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Wen J, Cui W, Yin X, Chen Y, Liu A, Wang Q, Meng X. Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer. Cancer Biol Med 2025; 22:j.issn.2095-3941.2024.0470. [PMID: 40192238 PMCID: PMC12032835 DOI: 10.20892/j.issn.2095-3941.2024.0470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 03/05/2025] [Indexed: 04/29/2025] Open
Abstract
As the leading cause of cancer-related deaths, lung cancer remains a noteworthy threat to human health. Although immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly increased the efficacy of lung cancer treatment, a significant percentage of patients are not sensitive to immunotherapies and patients who initially respond to treatment can quickly develop acquired drug resistance. Bispecific antibodies (bsAbs) bind two different antigens or epitopes simultaneously and have been shown to enhance antitumor efficacy with suitable safety profiles, thus attracting increasing attention as novel antitumor therapies. At present, in addition to the approved bsAb, amivantamab, three novel bsAbs (KN046, AK112, and SHR-1701) are being evaluated in phase 3 clinical trials and many bsAbs are being evaluated in phase 1/2 clinical trials for patients with non-small cell lung cancer (NSCLC). Herein we present the structure, classification, and mechanism of action underlying bsAbs in NSCLC and introduce related clinical trials. Finally, we discuss challenges, potential solutions, and future prospects in the context of cancer treatment with bsAbs.
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Affiliation(s)
- Junxu Wen
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Wenxing Cui
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Xiaoyan Yin
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Yu Chen
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Ailing Liu
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Qian Wang
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Xiangjiao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
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Khan SR, Breadner D. Unveiling the Synergistic Potential: Bispecific Antibodies in Conjunction with Chemotherapy for Advanced Non-Small-Cell Lung Cancer Treatment. Curr Oncol 2025; 32:206. [PMID: 40277763 PMCID: PMC12025875 DOI: 10.3390/curroncol32040206] [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: 02/28/2025] [Revised: 03/23/2025] [Accepted: 03/27/2025] [Indexed: 04/26/2025] Open
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of the cases. Despite advancements in targeted therapies and immunotherapies, many patients still rely on chemotherapy, highlighting the need for innovative treatment strategies. Bispecific antibodies (bsAbs), which feature two distinct binding sites capable of targeting different antigens, have emerged as a promising therapeutic approach, particularly in combination with chemotherapy. This review explores the scientific evolution and clinical application of bsAbs in NSCLC, focusing on their synergistic potential with chemotherapy. BsAbs, such as amivantamab, which targets EGFR and MET, have demonstrated significant efficacy in clinical trials, particularly in patients with EGFR mutations. The combination of bsAbs with chemotherapy enhances immune-mediated tumor destruction by modulating the tumor microenvironment and overcoming resistance mechanisms. Recent clinical trials have shown improved progression-free survival and overall survival when bsAbs such as amivantamab are combined with chemotherapy, underscoring their potential to transform NSCLC treatment. Many other clinical trials are underway that are evaluating newer bsAbs, such as ivonescimab, which targets PD1 and VEGF. This review also discusses ongoing clinical trials investigating various bsAbs targeting EGFR, PD-1, PD-L1, HER2, and other pathways, highlighting the future directions of bsAb-based therapies. As the field evolves, bsAbs are poised to become a cornerstone of multimodal NSCLC treatment, offering more effective and personalized therapeutic options for patients with advanced disease.
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Affiliation(s)
- Saqib Raza Khan
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada;
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Daniel Breadner
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada;
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
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Vierra MA, Morgan RB, Bhutiani N, White MG, Eng OS. Contemporary Management of Malignant Ascites. J Surg Res 2025; 307:157-175. [PMID: 40037156 DOI: 10.1016/j.jss.2025.01.025] [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: 08/30/2024] [Revised: 12/08/2024] [Accepted: 01/26/2025] [Indexed: 03/06/2025]
Abstract
INTRODUCTION Malignant ascites (MA) develops when malignant disease of the peritoneum causes excess fluid to accumulate in the abdominal cavity. It portends a poor prognosis and is associated with debilitating symptoms. While several palliative therapies exist, none have proven curative or free from side effects and complications. This review article describes experimental therapies on the horizon and the contemporary management of MA. MATERIALS AND METHODS A literature review was performed using MEDLINE/PubMed, in which studies of emerging or experimental therapies under investigation for the management of MA were reviewed. Current therapies were also reviewed to provide important context. Data, including study design, sample size, primary and secondary outcomes, and side effects were recorded and described. Studies were then categorized into distinct sections and subsections, with tables corresponding to each section. RESULTS Five current therapies, including paracentesis, diuretics, peritoneovenous shunting, permanent catheters, and intraperitoneal chemotherapy, are described. Their limitations in effectively managing MA are highlighted. The "Experimental therapies" section is subsectioned into several categories, with the major studies corresponding to each section thoroughly described regarding methods, results, and validity. A final section describes treatments for mucinous ascites, which has distinct characteristics. CONCLUSIONS While each of the experimental therapies described offers unique benefits and has demonstrated some promise in managing MA, they all have limitations that have thus far prevented any one of them from being routinely used in practice. MA remains a challenging condition to treat, warranting further research into novel therapies.
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Affiliation(s)
- Mason A Vierra
- Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
| | - Ryan B Morgan
- Department of Surgery, University of Chicago Medical Center, Chicago, Illinois
| | - Neal Bhutiani
- Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Michael G White
- Department of Colon & Rectal Surgery, MD Anderson Cancer Center, Houston, Texas
| | - Oliver S Eng
- Department of Surgery, University of California Irvine, Orange, California
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Lim S, Chung HJ, Oh YJ, Hinterdorfer P, Myung SC, Seo Y, Ko K. Modification of Fc-fusion protein structures to enhance efficacy of cancer vaccine in plant expression system. PLANT BIOTECHNOLOGY JOURNAL 2025; 23:960-982. [PMID: 39724301 PMCID: PMC11869200 DOI: 10.1111/pbi.14552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024]
Abstract
Epithelial cell adhesion molecule (EpCAM) fused to IgG, IgA and IgM Fc domains was expressed to create IgG, IgA and IgM-like structures as anti-cancer vaccines in Nicotiana tabacum. High-mannose glycan structures were generated by adding a C-terminal endoplasmic reticulum (ER) retention motif (KDEL) to the Fc domain (FcK) to produce EpCAM-Fc and EpCAM-FcK proteins in transgenic plants via Agrobacterium-mediated transformation. Cross-fertilization of EpCAM-Fc (FcK) transgenic plants with Joining chain (J-chain, J and JK) transgenic plants led to stable expression of large quaternary EpCAM-IgA Fc (EpCAM-A) and IgM-like (EpCAM-M) proteins. Immunoblotting, SDS-PAGE and ELISA analyses demonstrated that proteins with KDEL had higher expression levels and binding activity to anti-EpCAM IgGs. IgM showed the strongest binding among the fusion proteins, followed by IgA and IgG. Sera from BALB/c mice immunized with these vaccines produced anti-EpCAM IgGs. Flow cytometry indicated that the EpCAM-Fc fusion proteins significantly activated CD8+ cytotoxic T cells, CD4+ helper T cells and B cells, particularly with EpCAM-FcKP and EpCAM-FcP (FcKP) × JP (JKP). The induced anti-EpCAM IgGs captured human prostate cancer PC-3 and colorectal cancer SW620 cells. Sera from immunized mice inhibited cancer cell proliferation, migration and invasion; down-regulated proliferation markers (PCNA, Ki-67) and epithelial-mesenchymal transition markers (Vimentin); and up-regulated E-cadherin. These findings suggest that N. tabacum can produce effective vaccine candidates to induce anti-cancer immune responses.
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Affiliation(s)
- Sohee Lim
- BioSystems Design Lab, Department of Medicine, College of MedicineChung‐Ang UniversitySeoulKorea
| | - Hyun Joo Chung
- Department of Urology, College of MedicineChung‐Ang UniversitySeoulKorea
| | - Yoo Jin Oh
- Department of Applied Experimental BiophysicsJohannes Kepler UniversityLinzAustria
| | - Peter Hinterdorfer
- Department of Applied Experimental BiophysicsJohannes Kepler UniversityLinzAustria
| | - Soon Chul Myung
- Department of Urology, College of MedicineChung‐Ang UniversitySeoulKorea
| | - Young‐Jin Seo
- Department of Life ScienceChung‐Ang UniversitySeoulKorea
| | - Kisung Ko
- BioSystems Design Lab, Department of Medicine, College of MedicineChung‐Ang UniversitySeoulKorea
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Kappen J, Abdel-Rahman O. Advances in pharmacotherapy for the treatment of peritoneal metastases from colorectal cancer. Expert Opin Pharmacother 2025; 26:17-30. [PMID: 39604139 DOI: 10.1080/14656566.2024.2435946] [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: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 11/29/2024]
Abstract
INTRODUCTION Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) typically have a poor prognosis with historically few treatment options. Cytoreductive surgery (CRS) is the mainstay of treatment to remove macrometastases into the peritoneum, but residual micrometastases are often left behind. Systemic chemotherapy remains a cornerstone of treatment for micrometastases, but intraperitoneal therapy offers advantages including higher local dose concentration with fewer systemic side effects from treatment. AREAS COVERED This review covers advancements in the routes and types of pharmacotherapies for PM in CRC. EXPERT OPINION More evidence is needed to justify HIPEC with CRS as the standard of care treatment modality for patients with resectable PM in CRC. New therapies such as oncolytic viruses, biologics, and small-molecule inhibitors may become additional treatment modalities for PM.
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Affiliation(s)
- Janson Kappen
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada
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Gu Y, Zhao Q. Clinical Progresses and Challenges of Bispecific Antibodies for the Treatment of Solid Tumors. Mol Diagn Ther 2024; 28:669-702. [PMID: 39172329 PMCID: PMC11512917 DOI: 10.1007/s40291-024-00734-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2024] [Indexed: 08/23/2024]
Abstract
In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic strategy against tumors. BsAbs can recruit and activate immune cells, block multiple signaling pathways, and deliver therapeutic payloads directly to tumor sites. This review provides a comprehensive overview of the recent advances in the development and clinical application of BsAbs for the treatment of solid tumors. We discuss the different formats, the unique mechanisms of action, and the clinical outcomes of the most advanced BsAbs in solid tumor therapy. Several studies have also analyzed the clinical progress of bispecific antibodies. However, this review distinguishes itself by exploring the challenges associated with bispecific antibodies and proposing potential solutions. As the field progresses, BsAbs hold promise to redefine cancer treatment paradigms and offer new hope to patients with solid tumors.
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Affiliation(s)
- Yuheng Gu
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China
| | - Qi Zhao
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, 999078, China.
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Shen J, Qian N, Xu G, Dou X, An Y, Yang C, Liu Y, Liu Y, Pan X, Wang J, Bai G, Chen H, Zhu X, Gao X, Zhou G, Xu Q. IMT030122, A novel engineered EpCAM/CD3/4-1BB tri-specific antibody, enhances T-cell recruitment and demonstrates anti-tumor activity in mouse models of colorectal cancer. Int Immunopharmacol 2024; 137:112424. [PMID: 38878486 DOI: 10.1016/j.intimp.2024.112424] [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: 03/30/2024] [Revised: 05/24/2024] [Accepted: 06/04/2024] [Indexed: 07/11/2024]
Abstract
Colorectal cancer is a major global health burden, with limited efficacy of traditional treatment modalities in improving survival rates. However, recently advances in immunotherapy has improved treatment outcomes for patients with this cancer. To address the continuing need for improved treatment efficacy, this study introduced a novel tri-specific antibody, IMT030122, that targets EpCAM, 4-1BB, and CD3. We evaluated the pharmacological efficacy and mechanism of action of IMT030122 in vitro and in vivo. In in vitro studies, IMT030122 exhibited differential binding to antigens and cells expressing EpCAM, 4-1BB, and CD3. Moreover, IMT030122 relied on EpCAM-targeted activation of intracellular CD3 and 4-1BB signaling and mediated T cell cytotoxicity specific to HCT116 colorectal cancer cells. In vivo, IMT030122 demonstrated potent anti-tumor activity, significantly inhibiting the growth of colon cancer HCT116 and MC38-hEpCAM subcutaneous grafts. Further pharmacological analysis revealed that IMT030122 recruited lymphocytes from peripheral blood into colorectal cancer tissue and exerted durable anti-tumor activity, predominantly by promoting the activation, proliferation, and differentiation of CD8T cells. Notably, IMT030122 still exhibited anti-tumor efficacy even in the presence of significantly depleted lymphocytes in colorectal cancer tissue. The potent pharmacological activity and anti-tumor effects of IMT030122 suggest it may enhance treatment efficacy and substantially extend the survival of patients with colorectal cancer in the future.
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Affiliation(s)
- Jianbo Shen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Niliang Qian
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Guili Xu
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Xiaoqian Dou
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Ying An
- Department of Preventive Treatment of Disease, Chengde Traditional Medicine Hospital, Hebei 067000, China
| | - Cuima Yang
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Yujie Liu
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Yunhui Liu
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Xiujie Pan
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Jingjing Wang
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Guijun Bai
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Hao Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Xiaolin Zhu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Xin Gao
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China
| | - Guoxiong Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China.
| | - Qinzhi Xu
- Beijing Immunoah Pharma Tech Co., Ltd., Beijing 100141, China.
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Houvast RD, Badr N, March T, de Muynck LDAN, Sier VQ, Schomann T, Bhairosingh S, Baart VM, Peeters JAHM, van Westen GJP, Plückthun A, Burggraaf J, Kuppen PJK, Vahrmeijer AL, Sier CFM. Preclinical evaluation of EpCAM-binding designed ankyrin repeat proteins (DARPins) as targeting moieties for bimodal near-infrared fluorescence and photoacoustic imaging of cancer. Eur J Nucl Med Mol Imaging 2024; 51:2179-2192. [PMID: 37642704 PMCID: PMC11178671 DOI: 10.1007/s00259-023-06407-w] [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: 05/27/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
PURPOSE Fluorescence-guided surgery (FGS) can play a key role in improving radical resection rates by assisting surgeons to gain adequate visualization of malignant tissue intraoperatively. Designed ankyrin repeat proteins (DARPins) possess optimal pharmacokinetic and other properties for in vivo imaging. This study aims to evaluate the preclinical potential of epithelial cell adhesion molecule (EpCAM)-binding DARPins as targeting moieties for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of cancer. METHODS EpCAM-binding DARPins Ac2, Ec4.1, and non-binding control DARPin Off7 were conjugated to IRDye 800CW and their binding efficacy was evaluated on EpCAM-positive HT-29 and EpCAM-negative COLO-320 human colon cancer cell lines. Thereafter, NIRF and PA imaging of all three conjugates were performed in HT-29_luc2 tumor-bearing mice. At 24 h post-injection, tumors and organs were resected and tracer biodistributions were analyzed. RESULTS Ac2-800CW and Ec4.1-800CW specifically bound to HT-29 cells, but not to COLO-320 cells. Next, 6 nmol and 24 h were established as the optimal in vivo dose and imaging time point for both DARPin tracers. At 24 h post-injection, mean tumor-to-background ratios of 2.60 ± 0.3 and 3.1 ± 0.3 were observed for Ac2-800CW and Ec4.1-800CW, respectively, allowing clear tumor delineation using the clinical Artemis NIRF imager. Biodistribution analyses in non-neoplastic tissue solely showed high fluorescence signal in the liver and kidney, which reflects the clearance of the DARPin tracers. CONCLUSION Our encouraging results show that EpCAM-binding DARPins are a promising class of targeting moieties for pan-carcinoma targeting, providing clear tumor delineation at 24 h post-injection. The work described provides the preclinical foundation for DARPin-based bimodal NIRF/PA imaging of cancer.
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Affiliation(s)
- Ruben D Houvast
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
| | - Nada Badr
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Taryn March
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Vincent Q Sier
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Timo Schomann
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Shadhvi Bhairosingh
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Victor M Baart
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Judith A H M Peeters
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Gerard J P van Westen
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, the Netherlands
| | - Andreas Plückthun
- Department of Biochemistry, University of Zürich, Zurich, Switzerland
| | - Jacobus Burggraaf
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Centre for Human Drug Research, Leiden, the Netherlands
| | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Cornelis F M Sier
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
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Xiao D, Xiong M, Wang X, Lyu M, Sun H, Cui Y, Chen C, Jiang Z, Sun F. Regulation of the Function and Expression of EpCAM. Biomedicines 2024; 12:1129. [PMID: 38791091 PMCID: PMC11117676 DOI: 10.3390/biomedicines12051129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research.
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Affiliation(s)
- Di Xiao
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Mingrui Xiong
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Xin Wang
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Mengqing Lyu
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Hanxiang Sun
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Yeting Cui
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Chen Chen
- Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China;
| | - Ziyu Jiang
- Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China;
| | - Fan Sun
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
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Cheng L, Chen L, Shi Y, Gu W, Ding W, Zheng X, Liu Y, Jiang J, Zheng Z. Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison. Mol Cancer 2024; 23:77. [PMID: 38627681 PMCID: PMC11020943 DOI: 10.1186/s12943-024-01956-6] [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: 11/22/2023] [Accepted: 02/07/2024] [Indexed: 04/19/2024] Open
Abstract
Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment.
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Affiliation(s)
- Linyan Cheng
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute for Cell Therapy of Soochow University, Changzhou, China
| | - Yuan Shi
- Laboratory of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Weiying Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Weidong Ding
- Department of Hematology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.
- Institute for Cell Therapy of Soochow University, Changzhou, China.
| | - Yan Liu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
| | - Jingting Jiang
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.
- Institute for Cell Therapy of Soochow University, Changzhou, China.
| | - Zhuojun Zheng
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
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Li X, Liu G, Wu W. Progress in Biological Research and Treatment of Pseudomyxoma Peritonei. Cancers (Basel) 2024; 16:1406. [PMID: 38611084 PMCID: PMC11010892 DOI: 10.3390/cancers16071406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/28/2024] [Accepted: 03/30/2024] [Indexed: 04/14/2024] Open
Abstract
Pseudomyxoma peritonei (PMP) is a rare disease characterized by extensive peritoneal implantation and mass secretion of mucus after primary mucinous tumors of the appendix or other organ ruptures. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is currently the preferred treatment, with excellent efficacy and safety, and is associated with breakthrough progress in long-term disease control and prolonged survival. However, the high recurrence rate of PMP is the key challenge in its treatment, which limits the clinical application of multiple rounds of CRS-HIPEC and does not benefit from conventional systemic chemotherapy. Therefore, the development of alternative therapies for patients with refractory or relapsing PMP is critical. The literature related to PMP research progress and treatment was searched in the Web of Science, PubMed, and Google Scholar databases, and a literature review was conducted. The overview of the biological research, treatment status, potential therapeutic strategies, current research limitations, and future directions associated with PMP are presented, focuses on CRS-HIPEC therapy and alternative or combination therapy strategies, and emphasizes the clinical transformation prospects of potential therapeutic strategies such as mucolytic agents and targeted therapy. It provides a theoretical reference for the treatment of PMP and the main directions for future research.
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Affiliation(s)
- Xi Li
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha 410008, China;
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Guodong Liu
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha 410008, China;
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Wei Wu
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha 410008, China;
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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12
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Yue Y, Ouyang H, Ma M, Yang Y, Zhang H, He A, Liu R. Nucleic acid aptasensor with magnetically induced self-assembly for the detection of EpCAM glycoprotein. Mikrochim Acta 2023; 191:64. [PMID: 38157059 DOI: 10.1007/s00604-023-06117-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/23/2023] [Indexed: 01/03/2024]
Abstract
A "turn-on" aptasensor for label-free and cell-free EpCAM detection was constructed by employing magnetic α-Fe2O3/Fe3O4@Au nanocomposites as a matrix for signal amplification and double-stranded complex (SH-DNA/Apt probes) immobilization through Au-S binding. α-Fe2O3/Fe3O4@Au could be efficiently assembled into uniform and stable self-assembly films via magnetic-induced self-assembly technique on a magnetic glassy carbon electrode (MGCE). The effectiveness of the platform for EpCAM detection was confirmed through differential pulse voltammetry (DPV). Under optimized conditions, the platform exhibited excellent specificity for EpCAM, and a strong linear correlation was observed between the current and the logarithm of EpCAM protein concentration in the range 1 pg/mL-1000 pg/mL (R2 = 0.9964), with a limit of detection (LOD) of 0.27 pg/mL. Furthermore, the developed platform demonstrated good stability during a 14-day storage test, with fluctuations remaining below 93.33% of the initial current value. Promising results were obtained when detecting EpCAM in spiked serum samples, suggesting its potential as a point-of-care (POC) testing.
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Affiliation(s)
- Yao Yue
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Hezhong Ouyang
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, 212300, People's Republic of China
| | - Mingyi Ma
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Yaping Yang
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Haoda Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Aolin He
- Affiliated Kunshan Hospital, Jiangsu University, Suzhou, 215300, People's Republic of China.
| | - Ruijiang Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
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13
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Khosla AA, Jatwani K, Singh R, Reddy A, Jaiyesimi I, Desai A. Bispecific Antibodies in Lung Cancer: A State-of-the-Art Review. Pharmaceuticals (Basel) 2023; 16:1461. [PMID: 37895932 PMCID: PMC10609957 DOI: 10.3390/ph16101461] [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: 08/31/2023] [Revised: 09/25/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Bispecific antibodies have emerged as a promising class of therapeutics in the field of oncology, offering an innovative approach to target cancer cells while sparing healthy tissues. These antibodies are designed to bind two different antigens, enabling them to bridge immune cells with cancer cells, resulting in enhanced tumor cell killing and improved treatment responses. This review article summarizes the current landscape of bispecific antibodies in lung cancer, including their mechanisms of action, clinical development, and potential applications in other solid tumor malignancies. Additionally, the challenges and opportunities associated with their use in the clinic are discussed, along with future directions for research and development in this exciting area of cancer immunotherapy.
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Affiliation(s)
- Atulya Aman Khosla
- Division of Internal Medicine, William Beaumont University Hospital, Royal Oak, MI 48073, USA;
| | - Karan Jatwani
- Division of Hematology-Oncology, Roswell Park Cancer Center, Buffalo, NY 14203, USA
| | - Rohit Singh
- Division of Hematology-Oncology, University of Vermont, Burlington, VT 05405, USA
| | - Aswanth Reddy
- Division of Hematology-Oncology, Mercy Clinic, Fort Smith, AR 72903, USA
| | - Ishmael Jaiyesimi
- Division of Hematology-Oncology, William Beaumont University Hospital, Royal Oak, MI 48073, USA
| | - Aakash Desai
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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14
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Pabani A, Gainor JF. Facts and Hopes: Immunocytokines for Cancer Immunotherapy. Clin Cancer Res 2023; 29:3841-3849. [PMID: 37227449 DOI: 10.1158/1078-0432.ccr-22-1837] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/26/2023] [Accepted: 05/11/2023] [Indexed: 05/26/2023]
Abstract
The clinical development of cytokines as cancer therapeutics has been limited due to significant toxicities generally observed with systemic administration. This narrow therapeutic window, together with relatively modest efficacy, has made natural cytokines unattractive drug candidates. Immunocytokines represent a class of next-generation cytokines designed to overcome the challenges associated with traditional cytokines. These agents seek to improve the therapeutic index of cytokines by using antibodies as vehicles for the targeted delivery of immunomodulatory agents within the local tumor microenvironment (TME). Various molecular formats and cytokine payloads have been studied. In this review, we provide an overview of the rationale, preclinical support, and current clinical development strategies for immunocytokines.
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Affiliation(s)
- Aliyah Pabani
- Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Justin F Gainor
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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15
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Pourali G, Zafari N, Fiuji H, Batra J, Nazari E, Khazaei M, Hassanian SM, Vahabi M, Kiani M, Ghayour-Mobarhan M, Peters GJ, Ferns GA, Lam AKY, Giovannetti E, Avan A. Extracellular vesicles: Emerging mediators of cell communication in gastrointestinal cancers exhibiting metabolic abnormalities. Cytokine Growth Factor Rev 2023; 73:101-113. [PMID: 37573251 DOI: 10.1016/j.cytogfr.2023.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/14/2023]
Abstract
There is a complex interaction between pro-tumoural and anti-tumoural networks in the tumour microenvironment (TME). Throughout tumourigenesis, communication between malignant cells and various cells of the TME contributes to metabolic reprogramming. Tumour Dysregulation of metabolic pathways offer an evolutional advantage in the TME and enhance the tumour progression, invasiveness, and metastasis. Therefore, understanding these interactions within the TME is crucial for the development of innovative cancer treatments. Extracellular vesicles (EVs) serve as carriers of various materials that include microRNAs, proteins, and lipids that play a vital role in the communication between tumour cells and non-tumour cells. EVs are actively involved in the metabolic reprogramming process. This review summarized recent findings regarding the involvement of EVs in the metabolic reprogramming of various cells in the TME of gastrointestinal cancers. Additionally, we highlight identified microRNAs involved in the reprogramming process in this group of cancers and explained the abnormal tumour metabolism targeted by exosomal cargos as well as the novel potential therapeutic approaches.
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Affiliation(s)
- Ghazaleh Pourali
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Zafari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Fiuji
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands
| | - Jyotsna Batra
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia; Translational Research Institute, Queensland University of Technology, Brisbane, Australia; Center for genomics and Personalised Health, Queensland University of Technology, Brisbane, Australia
| | - Elham Nazari
- Department of Health Information Technology and Management, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahrou Vahabi
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands
| | - MohammadAli Kiani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Godefridus J Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands; Professor In Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Alfred King-Yin Lam
- Pathology, School of Medicine and Dentistry, Gold Coast campus, Griffith University, Gold Coast, QLD 4222, Australia
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start up Unit, Fondazione Pisana per La Scienza, Pisa, Italy
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq,; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
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16
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Wang T, Wang C, Wang J, Wang B. An Intrabody against B-Cell Receptor-Associated Protein 31 (BAP31) Suppresses the Glycosylation of the Epithelial Cell-Adhesion Molecule (EpCAM) via Affecting the Formation of the Sec61-Translocon-Associated Protein (TRAP) Complex. Int J Mol Sci 2023; 24:14787. [PMID: 37834237 PMCID: PMC10572819 DOI: 10.3390/ijms241914787] [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: 07/31/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
The epithelial cell-adhesion molecule (EpCAM) is hyperglycosylated in carcinoma tissue and the oncogenic function of EpCAM primarily depends on the degree of glycosylation. Inhibiting EpCAM glycosylation is expected to have an inhibitory effect on cancer. We analyzed the relationship of BAP31 with 84 kinds of tumor-associated antigens and found that BAP31 is positively correlated with the protein level of EpCAM. Triple mutations of EpCAM N76/111/198A, which are no longer modified by glycosylation, were constructed to determine whether BAP31 has an effect on the glycosylation of EpCAM. Plasmids containing different C-termini of BAP31 were constructed to identify the regions of BAP31 that affects EpCAM glycosylation. Antibodies against BAP31 (165-205) were screened from a human phage single-domain antibody library and the effect of the antibody (VH-F12) on EpCAM glycosylation and anticancer was investigated. BAP31 increases protein levels of EpCAM by promoting its glycosylation. The amino acid region from 165 to 205 in BAP31 plays an important role in regulating the glycosylation of EpCAM. The antibody VH-F12 significantly inhibited glycosylation of EpCAM which, subsequently, reduced the adhesion of gastric cancer cells, inducing cytotoxic autophagy, inhibiting the AKT-PI3K-mTOR signaling pathway, and, finally, resulting in proliferation inhibition both in vitro and in vivo. Finally, we clarified that BAP31 plays a key role in promoting N-glycosylation of EpCAM by affecting the Sec61 translocation channels. Altogether, these data implied that BAP31 regulates the N-glycosylation of EpCAM and may represent a potential therapeutic target for cancer therapy.
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Affiliation(s)
| | | | | | - Bing Wang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China; (T.W.); (C.W.); (J.W.)
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17
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Zhou Q, Xiang J, Qiu N, Wang Y, Piao Y, Shao S, Tang J, Zhou Z, Shen Y. Tumor Abnormality-Oriented Nanomedicine Design. Chem Rev 2023; 123:10920-10989. [PMID: 37713432 DOI: 10.1021/acs.chemrev.3c00062] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.
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Affiliation(s)
- Quan Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jiajia Xiang
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Nasha Qiu
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Yechun Wang
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Ying Piao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Shiqun Shao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Jianbin Tang
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Zhuxian Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Youqing Shen
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- State Key Laboratory of Chemical Engineering, Zhejiang University, Hangzhou 310058, China
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18
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Paglia EB, Baldin EKK, Freitas GP, Santiago TSA, Neto JBMR, Silva JVL, Carvalho HF, Beppu MM. Circulating Tumor Cells Adhesion: Application in Biosensors. BIOSENSORS 2023; 13:882. [PMID: 37754116 PMCID: PMC10526177 DOI: 10.3390/bios13090882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/23/2023] [Accepted: 09/01/2023] [Indexed: 09/28/2023]
Abstract
The early and non-invasive diagnosis of tumor diseases has been widely investigated by the scientific community focusing on the development of sensors/biomarkers that act as a way of recognizing the adhesion of circulating tumor cells (CTCs). As a challenge in this area, strategies for CTCs capture and enrichment currently require improvements in the sensors/biomarker's selectivity. This can be achieved by understanding the biological recognition factors for different cancer cell lines and also by understanding the interaction between surface parameters and the affinity between macromolecules and the cell surface. To overcome some of these concerns, electrochemical sensors have been used as precise, fast-response, and low-cost transduction platforms for application in cytosensors. Additionally, distinct materials, geometries, and technologies have been investigated to improve the sensitivity and specificity properties of the support electrode that will transform biochemical events into electrical signals. This review identifies novel approaches regarding the application of different specific biomarkers (CD44, Integrins, and EpCAm) for capturing CTCs. These biomarkers can be applied in electrochemical biosensors as a cytodetection strategy for diagnosis of cancerous diseases.
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Affiliation(s)
- Eduarda B. Paglia
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
| | - Estela K. K. Baldin
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
- Renato Archer Information Technology Center, Campinas 13069-901, Brazil;
| | - Gabriela P. Freitas
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
- Renato Archer Information Technology Center, Campinas 13069-901, Brazil;
| | - Thalyta S. A. Santiago
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
| | - João B. M. R. Neto
- Technology Center, Federal University of Alagoas, Maceió 57072-900, Brazil;
| | - Jorge V. L. Silva
- Renato Archer Information Technology Center, Campinas 13069-901, Brazil;
| | - Hernandes F. Carvalho
- Institute of Biology, Department of Structural and Functional Biology, University of Campinas, Campinas 13083-864, Brazil;
| | - Marisa M. Beppu
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
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Ding P, Chen P, Ouyang J, Li Q, Li S. Clinicopathological and prognostic value of epithelial cell adhesion molecule in solid tumours: a meta-analysis. Front Oncol 2023; 13:1242231. [PMID: 37664060 PMCID: PMC10468606 DOI: 10.3389/fonc.2023.1242231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 07/27/2023] [Indexed: 09/05/2023] Open
Abstract
Background Malignant tumors, mainly solid tumors, are a significant obstacle to the improvement of life expectancy at present. Epithelial cell adhesion molecule (EpCAM), a cancer stem cell biomarker, showed widespread expression in most normal epithelial cells and most cancers. Although the clinical significance of EpCAM in various malignant solid tumors has been studied extensively, the latent relationships between EpCAM and pathological and clinical characteristics in solid tumors and differences in the roles of EpCAM among tumors have not been clearly determined. The destination point of this study was to analyze the value of EpCAM in solid tumors in clinicopathological and prognostic dimension using a meta-analysis approach. Method and materials A comprehensive and systematic search of the researches published up to March 7th, 2022, in PubMed, EMBASE, Web of Science, Cochrane library and PMC databases was performed. The relationships between EpCAM overexpression, clinicopathological characteristics, and survival outcomes were analyzed. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) and odds ratios (ORs) were estimated as indicators of the degree of correlation. This research was registered on PROSPERO (International prospective register of systematic reviews), ID: CRD42022315070. Results In total, 57 articles and 14184 cases were included in this study. High EpCAM expression had a significant coherence with a poorer overall survival (OS) (HR: 1.30, 95% CI: 1.08-1.58, P < 0.01) and a worse disease-free survival (DFS) (HR: 1.58, 95% CI: 1.28-1.95, P < 0.01), especially of gastrointestinal tumors' OS (HR: 1.50, 95% CI: 1.15-1.95, P < 0.01), and DFS (HR: 1.84, 95% CI: 1.52-2.33, P < 0.01). The DFS of head and neck tumors (HR: 2.33, 95% CI: 1.51-3.61, P < 0.01) was also associated with the overexpression of EpCAM. There were no positive relationships between the overexpression of EpCAM and sex (RR: 1.03, 95% CI: 0.99-1.07, P = 0.141), T classification (RR: 0.93, 95% CI: 0.82-1.06, P = 0.293), lymph node metastasis (RR: 0.85, 95% CI: 0.54-1.32, P = 0.461), distant metastasis (RR: 0.97, 95% CI: 0.84-1.10, P = 0.606), vascular infiltration (RR: 1.05, 95% CI: 0.85-1.29, P = 0.611), and TNM stage (RR: 0.93, 95% CI: 0.83-1.04, P = 0.187). However, the overexpression of EpCAM exhibited a significant association with the histological grades (RR: 0.88, 95% CI: 0.80-0.97, P < 0.01). Conclusion Based on pooled HRs, the positive expression of EpCAM was totally correlated to a worse OS and DFS in solid tumors. The expression of EpCAM was related to a worse OS in gastrointestinal tumors and a worse DFS in gastrointestinal tumors and head and neck tumors. Moreover, EpCAM expression was correlated with the histological grade. The results presented pointed out that EpCAM could serve as a prognostic biomarker for gastrointestinal and head and neck tumors. Systematic review registration https://www.crd.york.ac.uk/prospero, identifier CRD42022315070.
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Affiliation(s)
- Peiwen Ding
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Clinical School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Panyu Chen
- Operating Room, Sichuan University West China Hospital School of Nursing, Chengdu, China
| | - Jiqi Ouyang
- Department of Gastroenterology, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
| | - Qiang Li
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Clinical School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shijie Li
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Clinical School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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20
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Kalaitsidou I, Pasteli N, Venetis G, Poulopoulos A, Antoniades K. Immunohistochemical Expression of Epithelial Cell Adhesion Molecule (EpCAM) in Salivary Gland Cancer: Correlation with the Biological Behavior. Diagnostics (Basel) 2023; 13:2652. [PMID: 37627911 PMCID: PMC10453306 DOI: 10.3390/diagnostics13162652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Salivary gland neoplasms comprise a diverse group of tumors with different biological behaviors and clinical outcomes. Understanding the underlying molecular alterations associated with these malignancies is critical for accurate diagnosis, prognosis, and treatment strategies. Among the many biomarkers under investigation, epithelial cell adhesion molecule (EpCAM) has emerged as a promising candidate in salivary gland cancer research. This article aims to provide a comprehensive overview of the differential expression of EpCAM in salivary gland cancer and its potential correlation with the biological behavior of these tumors. The clinical characteristics of 65 patients with salivary gland malignancy of different histopathological subtypes were included. We report the differential expression of EpCAM and the relationship between the clinical and histopathologic features of these tumors. Regarding the evaluation of the effect of EpCAM expression on survival, in our study, we showed that tumors with high EpCAM expression had reduced disease-free survival (DFS) and overall survival (OS) (p < 0.001) compared to patients with cancers with low EpCAM expression. In addition, the concurrent presence of perineural invasion and positive EpCAM expression appeared to be associated with shorter disease-free survival and overall survival. In conclusion, our study confirmed the prognostic value of detecting perineural invasion and EpCAM expression.
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Affiliation(s)
- Ioanna Kalaitsidou
- Department of Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.V.)
- Department of Cranio-Maxillofacial Surgery, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
| | - Nikoleta Pasteli
- Pathology Department, G. Papanikolaou Hospital, 57010 Thessaloniki, Greece
| | - Gregory Venetis
- Department of Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.V.)
| | - Athanasios Poulopoulos
- Department of Oral Medicine and Maxillofacial Pathology, Aristotle University, 54124 Thessaloniki, Greece;
| | - Konstantinos Antoniades
- Department of Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.V.)
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21
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Ezenkwa US, Ogun GO, Mashor MI, Ogunbiyi OJ. EpCAM expression negatively regulates E-cadherin function in colorectal carcinomas. Ecancermedicalscience 2023; 17:1569. [PMID: 37533952 PMCID: PMC10393316 DOI: 10.3332/ecancer.2023.1569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Indexed: 08/04/2023] Open
Abstract
Background This study aimed to characterise epithelial cell adhesion molecule (EpCAM) expression patterns in colorectal carcinomas (CRC) from Nigerian patients, its association with E-cadherin and tumour characteristics, to forecast patient selection for anti-EpCAM therapy among whom no data existed previously. Methods Tissue microarray blocks of formalin-fixed and paraffin-embedded CRC tissues, with their non-cancer margins of resection, were sectioned and stained with EpCAM and E-cadherin primary antibodies. Scoring for antibody staining was done semiquantitatively by combining staining proportion and intensity. The outcome was correlated with patient age, gender and tumour histological parameters with p ≤ 0.05 regarded as statistically significant. Results Sixty-three carcinoma tissues had staining status for the two markers and were included in this study. Of these, 36 (57.1%) showed positive EpCAM expression (immunoscore ≥3) out of which 83% (30/36 positive cases) were overexpressed (combined immunoscore ≥4) while 12 (19%) tissues were positive for E-cadherin. Non-tumour margins of resection tissues showed less EpCAM positivity in 24% (6/25) of histospots. The difference in staining between tumour and non-tumour margin tissues with EpCAM was significant (p < 0.001). Also, EpCAM overexpression was significantly associated with reduced E-cadherin (p < 0.035) expression in tumour cells. Tumour extent within the gut wall was equal (50% each) for early and late pT stages among EpCAM overexpressing tumours but two-thirds (8/12) of cases expressing E-cadherin had later pT stage paradoxically, while distant metastasis was negligible among tumours bearing both markers. Also, tumours overexpressing EpCAM had significant association with tumour-associated lymphocytes (p < 0.02 each). Conclusion CRC in this study preferentially overexpress EpCAM over E-cadherin whose strong cell-cell contact inhibitory role is weakened even when expressed, resulting in further local tumour spread. This, and the observed immune response, supports targeted therapy among eligible patients.
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Affiliation(s)
- Uchenna Simon Ezenkwa
- Federal Medical Centre Azare, Azare 751101, Bauchi, Nigeria
- https://orcid.org/0000-0002-7022-8268
| | - Gabriel Olabiyi Ogun
- Department of Pathology, University College Hospital, Ibadan 200285, Oyo, Nigeria
| | - Mbwas Isaac Mashor
- Department of Pathology, Bringham University, Jos 930105, Plateau, Nigeria
| | - Olufemi John Ogunbiyi
- Department of Pathology, University College Hospital, Ibadan 200285, Oyo, Nigeria
- https://orcid.org/0000-0002-8748-2879
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22
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Omar FA, Brown TC, Gillanders WE, Fleming TP, Smith MA, Bremner RM, Sankpal NV. Cytosolic EpCAM cooperates with H-Ras to regulate epithelial to mesenchymal transition through ZEB1. PLoS One 2023; 18:e0285707. [PMID: 37192201 PMCID: PMC10187930 DOI: 10.1371/journal.pone.0285707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/30/2023] [Indexed: 05/18/2023] Open
Abstract
Next generation sequencing of human cancer mutations has identified novel therapeutic targets. Activating Ras oncogene mutations play a central role in oncogenesis, and Ras-driven tumorigenesis upregulates an array of genes and signaling cascades that can transform normal cells into tumor cells. In this study, we investigated the role of altered localization of epithelial cell adhesion molecule (EpCAM) in Ras-expressing cells. Analysis of microarray data demonstrated that Ras expression induced EpCAM expression in normal breast epithelial cells. Fluorescent and confocal microscopy showed that H-Ras mediated transformation also promoted epithelial-to-mesenchymal transition (EMT) together with EpCAM. To consistently localize EpCAM in the cytosol, we generated a cancer-associated EpCAM mutant (EpCAM-L240A) that is retained in the cytosol compartment. Normal MCF-10A cells were transduced with H-Ras together with EpCAM wild-type (WT) or EpCAM-L240A. WT-EpCAM marginally effected invasion, proliferation, and soft agar growth. EpCAM-L240A, however, markedly altered cells and transformed to mesenchymal phenotype. Ras-EpCAM-L240A expression also promoted expression of EMT factors FRA1, ZEB1 with inflammatory cytokines IL-6, IL-8, and IL1. This altered morphology was reversed using MEK-specific inhibitors and to some extent JNK inhibition. Furthermore, these transformed cells were sensitized to apoptosis using paclitaxel and quercetin, but not other therapies. For the first time, we have demonstrated that EpCAM mutations can cooperate with H-Ras and promote EMT. Collectively, our results highlight future therapeutic opportunities in EpCAM and Ras mutated cancers.
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Affiliation(s)
- Fatma A. Omar
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Taylor C. Brown
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - William E. Gillanders
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Timothy P. Fleming
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Michael A. Smith
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Ross M. Bremner
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Narendra V. Sankpal
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
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Huang Y, Li X, Hou J, Luo Z, Yang G, Zhou S. Conductive Nanofibers-Enhanced Microfluidic Device for the Efficient Capture and Electrical Stimulation-Triggered Rapid Release of Circulating Tumor Cells. BIOSENSORS 2023; 13:bios13050497. [PMID: 37232858 DOI: 10.3390/bios13050497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/18/2023] [Accepted: 04/22/2023] [Indexed: 05/27/2023]
Abstract
The effective detection and release of circulating tumor cells (CTCs) are of great significance for cancer diagnosis and monitoring. The microfluidic technique has proved to be a promising method for CTCs isolation and subsequent analysis. However, complex micro-geometries or nanostructures were often constructed and functionalized to improve the capture efficiency, which limited the scale-up for high-throughput production and larger-scale clinical applications. Thus, we designed a simple conductive nanofiber chip (CNF-Chip)-embedded microfluidic device with a herringbone microchannel to achieve the efficient and specific capture and electrical stimulation-triggered rapid release of CTCs. Here, the most used epithelial cell adhesion molecule (EpCAM) was selected as the representative biomarker, and the EpCAM-positive cancer cells were mainly studied. Under the effects of the nanointerface formed by the nanofibers with a rough surface and the herringbone-based high-throughput microfluidic mixing, the local topographic interaction between target cells and nanofibrous substrate in the microfluidic was synergistically enhanced, and the capture efficiency for CTCs was further improved (more than 85%). After capture, the sensitive and rapid release of CTCs (release efficiency above 97%) could be conveniently achieved through the cleavage of the gold-sulfur bond by applying a low voltage (-1.2 V). The device was successfully used for the effective isolation of CTCs in clinical blood samples from cancer patients, indicating the great potential of this CNF-Chip-embedded microfluidic device in clinical applications.
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Affiliation(s)
- Yisha Huang
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Xilin Li
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Jianwen Hou
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Zhouying Luo
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Guang Yang
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
| | - Shaobing Zhou
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
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Shishparenok AN, Furman VV, Zhdanov DD. DNA-Based Nanomaterials as Drug Delivery Platforms for Increasing the Effect of Drugs in Tumors. Cancers (Basel) 2023; 15:2151. [PMID: 37046816 PMCID: PMC10093432 DOI: 10.3390/cancers15072151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023] Open
Abstract
DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. Gradually, modified nucleic acids have begun to be employed to construct multifunctional DNA nanostructures with a variety of architectural designs. Aptamers are single-stranded nucleic acids (both DNAs and RNAs) capable of self-pairing to acquire secondary structure and of specifically binding with the target. Diagnosis and tumor therapy are prospective fields in which aptamers can be applied. Many DNA nanomaterials with three-dimensional structures have been studied as drug delivery systems for different anticancer medications or gene therapy agents. Different chemical alterations can be employed to construct a wide range of modified DNA nanostructures. Chemically altered DNA-based nanomaterials are useful for drug delivery because of their improved stability and inclusion of functional groups. In this work, the most common oligonucleotide nanomaterials were reviewed as modern drug delivery systems in tumor cells.
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Affiliation(s)
- Anastasiya N. Shishparenok
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
| | - Vitalina V. Furman
- Center of Chemical Engineering, ITMO University, Kronverkskiy Prospekt 49A, 197101 St. Petersburg, Russia
| | - Dmitry D. Zhdanov
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
- Department of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St. 6, 117198 Moscow, Russia
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25
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Wei Z, Zhou Y, Wang R, Wang J, Chen Z. Aptamers as Smart Ligands for Targeted Drug Delivery in Cancer Therapy. Pharmaceutics 2022; 14:2561. [PMID: 36559056 PMCID: PMC9781707 DOI: 10.3390/pharmaceutics14122561] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022] Open
Abstract
Undesirable side effects and multidrug tolerance are the main holdbacks to the treatment of cancer in conventional chemotherapy. Fortunately, targeted drug delivery can improve the enrichment of drugs at the target site and reduce toxicity to normal tissues and cells. A targeted drug delivery system is usually composed of a nanocarrier and a targeting component. The targeting component is called a "ligand". Aptamers have high target affinity and specificity, which are identified as attractive and promising ligands. Therefore, aptamers have potential application in the development of smart targeting systems. For instance, aptamers are able to efficiently recognize tumor markers such as nucleolin, mucin, and epidermal growth factor receptor (EGFR). Besides, aptamers can also identify glycoproteins on the surface of tumor cells. Thus, the aptamer-mediated targeted drug delivery system has received extensive attention in the application of cancer therapy. This article reviews the application of aptamers as smart ligands for targeted drug delivery in cancer therapy. Special interest is focused on aptamers as smart ligands, aptamer-conjugated nanocarriers, aptamer targeting strategy for tumor microenvironment (TME), and aptamers that are specified to crucial cancer biomarkers for targeted drug delivery.
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Affiliation(s)
| | | | | | - Jin Wang
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, China
| | - Zhenhua Chen
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, China
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Yin H, Harrison TA, Thomas SS, Sather CL, Koehne AL, Malen RC, Reedy AM, Wurscher MA, Hsu L, Phipps AI, Zaidi SHE, Newcomb PA, Peters U, Huyghe JR. T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients. Cancer Med 2022; 12:6583-6593. [PMID: 36341526 PMCID: PMC10067089 DOI: 10.1002/cam4.5429] [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: 08/30/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The anti-tumor immune response plays a key role in colorectal cancer (CRC) progression and survival. The T cell-inflamed gene expression profile (GEP) is a biomarker predicting response to checkpoint inhibitor immunotherapy across immunogenic cancer types, but the prognostic value in CRC is unknown. We evaluated associations with disease-specific survival, somatic mutations, and examined its differentially expressed genes and pathways among 84 sporadic CRC patients from the Seattle Colon Cancer Family Registry. METHODS Gene expression profiling was performed using Nanostring's nCounter PanCancer IO 360 panel. Somatic mutations were identified by a targeted DNA sequencing panel. RESULTS The T cell-inflamed GEP was positively associated with tumor mutation burden and microsatellite instability high (MSI-H). Higher T cell-inflamed GEP had favorable CRC-specific survival (hazard ratio [HR] per standard deviation unit = 0.50, p = 0.004) regardless of hypermutation or MSI status. Analysis of recurrently mutated genes having at least 10 mutation carriers, suggested that the T cell-inflamed GEP is positively associated with RYR1, and negatively associated with APC. However, these associations were attenuated after adjusting for hypermutation or MSI status. We also found that expression of genes RPL23, EPCAM, AREG and ITGA6, and the Wnt signaling pathway was negatively associated with the T cell-inflamed GEP, which might indicate immune-inhibitory mechanisms. CONCLUSIONS Our results show that the T cell-inflamed GEP is a prognostic biomarker in non-hypermutated microsatellite-stable CRC. This also suggests that patient stratification for immunotherapy within this CRC subgroup should be explored further. Moreover, reported immune-inhibitory gene expression signals may suggest targets for therapeutic combination with immunotherapy.
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Affiliation(s)
- Hang Yin
- Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA
| | - Tabitha A Harrison
- Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA.,Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Sushma S Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Cassie L Sather
- Genomics Resource, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Amanda L Koehne
- Experimental Histopathology, Shared Resource, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Rachel C Malen
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Adriana M Reedy
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Michelle A Wurscher
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.,Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Syed H E Zaidi
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
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Kang J, Sun T, Zhang Y. Immunotherapeutic progress and application of bispecific antibody in cancer. Front Immunol 2022; 13:1020003. [PMID: 36341333 PMCID: PMC9630604 DOI: 10.3389/fimmu.2022.1020003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 10/05/2022] [Indexed: 08/19/2023] Open
Abstract
Bispecific antibodies (bsAbs) are artificial antibodies with two distinct antigen-binding sites that can bind to different antigens or different epitopes on the same antigen. Based on a variety of technology platforms currently developed, bsAbs can exhibit different formats and mechanisms of action. The upgrading of antibody technology has promoted the development of bsAbs, which has been effectively used in the treatment of tumors. So far, 7 bsAbs have been approved for marketing in the world, and more than 200 bsAbs are in clinical and preclinical research stages. Here, we summarize the development process of bsAbs, application in tumor treatment and look forward to the challenges in future development.
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Affiliation(s)
- Jingyue Kang
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tonglin Sun
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Zhang
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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28
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Development and characterization of DNA aptamer against Retinoblastoma by Cell-SELEX. Sci Rep 2022; 12:16178. [PMID: 36171412 PMCID: PMC9519959 DOI: 10.1038/s41598-022-20660-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/16/2022] [Indexed: 12/02/2022] Open
Abstract
Retinoblastoma (RB) is the most common paediatric intraocular tumour. The management of RB has improved the survival and vision with recent advances in the treatment. Improved therapeutic approaches focussing on targeting tumours and minimizing the treatment-associated side effects are being developed. In this study, we generated a ssDNA aptamer against RB by cell-SELEX and high-throughput sequencing using Weri-RB1 cell line as the target, and Muller glial cell line Mio-M1 as the control. Three aptamers were selected based on the number of repetitions in NGS and phylogenetic relationship and evaluated by flow cytometry to assess their binding affinity and selectivity. The dissociation constant, Kd values of three selected aptamers were found to be in the nanomolar range. Aptamer VRF-CSRB-01 with the best binding affinity and a Kd value of 49.41 ± 7.87 nM was further characterized. The proteinase and temperature treatment indicated that VRF-CSRB-01 targets surface proteins, and has a good binding affinity and excellent selectivity under physiological conditions. The aptamer VRF-CSRB-01 was stable over 72 h in serum and 96 h in cerebral spinal fluid and vitreous. With the high affinity, specificity, stability and specific recognition of clinical RB tumours, VRF-CSRB-01 aptamer holds potential for application in diagnosis and targeting RB.
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Wei GX, Du Y, Zhou YW, Li LJ, Qiu M. Peritoneal carcinomatosis with intraperitoneal immunotherapy: current treatment options and perspectives. Expert Rev Gastroenterol Hepatol 2022; 16:851-861. [PMID: 36107723 DOI: 10.1080/17474124.2022.2125866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Peritoneal carcinomatosis (PC) is an advanced malignancy that is not sensitive to systemic conventional chemotherapy. Treatment options for PC are usually palliative rather than curative. Cytoreductive surgery and hyperthermic intraperitoneal (IP) chemotherapy are associated with limited efficacy in patients with PC. However, the peritoneum can produce effective immunity by inducing T-lymphocyte recruitment and proliferation, and the unique immune environment of the peritoneum provides the rationale for IP immunotherapy in PC. AREAS COVERED The authors retrieved relevant documents of IP immunotherapy for PC from PubMed and Medline. This review elaborates on the knowledge of the peritoneal immune microenvironment and IP immunotherapy for PC covering immune stimulators, radioimmunotherapy, catumaxomab, cancer vaccines, chimeric antigen receptor (CAR)-T cells, and immune checkpoint inhibitors. EXPERT OPINION The prognosis of PC is poor. However, the peritoneal cavity is a unique immune compartment with abundant immune cells which can produce effective immunity. IP immunotherapy may be a promising strategy in patients with PC.
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Affiliation(s)
- Gui-Xia Wei
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yang Du
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yu-Wen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lin-Juan Li
- Thoracic Oncology Ward, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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Sputum analysis by flow cytometry; an effective platform to analyze the lung environment. PLoS One 2022; 17:e0272069. [PMID: 35976857 PMCID: PMC9385012 DOI: 10.1371/journal.pone.0272069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/12/2022] [Indexed: 11/19/2022] Open
Abstract
Low dose computed tomography (LDCT) is the standard of care for lung cancer screening in the United States (US). LDCT has a sensitivity of 93.8% but its specificity of 73.4% leads to potentially harmful follow-up procedures in patients without lung cancer. Thus, there is a need for additional assays with high accuracy that can be used as an adjunct to LDCT to diagnose lung cancer. Sputum is a biological fluid that can be obtained non-invasively and can be dissociated to release its cellular contents, providing a snapshot of the lung environment. We obtained sputum from current and former smokers with a 30+ pack-year smoking history and who were either confirmed to have lung cancer or at high risk of developing the disease. Dissociated sputum cells were counted, viability determined, and labeled with a panel of markers to separate leukocytes from non-leukocytes. After excluding debris and dead cells, including squamous epithelial cells, we identified reproducible population signatures and confirmed the samples’ lung origin. In addition to leukocyte and epithelial-specific fluorescent antibodies, we used the highly fluorescent meso-tetra(4-carboxyphenyl) porphyrin (TCPP), known to preferentially stain cancer (associated) cells. We looked for differences in cell characteristics, population size and fluorescence intensity that could be useful in distinguishing cancer samples from high-risk samples. We present our data demonstrating the feasibility of a flow cytometry platform to analyze sputum in a high-throughput and standardized matter for the diagnosis of lung cancer.
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Wang M, Cai W, Yang AJ, Wang CY, Zhang CL, Liu W, Xie XF, Gong YY, Zhao YY, Wu WC, Zhou Q, Zhao CY, Dong JF, Li M. Gastric cancer cell-derived extracellular vesicles disrupt endothelial integrity and promote metastasis. Cancer Lett 2022; 545:215827. [PMID: 35842018 DOI: 10.1016/j.canlet.2022.215827] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 07/05/2022] [Accepted: 07/10/2022] [Indexed: 11/26/2022]
Abstract
The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these "leaky" vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.
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Affiliation(s)
- Min Wang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Wei Cai
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Gansu Provincial Hospital, Lanzhou, China.
| | - Ai-Jun Yang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Chen-Yu Wang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Chen-Li Zhang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Wei Liu
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Xiao-Feng Xie
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; School of Medicine, Northwest MinZu University, Lanzhou, China.
| | - Yuan-Yuan Gong
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Institute of Pathology, Department of Basic Medical Sciences, Fenyang College of Shanxi Medical University, Fenyang, China.
| | - Ying-Ying Zhao
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Institute of Pathology, Department of Basic Medical Sciences, Fenyang College of Shanxi Medical University, Fenyang, China.
| | - Wen-Cheng Wu
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Quan Zhou
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Chan-Yuan Zhao
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, WA, USA; Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
| | - Min Li
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China.
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Dai Y, Tang Y, Huang W, Zhao Y, Gao X, Gu Y. Multi-modal imaging probe for EpCAM overexpressed in breast cancer. Talanta 2022; 250:123715. [PMID: 35868149 DOI: 10.1016/j.talanta.2022.123715] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/16/2022] [Accepted: 06/23/2022] [Indexed: 12/24/2022]
Abstract
Breast cancer is a highly lethal and aggressive form of cancer. Early-stager diagnosis and intraoperative guidance are important endeavors for reducing associated morbidity and mortality among breast cancer patients. Epithelial cell adhesion molecule (EpCAM) is aberrantly expressed in the majority of breast carcinoma, making it an attractive imaging biomarker. Herein, we have designed novel EpCAM-targeting peptides (denoted as YQ-S) for precise breast carcinoma detection. The greater binding affinity of the designed peptide YQ-S2 over YQ-S1 and the reported peptide SNF was displayed on different cell lines with flow cytometry analysis, showing a positive correlation with the expression of EpCAM. Besides, YQ-S2 displayed an ideal biosafety profile with no evidence of any acute toxicity. Thus, YQ-S2 was chosen to represent YQ-S. By linking with the near-infrared fluorescent dye (MPA), we further developed the EpCAM-targeting probe (YQ-S2-MPA) for real-time imaging and fluorescence-guided resection of breast cancer tumors. In vivo imaging of the MCF-7 tumor-bearing model demonstrated higher tumor uptake of YQ-S2-MPA compared with that of SNF-MPA. The maximum tumor-to-normal tissue signal ratio of YQ-S2-MPA was 5.1, which was about 2 times that of SNF-MPA. Meanwhile, the metastatic lesions in 4T1 lung metastasis, and lymph node metastasis (LNM) mice were successfully detected under this imaging system. Notably, YQ-S2-MPA had excellent performance in surgical navigation studies in the preclinical models. Moreover, we exploited the 99mTc-HYNIC-YQ-S2 to localize EpCAM positive tumors successfully. These data proved that YQ-S2 can distinguish EpCAM-positive orthotopic and metastatic tumors from surrounding normal tissues accurately, and possesses the clinical potential as a surgical navigation probe.
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Affiliation(s)
- Yaxue Dai
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 211198, China
| | - Yongjia Tang
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 211198, China
| | - Wenjing Huang
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 211198, China
| | - Yue Zhao
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 211198, China
| | - Xin Gao
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 211198, China
| | - Yueqing Gu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 211198, China.
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Fiorentini C, Sarti D, Guadagni S, Fiorentini G. Immune response and locoregional treatments for peritoneal carcinomatosis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 371:97-116. [PMID: 35965002 DOI: 10.1016/bs.ircmb.2022.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy.
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Affiliation(s)
- Caterina Fiorentini
- Department of Prevention and Sport Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Donatella Sarti
- Oncology Department, S. Maria Della Misericordia Hospital, ASUR1, Urbino, Italy
| | - Stefano Guadagni
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Giammaria Fiorentini
- Department of Onco-Hematology, Azienda Ospedaliera "Ospedali Riuniti Marche Nord", Pesaro, Italy.
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Novoselova M, Chernyshev VS, Schulga A, Konovalova EV, Chuprov-Netochin RN, Abakumova TO, German S, Shipunova VO, Mokrousov MD, Prikhozhdenko E, Bratashov DN, Nozdriukhin DV, Bogorodskiy A, Grishin O, Kosolobov SS, Khlebtsov BN, Inozemtseva O, Zatsepin TS, Deyev SM, Gorin DA. Effect of Surface Modification of Multifunctional Nanocomposite Drug Delivery Carriers with DARPin on Their Biodistribution In Vitro and In Vivo. ACS APPLIED BIO MATERIALS 2022; 5:2976-2989. [PMID: 35616387 DOI: 10.1021/acsabm.2c00289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We present a targeted drug delivery system for therapy and diagnostics that is based on a combination of contrasting, cytotoxic, and cancer-cell-targeting properties of multifunctional carriers. The system uses multilayered polymer microcapsules loaded with magnetite and doxorubicin. Loading of magnetite nanoparticles into the polymer shell by freezing-induced loading (FIL) allowed the loading efficiency to be increased 5-fold, compared with the widely used layer-by-layer (LBL) assembly. FIL also improved the photoacoustic signal and particle mobility in a magnetic field gradient, a result unachievable by the LBL alone. For targeted delivery of the carriers to cancer cells, the carrier surface was modified with a designed ankyrin repeat protein (DARPin) directed toward the epithelial cell adhesion molecule (EpCAM). Flow cytometry measurements showed that the DARPin-coated capsules specifically interacted with the surface of EpCAM-overexpressing human cancer cells such as MCF7. In vivo and ex vivo biodistribution studies in FvB mice showed that the carrier surface modification with DARPin changed the biodistribution of the capsules toward epithelial cells. In particular, the capsules accumulated substantially in the lungs─a result that can be effectively used in targeted lung cancer therapy. The results of this work may aid in the further development of the "magic bullet" concept and may bring the quality of personalized medicine to another level.
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Affiliation(s)
- Marina Novoselova
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia
| | - Vasiliy S Chernyshev
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia.,School of Biological and Medical Physics, Moscow Institute of Physics & Technology, Dolgoprudnyi, Moscow Region 141700, Russia
| | - Alexey Schulga
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia
| | - Elena V Konovalova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia
| | - Roman N Chuprov-Netochin
- School of Biological and Medical Physics, Moscow Institute of Physics & Technology, Dolgoprudnyi, Moscow Region 141700, Russia
| | - Tatiana O Abakumova
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia
| | - Sergei German
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia.,Institute of Spectroscopy of the Russian Academy of Sciences, Moscow 108840, Russia
| | - Victoria O Shipunova
- School of Biological and Medical Physics, Moscow Institute of Physics & Technology, Dolgoprudnyi, Moscow Region 141700, Russia.,Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia
| | - Maksim D Mokrousov
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia
| | | | - Daniil N Bratashov
- Saratov State University, 83 Astrakhanskaya Street, Saratov 410012, Russia
| | - Daniil V Nozdriukhin
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia
| | - Andrey Bogorodskiy
- School of Biological and Medical Physics, Moscow Institute of Physics & Technology, Dolgoprudnyi, Moscow Region 141700, Russia
| | - Oleg Grishin
- Saratov State University, 83 Astrakhanskaya Street, Saratov 410012, Russia
| | - Sergey S Kosolobov
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia
| | - Boris N Khlebtsov
- Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Saratov 410049, Russia
| | - Olga Inozemtseva
- Saratov State University, 83 Astrakhanskaya Street, Saratov 410012, Russia
| | - Timofei S Zatsepin
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia.,Lomonosov Moscow State University, Moscow 119991, Russia
| | - Sergey M Deyev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia
| | - Dmitry A Gorin
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow 121205, Russia
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Shin HG, Yang HR, Yoon A, Lee S. Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy. Int J Mol Sci 2022; 23:5686. [PMID: 35628495 PMCID: PMC9146966 DOI: 10.3390/ijms23105686] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 12/16/2022] Open
Abstract
Cancer is the second leading cause of death worldwide after cardiovascular diseases. Harnessing the power of immune cells is a promising strategy to improve the antitumor effect of cancer immunotherapy. Recent progress in recombinant DNA technology and antibody engineering has ushered in a new era of bispecific antibody (bsAb)-based immune-cell engagers (ICEs), including T- and natural-killer-cell engagers. Since the first approval of blinatumomab by the United States Food and Drug Administration (US FDA), various bsAb-based ICEs have been developed for the effective treatment of patients with cancer. Simultaneously, several potential therapeutic targets of bsAb-based ICEs have been identified in various cancers. Therefore, this review focused on not only highlighting the action mechanism, design and structure, and status of bsAb-based ICEs in clinical development and their approval by the US FDA for human malignancy treatment, but also on summarizing the currently known and emerging therapeutic targets in cancer. This review provides insights into practical considerations for developing next-generation ICEs.
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Affiliation(s)
- Ha Gyeong Shin
- Department of Biopharmaceutical Chemistry, College of Science and Technology, Kookmin University, Seoul 02707, Korea; (H.G.S.); (H.R.Y.)
| | - Ha Rim Yang
- Department of Biopharmaceutical Chemistry, College of Science and Technology, Kookmin University, Seoul 02707, Korea; (H.G.S.); (H.R.Y.)
| | - Aerin Yoon
- R&D Division, GC Biopharma, Yongin 16924, Korea
| | - Sukmook Lee
- Department of Biopharmaceutical Chemistry, College of Science and Technology, Kookmin University, Seoul 02707, Korea; (H.G.S.); (H.R.Y.)
- Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Korea
- Antibody Research Institute, Kookmin University, Seoul 02707, Korea
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Wang L, Qiao Y, Zong H, Han L, Ke Y, Pan Z, Chen J, Lu J, Li J, Ying T, Zhang B, Zhu J. IgG-like Bispecific Antibody CD3×EpCAM Generated by Split Intein Against Colorectal Cancer. Front Pharmacol 2022; 13:803059. [PMID: 35281893 PMCID: PMC8905292 DOI: 10.3389/fphar.2022.803059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/31/2022] [Indexed: 12/17/2022] Open
Abstract
Background: Colorectal cancer is a commonly diagnosed cancer with high mortality worldwide. Postoperative recidivation and metastasis still are the main challenges in clinical treatments. Thus, it is urgent to develop new therapies against colorectal cancer. Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in colorectal cancer cells and strongly associated with cancer development. Bispecific antibody (BsAb) is a kind of promising immunotherapy, which could recognize T cells and cancer cells simultaneously to achieve the anti-tumor effects. Methods: A bispecific antibody targeting EpCAM and CD3 with IgG format was genereated by split intein based on the Bispecific Antibody by Protein Splicing" platform. In vitro, the affinity of CD3×EpCAM BsAb was determined by Biolayer interferometry, its cytotoxicity was detected by LDH release assay, T cell recruitment and activation was detected by Flow Cytometry. In vivo, its pharmacokinetic parameters were detected, and anti-tumor effects were evaluated on the tumor cell xenograft mouse model. Results: The results showed that the CD3×EpCAM BsAb could activate and recruit T cells via binding colorectal cells and T cells, which could lead to more potent cytotoxicity to various colorectal cell lines than its parent EpCAM monoclonal antibody (mAb) in vitro. The CD3×EpCAM BsAb had similar pharmacokinetic parameters with EpCAM mAb and inhibits tumor growth on the SW480 tumor cell xenograft mouse model. Conclusion: The CD3×EpCAM BsAb could be a promising candidate for colorectal cancer treatment.
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Affiliation(s)
- Lei Wang
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Qiao
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Huifang Zong
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Han
- Jecho Institute, Co. Ltd., Shanghai, China
- Jecho Biopharmaceuticals Co. Ltd., Tianjin, China
| | - Yong Ke
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - ZhiDi Pan
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Chen
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Lu
- School of Science, and School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Baohong Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jianwei Zhu
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- Jecho Institute, Co. Ltd., Shanghai, China
- Jecho Biopharmaceuticals Co. Ltd., Tianjin, China
- Jecho Laboratories, Inc., Frederick, MD, United States
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37
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Motawi TMK, Sadik NAH, Sabry D, Fahim SA, Shahin NN. rs62139665 Polymorphism in the Promoter Region of EpCAM Is Associated With Hepatitis C Virus-Related Hepatocellular Carcinoma Risk in Egyptians. Front Oncol 2022; 11:754104. [PMID: 35070966 PMCID: PMC8766815 DOI: 10.3389/fonc.2021.754104] [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: 08/05/2021] [Accepted: 12/06/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a universal health problem that is particularly alarming in Egypt. The major risk factor for HCC is hepatitis C virus (HCV) infection which is a main burden in Egypt. The epithelial cell adhesion molecule (EpCAM) is a stem cell marker involved in the tumorigenesis and progression of many malignancies, including HCC. We investigated the association of -935 C/G single nucleotide polymorphism in EpCAM promoter region (rs62139665) with HCC risk, EpCAM expression and overall survival in Egyptians. A total of 266 patients (128 HCV and 138 HCC cases) and 117 age- and sex-matched controls participated in this study. Genotyping, performed using allelic discrimination and confirmed by sequencing, revealed a significant association between EpCAM rs62139665 and HCC susceptibility, with higher GG genotype and G allele distribution in HCC patients than in non-HCC subjects. Such association was not detected in HCV patients compared to controls. EpCAM gene expression levels, determined in blood by RT-qPCR, and its serum protein expression levels, determined by ELISA, were significantly higher in GG relative to GC+CC genotype carriers in HCV and HCC patients in a recessive model. ROC analysis of EpCAM protein levels revealed significant discriminatory power between HCC patients and non-HCC subjects, with improved diagnostic accuracy when combining α-fetoprotein and EpCAM compared to that of α-fetoprotein alone. Altogether, EpCAM rs62139665 polymorphism is significantly associated with HCC and with EpCAM gene and protein expression levels in the Egyptian population. Moreover, serum EpCAM levels may hold promise for HCC diagnosis and for improving the diagnostic accuracy of α-fetoprotein.
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Affiliation(s)
| | | | - Dina Sabry
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Badr University in Cairo, Badr City, Egypt.,Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sally Atef Fahim
- Biochemistry Department, School of Pharmacy, Newgiza University (NGU), Cairo, Egypt
| | - Nancy Nabil Shahin
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Preclinical evaluation of [ 99mTc]Tc-labeled anti-EpCAM nanobody for EpCAM receptor expression imaging by immuno-SPECT/CT. Eur J Nucl Med Mol Imaging 2022; 49:1810-1821. [PMID: 35013776 DOI: 10.1007/s00259-021-05670-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/20/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE Overexpression of epithelial cell adhesion molecule (EpCAM) plays essential roles in tumorigenesis and tumor progression in almost all epithelium-derived cancer. Monitoring EpCAM expression in tumors can be used for the diagnosis, staging, and prognosis of cancer patients, as well as guiding the individualized treatment of EpCAM-targeted drugs. In this study, we described the synthesis and evaluation of a site-specifically [99mTc]Tc-labeled EpCAM-targeted nanobody for the SPECT/CT imaging of EpCAM expression. METHODS We first prepared the [99mTc]Tc-HYNIC-G4K; then, it was site-specifically connected to EpCAM-targeted nanobody NB4. The in vitro characteristics of [99mTc]Tc-NB4 were investigated in HT-29 (EpCAM positive) and HL-60 (EpCAM negative) cells, while the in vivo studies were performed using small-animal SPECT/CT in the subcutaneous tumor models and the lymph node metastasis model to verify the specific targeting capacity as well as the potential applications of [99mTc]Tc-NB4. RESULTS [99mTc]Tc-NB4 displayed a high EpCAM specificity both in vitro and in vivo. SPECT/CT imaging revealed that [99mTc]Tc-NB4 was cleared rapidly from the blood and normal organs except for the kidneys, and HT-29 tumors were clearly visualized in contrast with HL-60 tumors. The uptake value of [99mTc]Tc-NB4 in HT-29 tumors was increased continuously from 3.77 ± 0.39%ID/g at 0.5 h to 5.53 ± 0.82%ID/g at 12 h after injection. Moreover, the [99mTc]Tc-NB4 SPECT/CT could clearly image tumor-draining lymph nodes. CONCLUSION [99mTc]Tc-NB4 is a broad-spectrum, specific, and sensitive SPECT radiotracer for the noninvasive imaging of EpCAM expression in the epithelium-derived cancer and revealed a great potential for the clinical translation.
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Kalantari E, Taheri T, Fata S, Abolhasani M, Mehrazma M, Madjd Z, Asgari M. Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer. World J Surg Oncol 2022; 20:15. [PMID: 35016698 PMCID: PMC8751119 DOI: 10.1186/s12957-021-02469-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/02/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The crucial oncogenic role of cancer stem cells (CSCs) in tumor maintenance, progression, drug resistance, and relapse has been clarified in different cancers, particularly in colorectal cancer (CRC). The current study was conducted to evaluate the co-expression pattern and clinical significance of epithelial cell adhesion molecules (EpCAM) and activated leukocyte cell adhesion (CD166 or ALCAM) in CRC patients. METHODS This study was carried out on 458 paraffin-embedded CRC specimens by immunohistochemistry on tissue microarray (TMA) slides. RESULTS Elevated expression of EpCAM and CD166 was observed in 61.5% (246/427) and 40.5% (164/405) of CRC cases. Our analysis showed a significant positive association of EpCAM expression with tumor size (P = 0.02), tumor stage (P = 0.007), tumor differentiate (P = 0.005), vascular (P = 0.01), neural (P = 0.01), and lymph node (P = 0.001) invasion. There were no significant differences between CD166 expression and clinicopathological parameters. Moreover, the combined analysis demonstrated a reciprocal significant correlation between EpCAM and CD166 expression (P = 0.02). Interestingly, there was a significant positive correlation between EpCAM/CD166 phenotypes expression and tumor stage (P = 0.03), tumor differentiation (P = 0.05), neural, and lymph node invasion (P =0.01). CONCLUSIONS The significant correlation of EpCAM and CD166 expression and their association with tumor progression and aggressive behavior is the reason for the suggestion of these two CSC markers as promising targets to promote novel effective targeted-therapy strategies for cancer treatment in the present study.
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Affiliation(s)
- Elham Kalantari
- Oncopathology Research Center, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
| | - Tahereh Taheri
- Department of Pathology, Iran University of Medical Sciences, Tehran, Iran
| | - Saba Fata
- Department of Pathology, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Abolhasani
- Oncopathology Research Center, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
- Department of Pathology, Hasheminejad kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mitra Mehrazma
- Oncopathology Research Center, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Mojgan Asgari
- Oncopathology Research Center, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
- Department of Pathology, Hasheminejad kidney Center, Iran University of Medical Sciences, Tehran, Iran.
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Joshi J, Patel H, Bhavnagari H, Tarapara B, Pandit A, Shah F. Eliminating Cancer Stem-Like Cells in Oral Cancer by Targeting Elementary Signaling Pathways. Crit Rev Oncog 2022; 27:65-82. [PMID: 37199303 DOI: 10.1615/critrevoncog.2022047207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Oral cancer is a heterogeneous, aggressive, and complex entity. Current major treatment options for the disease are surgery, chemo, and/or radiotherapy either alone or in combination with each other. Each treatment method has its own limitations such as a significant journey with deformities and a protracted rehabilitation process leading to loss of self-esteem, loss of tolerance, and therapeutic side effects. Conventional therapies are frequently experienced with regimen resistance and recurrence attributed to the cancer stem cells (CSCs). Given that CSCs exert their tumorigenesis by affecting several cellular and molecular targets and pathways an improved understanding of CSCs' actions is required. Hence, more research is recommended to fully understand the fundamental mechanisms driving CSC-mediated treatment resistance. Despite the difficulties and disagreements surrounding the removal of CSCs from solid tumors, a great amount of knowledge has been derived from the characterization of CSCs. Various efforts have been made to identify the CSCs using several cell surface markers. In the current review, we will discuss numerous cell surface markers such as CD44, ALDH1, EPCAM, CD24, CD133, CD271, CD90, and Cripto-1 for identifying and isolating CSCs from primary oral squamous cell carcinoma (OSCC). Further, a spectrum of embryonic signaling pathways has been thought to be the main culprit of CSCs' active state in cancers, resulting in conventional therapeutic resistance. Hence, we discuss the functional and molecular bases of several signaling pathways such as the Wnt/beta;-catenin, Notch, Hedgehog, and Hippo pathways and their associations with disease aggressiveness. Moreover, numerous inhibitors targeting the above mentioned signaling pathways have already been identified and some of them are already undergoing clinical trials. Hence, the present review encapsulates the characterization and effectiveness of the prospective potential targeted therapies for eradicating CSCs in oral cancers.
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Affiliation(s)
- Jigna Joshi
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Hitarth Patel
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Hunayna Bhavnagari
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Bhoomi Tarapara
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Apexa Pandit
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Franky Shah
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
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Kim Y, Laradji AM, Sharma S, Zhang W, Yadavalli NS, Xie J, Popik V, Minko S. Refining of Particulates at Stimuli‐Responsive Interfaces: Label‐Free Sorting and Isolation. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202110990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Yongwook Kim
- Nanostructured Materials Lab University of Georgia Athens GA 30602 USA
| | - Amine M. Laradji
- Nanostructured Materials Lab University of Georgia Athens GA 30602 USA
- Current address: Department of Ophthalmology and Visual Sciences Washington University School of Medicine St. Louis MO 63110 USA
| | - Shubham Sharma
- Department of Chemistry University of Georgia Athens GA 30602 USA
| | - Weizhong Zhang
- Department of Chemistry University of Georgia Athens GA 30602 USA
| | | | - Jin Xie
- Department of Chemistry University of Georgia Athens GA 30602 USA
| | - Vladimir Popik
- Department of Chemistry University of Georgia Athens GA 30602 USA
| | - Sergiy Minko
- Nanostructured Materials Lab University of Georgia Athens GA 30602 USA
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Wu Y, Yi M, Zhu S, Wang H, Wu K. Recent advances and challenges of bispecific antibodies in solid tumors. Exp Hematol Oncol 2021; 10:56. [PMID: 34922633 PMCID: PMC8684149 DOI: 10.1186/s40164-021-00250-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/03/2021] [Indexed: 12/29/2022] Open
Abstract
Cancer immunotherapy has made remarkable progress in the past decade. Bispecific antibodies (BsAbs) have acquired much attention as the next generation strategy of antibody-target cancer immunotherapy, which overwhelmingly focus on T cell recruitment and dual receptors blockade. So far, BsAb drugs have been proved clinically effective and approved for the treatment of hematologic malignancies, but no BsAb have been approved in solid tumors. Numerous designed BsAb drugs for solid tumors are now undergoing evaluation in clinical trials. In this review, we will introduce the formats of bispecific antibodies, and then update the latest preclinical studies and clinical trials in solid tumors of BsAbs targeting EpCAM, CEA, PMSA, ErbB family, and so on. Finally, we discuss the BsAb-related adverse effects and the alternative strategy for future study.
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Affiliation(s)
- Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shuangli Zhu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haiyong Wang
- Beijing Anjianxi Medicinal Technology Co., Ltd., No.2 Cuiwei Road, Haidian District, Beijing, 100036, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Havaei SM, Aucoin MG, Jahanian-Najafabadi A. Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin. Front Oncol 2021; 11:781800. [PMID: 34976821 PMCID: PMC8716853 DOI: 10.3389/fonc.2021.781800] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/16/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.
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Affiliation(s)
- Seyed Mehdi Havaei
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marc G. Aucoin
- Department of Chemical Engineering, Faculty of Engineering, University of Waterloo, Waterloo, ON, Canada
| | - Ali Jahanian-Najafabadi
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Kim Y, Laradji AM, Sharma S, Zhang W, Yadavalli NS, Xie J, Popik V, Minko S. Refining of Particulates at Stimuli-Responsive Interfaces: Label-Free Sorting and Isolation. Angew Chem Int Ed Engl 2021; 61:e202110990. [PMID: 34841648 DOI: 10.1002/anie.202110990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Indexed: 11/07/2022]
Abstract
The mechanism of separation methods, for example, liquid chromatography, is realized through rapid multiple adsorption-desorption steps leading to the dynamic equilibrium state in a mixture of molecules with different partition coefficients. Sorting of colloidal particles, including protein complexes, cells, and viruses, is limited due to a high energy barrier, up to millions kT, required to detach particles from the interface, which is in dramatic contrast to a few kT for small molecules. Such a strong interaction renders particle adsorption quasi-irreversible. The dynamic adsorption-desorption equilibrium is approached very slowly, if ever attainable. This limitation is alleviated with a local oscillating repulsive mechanical force generated at the microstructured stimuli-responsive polymer interface to switch between adsorption and mechanical-force-facilitated desorption of the particles. Such a dynamic regime enables the separation of colloidal mixtures based on the particle-polymer interface affinity, and it could find use in research, diagnostics, and industrial-scale label-free sorting of highly asymmetric mixtures of colloids and cells.
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Affiliation(s)
- Yongwook Kim
- Nanostructured Materials Lab, University of Georgia, Athens, GA, 30602, USA
| | - Amine M Laradji
- Nanostructured Materials Lab, University of Georgia, Athens, GA, 30602, USA.,Current address: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Shubham Sharma
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Weizhong Zhang
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | | | - Jin Xie
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Vladimir Popik
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Sergiy Minko
- Nanostructured Materials Lab, University of Georgia, Athens, GA, 30602, USA
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Novel Perspectives in Pseudomyxoma Peritonei Treatment. Cancers (Basel) 2021; 13:cancers13235965. [PMID: 34885075 PMCID: PMC8656832 DOI: 10.3390/cancers13235965] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/11/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Pseudomyxoma Peritonei (PMP) represents a rare entity which greatly benefits from Cytoreductive Surgery (CRS) associated with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). In fact, CRS-HIPEC represents the treatment with potential chances of cure and long-term disease control of patients affected by PMP. This therapeutic strategy should be performed in referral centers, where a consolidated know-how of this locoregional treatment and a multidisciplinary approach are available. CRS-HIPEC provides excellent results for PMP patients in terms of postoperative outcome, overall and disease-free survival, and quality of life. However, in patients with an extensive or recurrent disease, few therapeutic opportunities are available. This review is focused on the most recent clinical evidence and provides a better understanding of the molecular prognostic factors and potential therapeutic targets in this rare malignancy. Abstract Pseudomyxoma Peritonei (PMP) is an anatomo-clinical condition characterized by the implantation of neoplastic cells on peritoneal surfaces with the production of a large amount of mucin. The rarity of the disease precludes the evaluation of treatment strategies within randomized controlled trials. Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has proven to be the only therapeutic option with potential chances of cure and long-term disease control. The present review discusses the epidemiology, pathogenesis, clinical presentation and treatment of PMP, focusing on the molecular factors involved in tumor progression and mucin production that could be used, in the upcoming future, to improve patient selection for surgery and to expand the therapeutic armamentarium.
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Ben Rejeb S, Beltaifa D, Ghozzi A, Bellil K, Turki S. EpCAM (MOC-31) - immunohistochemical expression in papillary thyroid carcinoma and non invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). LA TUNISIE MEDICALE 2021; 99:1066-1071. [PMID: 35288910 PMCID: PMC8974436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
INTRODUCTION Ep-CAM, is a cell adhesion glycoprotein located on the basolateral cell membrane surface and in the cytoplasm of most normal epithelial cells. It has also been described to be expressed in several malignancies such as lung, digestive, prostate and renal carcinomas suggesting it has a potential role in carcinogenesis. In thyroid carcinoma, Ep-CAM expression has rarely been studied especially in papillary thyroid carcinoma. OBJECTIVE We sought to describe and compare the immunohistochemical expression of MOC31 in papillary thyroid carcinoma and in non invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). METHODS We have retrospectively collected 33 cases of PTC diagnosed in the pathology department of the Security forces hospital during a period of 13 years (2008-2021). We have microscopically reviewed all cases and reclassified 9 of 33 cases as NIFTP. An immunohistochemical automated study have been performed with MOC-31 antibody. The immunostaining was considered positive when it was membranous and/or cytoplasmic. The intensity of staining was scored as weak (score 1), moderate (score 2), and strong (score 3). We have used an immunoscore for assessing level of expression of MOC31 as follows: 0 for <5% of positive cells, 1 for 5-30%, 2 for 31-50%, 3 for 51-70%.The total score resulted by summing the percentage score with the intensity score; the final score was varying from 0 to 7, considered low between 1-4 and high 5-7. RESULTS The mean age of patients was 45,2 years-old for PTC cases and 48,1 years-old for NIFTP cases. A net female predominance was found in both groups (male to female ratio of respectively 0,4 and 0,3). MOC31 expression was found in 19 cases of PTC with a percentage of positive cells varying from 5 to 90%. Percentage of positive cells was variable from 5 to 90%. The immunoscore for positive cells was: 0 in 5/24cases, 1 in 4/24cases, 3 in 9/24cases and 4 in 6/24cases. The intensity of staining was assessed score2 (moderate) in 8 cases and score 3 (high) in 7cases (Figure1-2). Final MOC31 staining score was low in 37,5% (9/24) and high in 62.5% (15/24). Patients with advanced pt2-pt3 stages mostly showed high score of MOC31 staining (61,5%).One case was associated with lymph node involvement and was of a high score. 6 cases showed vascular invasion and was of high MOC31 score. MOC31 was expressed in all NIFTP cases with variable proportion of positive cells (5%-80%). The immunoscore for positive cells was: 0 in 1/9cases, 1 in 2/9cases, 2 in 3/9cases, 3 in 1/9cases and 4 in 2/9cases. The intensity of staining was assessed score 1 (weak) in one case, score 2 (moderate) in 6 cases and score 3 (high) in one case (Figure3-4). The final combined score was low in 66,7 (6/9) and high in 33,3% (3/9). CONCLUSION Our study revealed different immunohistochemical profile of MOC31 in benign and malignant tumors. It has somewhat a diffuse and marked staining in the first group. The changes of MOC31 location as well as its score of staining in PTC and NIFTP could hence be helpful in the differential diagnosis. Our findings also support the potential prognostic value of this molecule that deserves further investigations.
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Affiliation(s)
- Sarra Ben Rejeb
- Hôpital des Forces de Sécurité Intérieure, Faculté de médecine de Tunis
| | - Dorsaf Beltaifa
- Hôpital des Forces de Sécurité Intérieure, Faculté de médecine de Tunis
| | - Amen Ghozzi
- Hôpital des Forces de Sécurité Intérieure, Faculté de médecine de Tunis
| | - Khadija Bellil
- Hôpital des Forces de Sécurité Intérieure, Faculté de médecine de Tunis
| | - Senda Turki
- Hôpital des Forces de Sécurité Intérieure, Faculté de médecine de Tunis
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Zhong J, Ding J, Deng L, Xiang Y, Liu D, Zhang Y, Chen X, Yang Q. Selection of DNA Aptamers Recognizing EpCAM-Positive Prostate Cancer by Cell-SELEX for in vitro and in vivo MR Imaging. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:3985-3996. [PMID: 34584404 PMCID: PMC8464308 DOI: 10.2147/dddt.s322854] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 09/06/2021] [Indexed: 11/23/2022]
Abstract
Background The sensitive and specific detection of pathogenic cells is important in tumor diagnosis at an early stage. Aptamers are short single-stranded oligonucleotides evolved from systematic evolution of ligands by exponential enrichment (SELEX). It has been proved that aptamers can interact with cognate target molecules with high affinity and specificity and have great potential in the development of medical imaging at molecular level. Purpose To select epithelial cell adhesion molecule (EpCAM) specific aptamers targeting prostate cancer and further to conjugate aptamers with GoldMag nanoparticles (a typical iron oxide core/gold shell structure) to construct magnetic molecular probes for medical imaging. Methods EpCAM-specific aptamers were selected by Cell-SELEX. The enrichment of specific aptamer candidates was monitored by flow cytometric analysis. Aptamers were further conjugated with GoldMag nanoparticles to construct magnetic molecular probes. The affinity and specificity of aptamer candidates and aptamer-conjugated GoldMag nanoparticles were evaluated. The MR imaging of aptamer-conjugated GoldMag nanoparticles to prostate cancer was further explored in vitro and in vivo. Results After 12 rounds of selection, aptamer candidates Eppc6 and Eppc14 could specifically target three types of prostate cancer cells, revealing a high affinity of Eppc6 and Eppc14. Moreover, aptamer-conjugated GoldMag nanoparticles not only exhibited good affinity to different prostate cancer cells but also produced strong T2WI signal intensity reduction distinguished from peritumoral tissue in MRI, indicating that the molecular probes possess both the affinity properties of EpCAM-specific aptamer and the superparamagnetic features of iron oxide. Conclusion Our study indicates that aptamer Eppc6 and Eppc14 can recognize prostate cancer cells and tissues. The aptamer-conjugated GoldMag nanoparticles constructed in the study can be used as a molecular imaging agent for detection of PCa in MRI.
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Affiliation(s)
- Jinman Zhong
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
| | - Jianke Ding
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China
| | - Lei Deng
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
| | - Ying Xiang
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
| | - Duoduo Liu
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
| | - Yanyan Zhang
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
| | - Xin Chen
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
| | - Quanxin Yang
- Department of Radiology, The Second Affiliated Hospital, Xi' an Jiaotong University, Xi'an, Shaanxi Province, 710004, People's Republic of China
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Wang C, Fakih M. Targeting MSS colorectal cancer with immunotherapy: are we turning the corner? Expert Opin Biol Ther 2021; 21:1347-1357. [PMID: 34030532 DOI: 10.1080/14712598.2021.1933940] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Immunotherapy with checkpoint inhibition has shown potent antitumor activity in patients with microsatellite instability (MSI) metastatic cancer. Microsatellite stable (MSS) colorectal cancer has long been considered resistant to immunotherapy. AREAS COVERED In this review, we provide an overview of current progress on strategies to overcome the resistance to immunotherapy in MSS colorectal cancer. EXPERT OPINION Emerging evidence suggest that combination of immune modulators such as regorafenib may improve the responsiveness of MSS colorectal cancer to checkpoint blockade. In addition, signs of clinical activity have also been observed in other combination strategies, such as the combination of checkpoint blockade with Stat3 inhibitor, or bispecific T-cell engagers. Nevertheless, predictive biomarkers that can identify patients who may benefit from immunotherapy are key for its implementation in clinical setting. Metastatic disease sites may predict for the response or resistance to checkpoint blockade, with liver metastases emerging as a strong predictive biomarker of lack of benefit from PD-1 targeting, even with combination therapies. Additional efforts are required to study the mechanism of resistance and to develop novel therapeutic strategies to overcome immune resistance. ABBREVIATIONS CEA: carcinoembryonic antigen; CR: complete response; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; DCR: disease control rate; MSI-H: microsatellite instability-high; MSS: Microsatellite stable (MSS); OS: overall survival; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand receptor 1; PR: partial response; PFS: progression-free survival; SD: stable disease; TMB: tumor mutation burden; VEGFR: vascular endothelial growth factor receptor.
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Affiliation(s)
- Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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Evaluation of a marker independent isolation method for circulating tumor cells in esophageal adenocarcinoma. PLoS One 2021; 16:e0251052. [PMID: 33961658 PMCID: PMC8104412 DOI: 10.1371/journal.pone.0251052] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/20/2021] [Indexed: 12/15/2022] Open
Abstract
Objective The enrichment of circulating tumor cells (CTCs) from blood provides a minimally invasive method for biomarker discovery in cancer. Longitudinal interrogation allows monitoring or prediction of therapy response, detection of minimal residual disease or progression, and determination of prognosis. Despite inherent phenotypic heterogeneity and differences in cell surface marker expression, most CTC isolation technologies typically use positive selection. This necessitates the optimization of marker-independent CTC methods, enabling the capture of heterogenous CTCs. The aim of this report is to compare a size-dependent and a marker-dependent CTC-isolation method, using spiked esophageal cells in healthy donor blood and blood from patients diagnosed with esophageal adenocarcinoma. Methods Using esophageal cancer cell lines (OE19 and OE33) spiked into blood of a healthy donor, we investigated tumor cell isolation by Parsortix post cell fixation, immunostaining and transfer to a glass slide, and benchmarked its performance against the CellSearch system. Additionally, we performed DEPArray cell sorting to infer the feasibility to select and isolate cells of interest, aiming towards downstream single-cell molecular characterization in future studies. Finally, we measured CTC prevalence by Parsortix in venous blood samples from patients with various esophageal adenocarcinoma tumor stages. Results OE19 and OE33 cells were spiked in healthy donor blood and subsequently processed using CellSearch (n = 16) or Parsortix (n = 16). Upon tumor cell enrichment and enumeration, the recovery rate ranged from 76.3 ± 23.2% to 21.3 ± 9.2% for CellSearch and Parsortix, respectively. Parsortix-enriched and stained cell fractions were successfully transferred to the DEPArray instrument with preservation of cell morphology, allowing isolation of cells of interest. Finally, despite low CTC prevalence and abundance, Parsortix detected traditional CTCs (i.e. cytokeratin+/CD45-) in 8/29 (27.6%) of patients with esophageal adenocarcinoma, of whom 50% had early stage (I-II) disease. Conclusions We refined an epitope-independent isolation workflow to study CTCs in patients with esophageal adenocarcinoma. CTC recovery using Parsortix was substantially lower compared to CellSearch when focusing on the traditional CTC phenotype with CD45-negative and cytokeratin-positive staining characteristics. Future research could determine if this method allows downstream molecular interrogation of CTCs to infer new prognostic and predictive biomarkers on a single-cell level.
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Edelman HE, McClymont SA, Tucker TR, Pineda S, Beer RL, McCallion AS, Parsons MJ. SOX9 modulates cancer biomarker and cilia genes in pancreatic cancer. Hum Mol Genet 2021; 30:485-499. [PMID: 33693707 DOI: 10.1093/hmg/ddab064] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/02/2021] [Accepted: 02/24/2021] [Indexed: 12/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with high mortality. The cellular origins of PDAC are largely unknown; however, ductal cells, especially centroacinar cells (CACs), have several characteristics in common with PDAC, such as expression of SOX9 and components of the Notch-signaling pathway. Mutations in KRAS and alterations to Notch signaling are common in PDAC, and both these pathways regulate the transcription factor SOX9. To identify genes regulated by SOX9, we performed siRNA knockdown of SOX9 followed by RNA-seq in PANC-1s, a human PDAC cell line. We report 93 differentially expressed (DE) genes, with convergence on alterations to Notch-signaling pathways and ciliogenesis. These results point to SOX9 and Notch activity being in a positive feedback loop and SOX9 regulating cilia production in PDAC. We additionally performed ChIP-seq in PANC-1s to identify direct targets of SOX9 binding and integrated these results with our DE gene list. Nine of the top 10 downregulated genes have evidence of direct SOX9 binding at their promoter regions. One of these targets was the cancer stem cell marker EpCAM. Using whole-mount in situ hybridization to detect epcam transcript in zebrafish larvae, we demonstrated that epcam is a CAC marker and that Sox9 regulation of epcam expression is conserved in zebrafish. Additionally, we generated an epcam null mutant and observed pronounced defects in ciliogenesis during development. Our results provide a link between SOX9, EpCAM and ciliary repression that can be exploited in improving our understanding of the cellular origins and mechanisms of PDAC.
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Affiliation(s)
- Hannah E Edelman
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Sarah A McClymont
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Tori R Tucker
- Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA
| | - Santiago Pineda
- Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA
| | - Rebecca L Beer
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Andrew S McCallion
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Michael J Parsons
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.,Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA
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