prognosis-predictive value to establish the SRLncSig in the TCGA cohort. IPS and TIDE algorithms were further applied to predict the efficacy of SRLncSig in TCGA and Zhongshan cohorts. IMvigor210 was composed of patients with clinical outcomes of immunotherapy. The results indicated that SRLncSig not only was confirmed as an independent risk factor for GCs but also identified as a robust indicator for immunotherapy. The patient with a lower SRLncSig score was more likely to benefit from immunotherapy, and the results were highly consistent in three cohorts. In conclusion, our study not only could clarify the correlations between stemness and immunotherapy in GC patients but also provided a model to guide the applications of immunotherapy in clinical practice.
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Affiliation(s)
- Quan Jiang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Lingli Chen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaoqing Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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15
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Jiang Q, Chen H, Tang Z, Sun J, Ruan Y, Liu F, Sun Y. Stemness-related LncRNA pair signature for predicting therapy response in gastric cancer. BMC Cancer 2021; 21:1067. [PMID: 34587919 PMCID: PMC8482617 DOI: 10.1186/s12885-021-08798-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/21/2021] [Indexed: 02/06/2023] Open
Abstract
Objective As a critical feature of cancers, stemness is acknowledged as a contributor to the development of drug resistance in gastric cancer (GC). LncRNAs have been revealed to participate in this process. In this study, we tried to develop a stemness-related lncRNA pair signature as guidance for clinical decisions. Methods The analysis was initiated by collecting stemness-related lncRNAs in TCGA cohort. The differentially expressed stemness-related lncRNAs between normal and tumor tissues in GC patients from TCGA datasets were further collected to establish the signature based on Lasso and Cox regression analyses. The predictive efficacy of the signature for chemotherapy and immunotherapy was also tested. The practicality of this signature was also validated by Zhongshan cohort. Results A 13-DEsrlncRNA pair-based signature was established. The cutoff point acquired by the AIC algorithm divided the TCGA cohort into high and low risk groups. We found that the low-risk group presented with better survival (Kaplan-Meier analysis, p < 0.001). Cox regression analyse was also conducted to confirm the signature as an independent risk factor for GC {p < 0.001, HR = 1.300, 95% CI (1.231–1.373)]}. As for the practicality of this signature, the IC50 of cytotoxic chemotherapeutics was significantly higher in the high-risk group. The low-risk group also presented with higher immunophenoscore (IPS) in both the “CTLA4+ PD1+” (Mann-Whitney U test, p = 0.019) and “CTLA4- PD1+” (Mann-Whitney U test, p = 0.013) groups, indicating higher sensitivity to immunotherapy. The efficacy of the signature was also validated by Zhongshan cohort. Conclusions This study could not only provide a stemness-related lncRNA signature for survival prediction in GC patients but also established a model with predictive potentials for GC patients’ sensitivity to chemotherapy and immunotherapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08798-1.
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Affiliation(s)
- Quan Jiang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Hao Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhaoqing Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jie Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuanyuan Ruan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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16
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Xue S, Ma M, Bei S, Li F, Wu C, Li H, Hu Y, Zhang X, Qian Y, Qin Z, Jiang J, Feng L. Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer. Front Immunol 2021; 12:702615. [PMID: 34322132 PMCID: PMC8311657 DOI: 10.3389/fimmu.2021.702615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/10/2021] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint blockade has attracted a lot of attention in the treatment of human malignant tumors. We are trying to establish a prognostic model of gastric cancer (GC) based on the expression profile of immunoregulatory factor-related genes. Based on the TCGA database, we identified 234 differentially expressed immunoregulatory factors. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) conducted enrichment analysis to clarify the biological functions of differential expression of immunoregulatory factors. STRING database predicted the interaction network between 234 differently expressed immune regulatory factors. The expression of 11 immunoregulatory factors was significantly related to the overall survival of gastric cancer patients. Univariate Cox regression analysis, Kaplan–Meier analysis and multivariate Cox regression analysis found that immunomodulatory factors were involved in the progression of gastric cancer and promising biomarkers for predicting prognosis. Among them, CXCR4 was related to the low survival of GC patients and a key immunomodulatory factor in GC. Based on TCGA data, the high expression of CXCR4 in GC was positively correlated with the advanced stage and grade of gastric cancer and related to poor prognosis. Univariate analysis and multivariate analysis indicated that CXCR4 was an independent prognostic indicator for TCGA gastric cancer patients. In vitro functional studies had shown that CXCR4 promoted the proliferation, migration, and invasion of gastric cancer cells. In summary, this study has determined the prognostic value of 11 immunomodulatory factors in gastric cancer. CXCR4 is an independent prognostic indicator for gastric cancer patients, which may help to improve the individualized prognostic prediction of GC and provide candidates for the diagnosis and treatment of GC.
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Affiliation(s)
- Shuai Xue
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Ming Ma
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai, China
| | - Songhua Bei
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Fan Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Chenqu Wu
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Huanqing Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Yanling Hu
- Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiaohong Zhang
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - YanQing Qian
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Zhe Qin
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Jun Jiang
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Li Feng
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
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17
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Kang MH, Eyun SI, Park YY. Estrogen-related receptor-gamma influences Helicobacter pylori infection by regulating TFF1 in gastric cancer. Biochem Biophys Res Commun 2021; 563:15-22. [PMID: 34058470 DOI: 10.1016/j.bbrc.2021.05.076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 05/19/2021] [Indexed: 12/23/2022]
Abstract
Helicobacter pylori infection is a crucial factor in the development of gastric cancer (GC). Molecular therapeutic targets and mechanisms contributing to H. pylori infection-associated GC induction are poorly understood and this study aimed to fill that research gap. We found that the nuclear receptor estrogen-related receptor gamma (ESRRG) is a candidate factor influencing H. pylori infection-driven GC. ESRRG suppressed H. pylori infection and cell growth induced by H. pylori infection in GC cells and organoid models In addition, H. pylori infection downregulates ESRRG expression. Gene expression profiling revealed that trefoil factor 1 (TFF1), a well-known tumor suppressor in GC, is a downstream target of ESRRG. Mechanistically, ESRRG directly binds to the TFF1 promoter and induces TFF1 gene expression. Furthermore, TFF1 activation by ESRRG was inhibited by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/p65, which is induced by inflammation, such as by H. pylori infection. Our current study provides new molecular insights into how ESRRG regulates H. pylori infection, contributing to GC development. We suggest that modulation of ESRRG-suppressing H. pylori infection could be a therapeutic target for the treatment of GC patients.
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Affiliation(s)
| | - Seong-Il Eyun
- Department of Life Science, Chung-Ang University, Seoul, South Korea
| | - Yun-Yong Park
- Department of Life Science, Chung-Ang University, Seoul, South Korea.
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