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Zhou ZR, Wu MS, Yang Z, Wu Y, Guo W, Li DW, Qian RC, Lu Y. Synthetic transmembrane DNA receptors enable engineered sensing and actuation. Nat Commun 2025; 16:1464. [PMID: 39920144 PMCID: PMC11806108 DOI: 10.1038/s41467-025-56758-1] [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: 07/16/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
In living organisms, cells synergistically couple cascade reaction pathways to achieve inter- and intracellular signal transduction by transmembrane protein receptors. The construction and assembly of synthetic receptor analogs that can mimic such biological processes is a central goal of synthetic biochemistry and bionanotechnology to endow receptors with user-defined signal transduction effects. However, designing artificial transmembrane receptors with the desired input, output, and performance parameters are challenging. Here we show that the dimerization of synthetic transmembrane DNA receptors executes a systematically engineered sensing and actuation cascade in response to external molecular signals. The synthetic DNA receptors are composed of three parts, including an extracellular signal reception part, a lipophilic transmembrane anchoring part, and an intracellular signal output part. Upon the input of external signals, the DNA receptors can form dimers on the cell surface triggered by configuration changes, leading to a series of downstream cascade events including communication between donor and recipient cells, gene transcription regulation, protein level control, and cell apoptosis. We believe this work establishes a flexible cell surface engineering strategy that is broadly applicable to implement sophisticated biological functions.
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Affiliation(s)
- Ze-Rui Zhou
- Key Laboratory for Advanced Materials. East China University of Science and Technology, Shanghai, 200237, P. R. China
- Feringa Nobel Prize Scientist Joint Research Center, Joint International Laboratory for Precision Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China
- Frontiers Science Center for Materiobiology & Dynamic Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China
- School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Man-Sha Wu
- Key Laboratory for Advanced Materials. East China University of Science and Technology, Shanghai, 200237, P. R. China
- Feringa Nobel Prize Scientist Joint Research Center, Joint International Laboratory for Precision Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China
- Frontiers Science Center for Materiobiology & Dynamic Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China
- School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Zhenglin Yang
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Yuting Wu
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Weijie Guo
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA
| | - Da-Wei Li
- Key Laboratory for Advanced Materials. East China University of Science and Technology, Shanghai, 200237, P. R. China
- Feringa Nobel Prize Scientist Joint Research Center, Joint International Laboratory for Precision Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China
- Frontiers Science Center for Materiobiology & Dynamic Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China
- School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Ruo-Can Qian
- Key Laboratory for Advanced Materials. East China University of Science and Technology, Shanghai, 200237, P. R. China.
- Feringa Nobel Prize Scientist Joint Research Center, Joint International Laboratory for Precision Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China.
- Frontiers Science Center for Materiobiology & Dynamic Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China.
- School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China.
| | - Yi Lu
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA.
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA.
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2
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Barai A, Piplani N, Saha SK, Dutta S, Gomathi V, Ghogale MM, Kumar S, Kulkarni M, Sen S. Bulky glycocalyx drives cancer invasiveness by modulating substrate-specific adhesion. PNAS NEXUS 2024; 3:pgae335. [PMID: 39211517 PMCID: PMC11358709 DOI: 10.1093/pnasnexus/pgae335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 07/30/2024] [Indexed: 09/04/2024]
Abstract
The majority of the eukaryotic cell surface is decorated with a layer of membrane-attached polysaccharides and glycoproteins collectively referred to as the glycocalyx. While the formation of a bulky glycocalyx has been associated with the cancer progression, the mechanisms by which the glycocalyx regulates cancer invasiveness are incompletely understood. We address this question by first documenting subtype-specific expression of the major glycocalyx glycoprotein Mucin-1 (MUC1) in breast cancer patient samples and breast cancer cell lines. Strikingly, glycocalyx disruption led to inhibition of 2D motility, loss of 3D invasion, and reduction of clonal scattering in breast cancer cells at the population level. Tracking of 2D cell motility and 3D invasiveness of MUC1-based sorted subpopulations revealed the fastest motility and invasiveness in intermediate MUC1-expressing cells, with glycocalyx disruption abolishing these effects. While differential sensitivity in 2D motility is attributed to a nonmonotonic dependence of focal adhesion size on MUC1 levels, higher MUC1 levels enhance 3D invasiveness via increased traction generation. In contrast to inducing cell rounding on collagen-coated substrates, high MUC1 level promotes cell adhesion and confers resistance to shear flow on substrates coated with the endothelial surface protein E-selectin. Collectively, our findings illustrate how MUC1 drives cancer invasiveness by differentially regulating cell-substrate adhesion in a substrate-dependent manner.
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Affiliation(s)
- Amlan Barai
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
| | - Niyati Piplani
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
| | - Sumon Kumar Saha
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
| | - Sarbajeet Dutta
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
| | - V Gomathi
- Center for Translational Cancer Research, IISER Pune and PCCM Pune, Pune 411008, India
| | - Mayank M Ghogale
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
| | - Sushil Kumar
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
| | - Madhura Kulkarni
- Center for Translational Cancer Research, IISER Pune and PCCM Pune, Pune 411008, India
| | - Shamik Sen
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India
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3
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Sun L, Zhang Y, Li W, Zhang J, Zhang Y. Mucin Glycans: A Target for Cancer Therapy. Molecules 2023; 28:7033. [PMID: 37894512 PMCID: PMC10609567 DOI: 10.3390/molecules28207033] [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: 09/13/2023] [Revised: 10/08/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the human body, which can be classified into secreted mucins and transmembrane mucins according to their distributions. The major difference between them is that secreted mucins do not have transmembrane structural domains, and the expression of each mucin is organ and cell-specific. Under physiological conditions, mucin glycans are involved in the composition of the mucus barrier and thus protect the body from infection and injury. However, abnormal expression of mucin glycans can lead to the occurrence of diseases, especially cancer, through various mechanisms. Therefore, targeting mucin glycans for the diagnosis and treatment of cancer has always been a promising research direction. Here, we first summarize the main types of glycosylation (O-GalNAc glycosylation and N-glycosylation) on mucins and the mechanisms by which abnormal mucin glycans occur. Next, how abnormal mucin glycans contribute to cancer development is described. Finally, we summarize MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example. In this section, we specifically elaborate on the recent new cancer therapy CAR-M, which may bring new hope to cancer patients.
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Affiliation(s)
- Lingbo Sun
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Yuhan Zhang
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Wenyan Li
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Jing Zhang
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Yuecheng Zhang
- Key Laboratory of Analytical Technology and Detection of Yan'an, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an 716000, China
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Ganguly K, Shah A, Atri P, Rauth S, Ponnusamy MP, Kumar S, Batra SK. Chemokine-mucinome interplay in shaping the heterogeneous tumor microenvironment of pancreatic cancer. Semin Cancer Biol 2022; 86:511-520. [PMID: 35346803 PMCID: PMC9793394 DOI: 10.1016/j.semcancer.2022.03.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/15/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer (PC) is exemplified by a complex immune-suppressive, fibrotic tumor microenvironment (TME), and aberrant expression of mucins. The constant crosstalk between cancer cells, cancer-associated fibroblasts (CAFs), and the immune cells mediated by the soluble factors and inflammatory mediators including cytokines, chemokines, reactive oxygen species (ROS) promote the dynamic temporal switch towards an immune-escape phenotype in the neoplastic cells and its microenvironment that bolsters disease progression. Chemokines have been studied in PC pathogenesis, albeit poorly in the context of mucins, tumor glycocalyx, and TME heterogeneity (CAFs and immune cells). With correlative analysis from PC patients' transcriptome data, support from available literature, and scientific arguments-based speculative extrapolations in terms of disease pathogenesis, we have summarized in this review a comprehensive understanding of chemokine-mucinome interplay during stromal modulation and immune-suppression in PC. Future studies should focus on deciphering the complexities of chemokine-mediated control of glycocalyx maturation, immune infiltration, and CAF-associated immune suppression. Knowledge extracted from such studies will be beneficial to mechanistically correlate the mucin-chemokine abundance in serum versus pancreatic tumors of patients, which may aid in prognostication and stratification of PC patients for immunotherapy.
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Affiliation(s)
- Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ashu Shah
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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5
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Ramos-Martín F, D'Amelio N. Biomembrane lipids: When physics and chemistry join to shape biological activity. Biochimie 2022; 203:118-138. [PMID: 35926681 DOI: 10.1016/j.biochi.2022.07.011] [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: 04/01/2022] [Revised: 07/13/2022] [Accepted: 07/21/2022] [Indexed: 11/02/2022]
Abstract
Biomembranes constitute the first lines of defense of cells. While small molecules can often permeate cell walls in bacteria and plants, they are generally unable to penetrate the barrier constituted by the double layer of phospholipids, unless specific receptors or channels are present. Antimicrobial or cell-penetrating peptides are in fact highly specialized molecules able to bypass this barrier and even discriminate among different cell types. This capacity is made possible by the intrinsic properties of its phospholipids, their distribution between the internal and external leaflet, and their ability to mutually interact, modulating the membrane fluidity and the exposition of key headgroups. Although common phospholipids can be found in the membranes of most organisms, some are characteristic of specific cell types. Here, we review the properties of the most common lipids and describe how they interact with each other in biomembrane. We then discuss how their assembly in bilayers determines some key physical-chemical properties such as permeability, potential and phase status. Finally, we describe how the exposition of specific phospholipids determines the recognition of cell types by membrane-targeting molecules.
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Affiliation(s)
- Francisco Ramos-Martín
- Unité de Génie Enzymatique et Cellulaire UMR 7025 CNRS, Université de Picardie Jules Verne, Amiens, 80039, France.
| | - Nicola D'Amelio
- Unité de Génie Enzymatique et Cellulaire UMR 7025 CNRS, Université de Picardie Jules Verne, Amiens, 80039, France.
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6
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Li Z, Yang D, Guo T, Lin M. Advances in MUC1-Mediated Breast Cancer Immunotherapy. Biomolecules 2022; 12:biom12070952. [PMID: 35883508 PMCID: PMC9313386 DOI: 10.3390/biom12070952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 02/04/2023] Open
Abstract
Breast cancer (BRCA) is the leading cause of death from malignant tumors among women. Fortunately, however, immunotherapy has recently become a prospective BRCA treatment with encouraging achievements and mild safety profiles. Since the overexpression and aberrant glycosylation of MUC1 (human mucin) are closely associated with BRCA, it has become an ideal target for BRCA immunotherapies. In this review, the structure and function of MUC1 are briefly introduced, and the main research achievements in different kinds of MUC1-mediated BRCA immunotherapy are highlighted, from the laboratory to the clinic. Afterward, the future directions of MUC1-mediated BRCA immunotherapy are predicted, addressing, for example, urgent issues in regard to how efficient immunotherapeutic strategies can be generated.
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Affiliation(s)
- Zhifeng Li
- Medical School of Nantong University, Nantong 226019, China; (Z.L.); (D.Y.)
| | - Dazhuang Yang
- Medical School of Nantong University, Nantong 226019, China; (Z.L.); (D.Y.)
| | - Ting Guo
- Research Center of Clinical Medicine, Jiangsu Taizhou People’s Hospital (Affiliated Hospital 5 of Nantong University), Taizhou 225300, China;
| | - Mei Lin
- Research Center of Clinical Medicine, Jiangsu Taizhou People’s Hospital (Affiliated Hospital 5 of Nantong University), Taizhou 225300, China;
- Correspondence:
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7
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Sancar S, Bolkent S. Cyclic Dodecapeptide Induces Cell Death Through Membrane–Peptide Interactions in Breast Cancer Cells. Int J Pept Res Ther 2022. [DOI: 10.1007/s10989-022-10369-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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8
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Xu L, Li Y, Jin R, Jiang D, Jiang D. High spatial resolution observation of Temporin A at cell membranes using scanning ion conductive microscopy. Electrochem commun 2022. [DOI: 10.1016/j.elecom.2021.107181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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9
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Marloye M, Inam H, Moore CJ, Mertens TR, Ingels A, Koch M, Nowicki MO, Mathieu V, Pritchard JR, Awuah SG, Lawler SE, Meyer F, Dufrasne F, Berger G. Self-assembled ruthenium and osmium nanosystems display a potent anticancer profile by interfering with metabolic activity. Inorg Chem Front 2022; 9:2594-2607. [PMID: 36311556 PMCID: PMC9610622 DOI: 10.1039/d2qi00423b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Amphiphilic ruthenium and osmium complexes auto-assemble to nanosystems that poison mitochondria and show highly promising in vitro and in vivo anticancer activity.
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Affiliation(s)
- Mickaël Marloye
- Microbiology, Bioorganic & Macromolecular Chemistry Unit, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
| | - Haider Inam
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA
| | - Connor J. Moore
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA
| | - Tyler R. Mertens
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Aude Ingels
- Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
| | - Marilin Koch
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michal O. Nowicki
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Véronique Mathieu
- Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
- ULB Cancer Research Center (UCRC), Université libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Justin R. Pritchard
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA
| | - Samuel G. Awuah
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Sean E. Lawler
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Franck Meyer
- Microbiology, Bioorganic & Macromolecular Chemistry Unit, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
| | - François Dufrasne
- Microbiology, Bioorganic & Macromolecular Chemistry Unit, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
| | - Gilles Berger
- Microbiology, Bioorganic & Macromolecular Chemistry Unit, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Kumar N, Fazal S, Miyako E, Matsumura K, Rajan R. Avengers against cancer: A new era of nano-biomaterial-based therapeutics. MATERIALS TODAY 2021; 51:317-349. [DOI: 10.1016/j.mattod.2021.09.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Development, Characterization, and In Vivo Evaluation of a Novel Aptamer (Anti-MUC1/Y) for Breast Cancer Therapy. Pharmaceutics 2021; 13:pharmaceutics13081239. [PMID: 34452200 PMCID: PMC8400696 DOI: 10.3390/pharmaceutics13081239] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/29/2022] Open
Abstract
MUC1, the transmembrane glycoprotein Mucin 1, is usually found to be overexpressed in a variety of epithelial cancers playing an important role in disease progression. MUC1 isoforms such as MUC1/Y, which lacks the entire variable number of tandem repeat region, are involved in oncogenic processes by enhancing tumour initiation. MUC1/Y is therefore considered a promising target for the identification and treatment of epithelial cancers; but so far, the precise role of MUC1/Y remains to be elucidated. In this work, we developed and identified a DNA aptamer that specifically recognizes the splice variant MUC1/Y for the first time. The DNA aptamer could bind to a wide variety of human cancer cells, and treatment of MUC1/Y positive cells resulted in reduced growth in vitro. Moreover, MUC1/Y aptamer inhibited the tumour growth of breast cancer cells in vivo. The present study highlights the importance of targeting MUC1/Y for cancer treatment and unravels the suitability of a DNA aptamer to act as a new therapeutic tool.
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Fuchigami T, Chiga T, Yoshida S, Oba M, Fukushima Y, Inoue H, Matsuura A, Toriba A, Nakayama M. Synthesis and Characterization of Radiogallium-Labeled Cationic Amphiphilic Peptides as Tumor Imaging Agents. Cancers (Basel) 2021; 13:cancers13102388. [PMID: 34069243 PMCID: PMC8155856 DOI: 10.3390/cancers13102388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 11/16/2022] Open
Abstract
SVS-1 is a cationic amphiphilic peptide (CAP) that exhibits a preferential cytotoxicity towards cancer cells over normal cells. In this study, we developed radiogallium-labeled SVS-1 (67Ga-NOTA-KV6), as well as two SVS-1 derivatives, with the repeating KV residues replaced by RV or HV (67Ga-NOTA-RV6 and 67Ga-NOTA-HV6). All three peptides showed high accumulation in epidermoid carcinoma KB cells (53-143% uptake/mg protein). Though 67Ga-NOTA-RV6 showed the highest uptake among the three CAPs, its uptake in 3T3-L1 fibroblasts was just as high, indicating a low selectivity. In contrast, the uptake of 67Ga-NOTA-KV6 and 67Ga-NOTA-HV6 into 3T3-L1 cells was significantly lower than that in KB cells. An endocytosis inhibition study suggested that the three 67Ga-NOTA-CAPs follow distinct pathways for internalization. In the biodistribution study, the tumor uptakes were found to be 4.46%, 4.76%, and 3.18% injected dose/g of tissue (% ID/g) for 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6, respectively, 30 min after administration. Though the radioactivity of these peptides in tumor tissue decreased gradually, 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6 reached high tumor/blood ratios (7.7, 8.0, and 3.8, respectively) and tumor/muscle ratios (5.0, 3.3, and 4.0, respectively) 120 min after administration. 67Ga-NOTA-HV6 showed a lower tumor uptake than the two other tracers, but it exhibited very low levels of uptake into peripheral organs. Overall, the replacement of lysine in SVS-1 with other basic amino acids significantly influenced its binding and internalization into cancer cells, as well as its in vivo pharmacokinetic profile. The high accessibility of these peptides to tumors and their ability to target the surface membranes of cancer cells make radiolabeled CAPs excellent candidates for use in tumor theranostics.
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Affiliation(s)
- Takeshi Fuchigami
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
- Correspondence: (T.F.); (M.N.); Tel.: +81-95-819-2442 (T.F.)
| | - Takeshi Chiga
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
| | - Sakura Yoshida
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
| | - Makoto Oba
- Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1–5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan;
| | - Yu Fukushima
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
| | - Hiromi Inoue
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
| | - Akari Matsuura
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
| | - Akira Toriba
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
| | - Morio Nakayama
- Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1–14 Bunkyo-machi, Nagasaki 852-8521, Japan; (T.C.); (S.Y.); (Y.F.); (H.I.); (A.M.); (A.T.)
- Correspondence: (T.F.); (M.N.); Tel.: +81-95-819-2442 (T.F.)
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13
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Houvast RD, Vankemmelbeke M, Durrant LG, Wuhrer M, Baart VM, Kuppen PJK, de Geus-Oei LF, Vahrmeijer AL, Sier CFM. Targeting Glycans and Heavily Glycosylated Proteins for Tumor Imaging. Cancers (Basel) 2020; 12:cancers12123870. [PMID: 33371487 PMCID: PMC7767531 DOI: 10.3390/cancers12123870] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Distinguishing malignancy from healthy tissue is essential for oncologic surgery. Targeted imaging during an operation aids the surgeon to operate better. The present tracers for detecting cancer are directed against proteins that are overexpressed on the membrane of tumor cells. This review evaluates the use of tumor-associated sugar molecules as an alternative for proteins to image cancer tissue. These sugar molecules are present as glycans on glycosylated membrane proteins and glycolipids. Due to their location and large numbers per cell, these sugar molecules might be better targets for tumor imaging than proteins. Abstract Real-time tumor imaging techniques are increasingly used in oncological surgery, but still need to be supplemented with novel targeted tracers, providing specific tumor tissue detection based on intra-tumoral processes or protein expression. To maximize tumor/non-tumor contrast, targets should be highly and homogenously expressed on tumor tissue only, preferably from the earliest developmental stage onward. Unfortunately, most evaluated tumor-associated proteins appear not to meet all of these criteria. Thus, the quest for ideal targets continues. Aberrant glycosylation of proteins and lipids is a fundamental hallmark of almost all cancer types and contributes to tumor progression. Additionally, overexpression of glycoproteins that carry aberrant glycans, such as mucins and proteoglycans, is observed. Selected tumor-associated glyco-antigens are abundantly expressed and could, thus, be ideal candidates for targeted tumor imaging. Nevertheless, glycan-based tumor imaging is still in its infancy. In this review, we highlight the potential of glycans, and heavily glycosylated proteoglycans and mucins as targets for multimodal tumor imaging by discussing the preclinical and clinical accomplishments within this field. Additionally, we describe the major advantages and limitations of targeting glycans compared to cancer-associated proteins. Lastly, by providing a brief overview of the most attractive tumor-associated glycans and glycosylated proteins in association with their respective tumor types, we set out the way for implementing glycan-based imaging in a clinical practice.
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Affiliation(s)
- Ruben D. Houvast
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Mireille Vankemmelbeke
- Scancell Limited, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (M.V.); (L.G.D.)
| | - Lindy G. Durrant
- Scancell Limited, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (M.V.); (L.G.D.)
- Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Victor M. Baart
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Lioe-Fee de Geus-Oei
- Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Biomedical Photonic Imaging Group, University of Twente, 7500 AE Enschede, The Netherlands
| | - Alexander L. Vahrmeijer
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Cornelis F. M. Sier
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
- Percuros BV, 2333 ZA Leiden, The Netherlands
- Correspondence: ; Tel.: +31-752662610
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14
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Thomas D, Rathinavel AK, Radhakrishnan P. Altered glycosylation in cancer: A promising target for biomarkers and therapeutics. Biochim Biophys Acta Rev Cancer 2020; 1875:188464. [PMID: 33157161 DOI: 10.1016/j.bbcan.2020.188464] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 10/08/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Glycosylation is a well-regulated cell and microenvironment specific post-translational modification. Several glycosyltransferases and glycosidases orchestrate the addition of defined glycan structures on the proteins and lipids. Recent advances and systemic approaches in glycomics have significantly contributed to a better understanding of instrumental roles of glycans in health and diseases. Emerging research evidence recognized aberrantly glycosylated proteins as the modulators of the malignant phenotype of cancer cells. The Cancer Genome Atlas has identified alterations in the expressions of glycosylation-specific genes that are correlated with cancer progression. However, the mechanistic basis remains poorly explored. Recent researches have shown that specific changes in the glycan structures are associated with 'stemness' and epithelial-to-mesenchymal transition of cancer cells. Moreover, epigenetic changes in the glycosylation pattern make the tumor cells capable of escaping immunosurveillance mechanisms. The deciphering roles of glycans in cancer emphasize that glycans can serve as a source for the development of novel clinical biomarkers. The ability of glycans in intervening various stages of tumor progression and the biosynthetic pathways involved in glycan structures constitute a promising target for cancer therapy. Advances in the knowledge of innovative strategies for identifying the mechanisms of glycan-binding proteins are hoped to hold great potential in cancer therapy. This review discusses the fundamental role of glycans in regulating tumorigenesis and tumor progression and provides insights into the influence of glycans in the current tactics of targeted therapies in the clinical setting.
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Affiliation(s)
- Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ashok Kumar Rathinavel
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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15
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Tran ENH, Day CJ, McCartney E, Poole J, Tse E, Jennings MP, Morona R. Shigella flexneri Targets Human Colonic Goblet Cells by O Antigen Binding to Sialyl-Tn and Tn Antigens via Glycan-Glycan Interactions. ACS Infect Dis 2020; 6:2604-2615. [PMID: 32926786 DOI: 10.1021/acsinfecdis.0c00178] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Shigella flexneri targets colonic cells in humans to initiate invasive infection processes that lead to dysentery, and direct interactions between their lipopolysaccharide O antigens and blood group A related glycans are involved in the cell adherence interactions. Here, we show that treatment with Tn and sialyl-Tn glycans, monoclonal antibodies and lectins reactive to Tn/sialyl-Tn, and luteolin (a Tn antigen synthesis inhibitor) all significantly inhibited S. flexneri adherence and invasion of cells in vitro. Surface plasmon resonance analysis showed that lipopolysaccharide O antigen had a high affinity interaction with Tn/sialyl-Tn. Immunofluorescence probing of human colon tissue with antibodies detected expression of Tn/sialyl-Tn by MUC2 producing goblet cells (GCs), and S. flexneri incubated with human colon tissue colocalized with GCs. Our findings demonstrate that S. flexneri targets GCs in the human colonic crypts via glycan-glycan interactions, establishing new insight into the infection process in humans.
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Affiliation(s)
- Elizabeth Ngoc Hoa Tran
- School of Biological Sciences, Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Christopher J. Day
- Institute for Glycomics, Griffith University, Gold Coast Campus, Brisbane, Queensland 4222, Australia
| | - Erin McCartney
- Gastroenterological/Hepatological Biobank, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia
| | - Jessica Poole
- Institute for Glycomics, Griffith University, Gold Coast Campus, Brisbane, Queensland 4222, Australia
| | - Edmund Tse
- Gastroenterological/Hepatological Biobank, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia
| | - Michael P. Jennings
- Institute for Glycomics, Griffith University, Gold Coast Campus, Brisbane, Queensland 4222, Australia
| | - Renato Morona
- School of Biological Sciences, Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia
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16
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Zhao H, Hayat H, Ma X, Fan D, Wang P, Moore A. Molecular imaging and deep learning analysis of uMUC1 expression in response to chemotherapy in an orthotopic model of ovarian cancer. Sci Rep 2020; 10:14942. [PMID: 32913224 PMCID: PMC7484755 DOI: 10.1038/s41598-020-71890-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Artificial Intelligence (AI) algorithms including deep learning have recently demonstrated remarkable progress in image-recognition tasks. Here, we utilized AI for monitoring the expression of underglycosylated mucin 1 (uMUC1) tumor antigen, a biomarker for ovarian cancer progression and response to therapy, using contrast-enhanced in vivo imaging. This was done using a dual-modal (magnetic resonance and near infrared optical imaging) uMUC1-specific probe (termed MN-EPPT) consisted of iron-oxide magnetic nanoparticles (MN) conjugated to a uMUC1-specific peptide (EPPT) and labeled with a near-infrared fluorescent dye, Cy5.5. In vitro studies performed in uMUC1-expressing human ovarian cancer cell line SKOV3/Luc and control uMUC1low ES-2 cells showed preferential uptake on the probe by the high expressor (n = 3, p < .05). A decrease in MN-EPPT uptake by SKOV3/Luc cells in vitro due to uMUC1 downregulation after docetaxel therapy was paralleled by in vivo imaging studies that showed a reduction in probe accumulation in the docetaxel treated group (n = 5, p < .05). The imaging data were analyzed using deep learning-enabled segmentation and quantification of the tumor region of interest (ROI) from raw input MRI sequences by applying AI algorithms including a blend of Convolutional Neural Networks (CNN) and Fully Connected Neural Networks. We believe that the algorithms used in this study have the potential to improve studying and monitoring cancer progression, amongst other diseases.
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Affiliation(s)
- Hongwei Zhao
- Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, Rm. 2022, East Lansing, MI, 48823, USA
- Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Gynecologic Oncology, Shanxi Provincial Cancer Hospital, Taiyuan, 030013, Shanxi, China
| | - Hasaan Hayat
- Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, Rm. 2022, East Lansing, MI, 48823, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, 48823, USA
| | - Xiaohong Ma
- Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, Rm. 2022, East Lansing, MI, 48823, USA
- Department of Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Daguang Fan
- Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, Rm. 2022, East Lansing, MI, 48823, USA
- Department of General Surgery, Shanxi People's Hospital, Taiyuan, 030012, Shanxi, China
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, Rm. 2022, East Lansing, MI, 48823, USA.
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI, 48823, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, Rm. 2022, East Lansing, MI, 48823, USA.
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Aptamers: a novel targeted theranostic platform for pancreatic ductal adenocarcinoma. Radiat Oncol 2020; 15:189. [PMID: 32758252 PMCID: PMC7409417 DOI: 10.1186/s13014-020-01624-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/17/2020] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely challenging disease with a high mortality rate and a short overall survival time. The poor prognosis can be explained by aggressive tumor growth, late diagnosis, and therapy resistance. Consistent efforts have been made focusing on early tumor detection and novel drug development. Various strategies aim at increasing target specificity or local enrichment of chemotherapeutics as well as imaging agents in tumor tissue. Aptamers have the potential to provide early detection and permit anti-cancer therapy with significantly reduced side effects. These molecules are in-vitro selected single-stranded oligonucleotides that form stable three-dimensional structures. They are capable of binding to a variety of molecular targets with high affinity and specificity. Several properties such as high binding affinity, the in vitro chemical process of selection, a variety of chemical modifications of molecular platforms for diverse function, non-immunoreactivity, modification of bioavailability, and manipulation of pharmacokinetics make aptamers attractive targets compared to conventional cell-specific ligands. To explore the potential of aptamers for early diagnosis and targeted therapy of PDAC - as single agents and in combination with radiotherapy - we summarize the generation process of aptamers and their application as biosensors, biomarker detection tools, targeted imaging tracers, and drug-delivery carriers. We are furthermore discussing the current implementation aptamers in clinical trials, their limitations and possible future utilization.
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18
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Wang S, You L, Dai M, Zhao Y. Mucins in pancreatic cancer: A well-established but promising family for diagnosis, prognosis and therapy. J Cell Mol Med 2020; 24:10279-10289. [PMID: 32745356 PMCID: PMC7521221 DOI: 10.1111/jcmm.15684] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/12/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Mucins are a family of multifunctional glycoproteins that mostly line the surface of epithelial cells in the gastrointestinal tract and exert pivotal roles in gut lubrication and protection. Pancreatic cancer is a lethal disease with poor early diagnosis, limited therapeutic effects, and high numbers of cancer‐related deaths. In this review, we introduce the expression profiles of mucins in the normal pancreas, pancreatic precursor neoplasia and pancreatic cancer. Mucins in the pancreas contribute to biological processes such as the protection, lubrication and moisturization of epithelial tissues. They also participate in the carcinogenesis of pancreatic cancer and are used as diagnostic biomarkers and therapeutic targets. Herein, we discuss the important roles of mucins that lead to the lethality of pancreatic adenocarcinoma, particularly MUC1, MUC4, MUC5AC and MUC16 in disease progression, and present a comprehensive analysis of the clinical application of mucins and their promising roles in cancer treatment to gain a better understanding of the role of mucins in pancreatic cancer.
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Affiliation(s)
- Shunda Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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19
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Sliker BH, Goetz BT, Barnes R, King H, Maurer HC, Olive KP, Solheim JC. HLA-B influences integrin beta-1 expression and pancreatic cancer cell migration. Exp Cell Res 2020; 390:111960. [PMID: 32194036 PMCID: PMC7182497 DOI: 10.1016/j.yexcr.2020.111960] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/13/2020] [Accepted: 03/14/2020] [Indexed: 12/22/2022]
Abstract
Human leukocyte antigen (HLA) class I molecules present antigenic peptides to cytotoxic T cells, causing lysis of malignant cells. Transplantation biology studies have implicated HLA class I molecules in cell migration, but there has been little evidence presented that they influence cancer cell migration, a contributing factor in metastasis. In this study, we examined the effect of HLA-B on pancreatic cancer cell migration. HLA-B siRNA transfection increased the migration of the S2-013 pancreatic cancer cells but, in contrast, reduced migration of the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. Integrin molecules have previously been implicated in the upregulation of pancreatic cancer cell migration, and knockdown of HLA-B in S2-013 cells heightened the expression of integrin beta 1 (ITGB1), but in the PANC-1 and MIA PaCa-2 cells HLA-B knockdown diminished ITGB1 expression. A transmembrane sequence in an S2-013 HLA-B heavy chain matches a corresponding sequence in HLA-B in the BxPC-3 pancreatic cancer cell line, and knockdown of BxPC-3 HLA-B mimics the effect of S2-013 HLA-B knockdown on migration. In total, our findings indicate that HLA-B influences the expression of ITGB1 in pancreatic cancer cells, with concurrent distinctions in transmembrane sequences and effects on the migration of the cells.
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Affiliation(s)
- Bailee H Sliker
- Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Benjamin T Goetz
- Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Raina Barnes
- Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Hannah King
- Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - H Carlo Maurer
- Columbia University Department of Medicine and the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - Kenneth P Olive
- Columbia University Department of Medicine and the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - Joyce C Solheim
- Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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20
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Pothuraju R, Krishn SR, Gautam SK, Pai P, Ganguly K, Chaudhary S, Rachagani S, Kaur S, Batra SK. Mechanistic and Functional Shades of Mucins and Associated Glycans in Colon Cancer. Cancers (Basel) 2020; 12:E649. [PMID: 32168759 PMCID: PMC7139953 DOI: 10.3390/cancers12030649] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/28/2020] [Accepted: 03/02/2020] [Indexed: 02/08/2023] Open
Abstract
Mucus serves as the chief protective barrier against pathogenic and mechanical insults in respiratory, gastrointestinal, and urogenital tracts. Altered mucin expression, the major component of mucus, in conjunction with differential glycosylation has been strongly associated with both benign and malignant pathologies of colon. Mucins and their associated glycans arbitrate their impact sterically as well as mechanically by altering molecular and microbial spectrum during pathogenesis. Mucin expression in normal and pathological conditions is regulated by nonspecific (dietary factors and gut microbiota) and specific (epigenetic and transcriptional) modulators. Further, recent studies highlight the impact of altering mucin glycome (cancer-associated carbohydrate antigens including Tn, Sialyl-Tn, Sialyl-Lew A, and Sialyl-Lewis X) on host immunomodulation, antitumor immunity, as well as gut microbiota. In light of emerging literature, the present review article digs into the impact of structural organization and of expressional and glycosylation alteration of mucin family members on benign and malignant pathologies of colorectal cancer.
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Affiliation(s)
- Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Shiv Ram Krishn
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Shailendra K. Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Priya Pai
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
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21
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Syrkina MS, Rubtsov MA. MUC1 in Cancer Immunotherapy - New Hope or Phantom Menace? BIOCHEMISTRY (MOSCOW) 2019; 84:773-781. [PMID: 31509728 DOI: 10.1134/s0006297919070083] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Understanding of the functioning of MUC1 (human mucin) has advanced significantly over 40 years of its investigation. The anti-adhesive properties of the extracellular domain, which were the main focus of early studies initially explaining overexpression of MUC1 in progressing oncological diseases, were gradually put on the back burner. Researchers became more interested in its regulatory and signaling functions in cells rather in its anti-adhesive properties. The found the ability of MUC1 for signal transduction, and its ability to participate in cell metabolism opened new possibilities for improved control over cancer cells in addition to just attracting antigens of the immune system to a target. Nevertheless, there are issues in the functioning of MUC1 that raise doubts about its effectiveness in cancer immunotherapy.
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Affiliation(s)
- M S Syrkina
- Lomonosov Moscow State University, Department of Biology, Moscow, 119234, Russia. .,Lomonosov Moscow State University, Laboratoire Franco-Russe de Recherches en Oncologie, Moscow, 119234, Russia
| | - M A Rubtsov
- Lomonosov Moscow State University, Department of Biology, Moscow, 119234, Russia. .,Lomonosov Moscow State University, Laboratoire Franco-Russe de Recherches en Oncologie, Moscow, 119234, Russia.,Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia
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22
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Caffrey T, Sagar S, Thomas D, Lewallen ME, Hollingsworth MA, Radhakrishnan P. The glycoprotein mucin-1 negatively regulates GalNAc transferase 5 expression in pancreatic cancer. FEBS Lett 2019; 593:2751-2761. [PMID: 31283009 PMCID: PMC7048170 DOI: 10.1002/1873-3468.13532] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/20/2019] [Accepted: 07/01/2019] [Indexed: 01/05/2023]
Abstract
Aberrant expression of the glycoprotein mucin-1 (MUC1) has been associated with pancreatic cancer progression and metastasis as a result of mediating the oncogenic transcriptional regulation of target genes. In the present study, we demonstrate that MUC1 downregulates the expression of the tumor suppressor polypeptide N-acetylgalactosaminyltransferase 5 in pancreatic cancer. ChIP-on-chip analysis revealed that the MUC1 cytoplasmic tail binds to regulatory elements in the GALNT5 gene. Additionally, MUC1 increases binding of p53 and c-Jun and decreases the binding of Sp1 to the proximal promoter and exonic regions of GALNT5. We also observed that expression of N-acetylgalactosaminyltransferase 5 is inversionally proportional to MUC1 expression in human pancreatic cancer. These results demonstrate that MUC1 downregulates the expression of N-acetylgalactosaminyltransferase 5 in pancreatic cancer by modifying the promoter occupancy of transcription factors through its cytoplasmic domain.
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Affiliation(s)
- Thomas Caffrey
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
| | - Satish Sagar
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
| | - Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
| | | | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
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Chen D, Zhou X, Chen X, Huang L, Xi X, Ma C, Zhou M, Wang L, Chen T. Evaluating the Bioactivity of a Novel Antimicrobial and Anticancer Peptide, Dermaseptin-PS4(Der-PS4), from the Skin Secretion of Phyllomedusa sauvagii. Molecules 2019; 24:molecules24162974. [PMID: 31426323 PMCID: PMC6719146 DOI: 10.3390/molecules24162974] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/11/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022] Open
Abstract
Dermaseptins belonging to a large family of cationic membrane-disruption antimicrobial peptides display extensive antibacterial and antiproliferative activities depending on a coil-to-helix transition and the specific structural parameters. Herein, a novel dermaseptin peptide named Der-PS4 was discovered from the skin secretion of the waxy monkey tree frog, Phyllomedusa sauvagii. The complementary DNA (cDNA)-encoding precursor was obtained relying on "shotgun" cloning, and afterwards, a mature peptide amino acid sequence was identified by reverse-phase high performance liquid chromatography (RP-HPLC) and MS/MS. Specimens were chemically synthesized and applied for further functional studies. Structural analysis demonstrated a higher α-helical content in the membrane-mimetic environment compared with that in the ammonium acetate/water circumstance. Der-PS4 displayed a broad spectrum of antimicrobial activities against tested pathogenic microorganisms, however, exhibiting slight membrane-damaging effectiveness towards horse red blood cells. Coincident with the inhibitory activities on pathogens, Der-PS4 also showed considerable biofilm eradicating impact. Also, Der-PS4 penetrated cell membrane in a relative short period under each minimum bactericidal concentration. In addition, Der-PS4 possessed antiproliferative capacity against five cancer cell lines, while presenting slight suppressing effect on human microvascular endothelial, HMEC-1. These findings provide a promising insight for the discovery and development of novel drugs from a natural source.
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Affiliation(s)
- Dong Chen
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
| | - Xiaowei Zhou
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
- Department of Nutrition, Henry Fok School of Food Science and Engineering, Shaoguan University, Shaoguan 512005, China
| | - Xi Chen
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
| | - Linyuan Huang
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK.
- School of Life Sciences and Technology, China Pharmaceutical University, Nanjing 211198, China.
| | - Xinping Xi
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK.
| | - Chengbang Ma
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
| | - Mei Zhou
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
| | - Lei Wang
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
| | - Tianbao Chen
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK
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24
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Wang W, Wang Y, Pan H, Cheddah S, Yan C. Aptamer-based fluorometric determination for mucin 1 using gold nanoparticles and carbon dots. Mikrochim Acta 2019; 186:544. [DOI: 10.1007/s00604-019-3516-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/18/2019] [Indexed: 12/12/2022]
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25
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Gasparini G, Pellegatta M, Crippa S, Lena MS, Belfiori G, Doglioni C, Taveggia C, Falconi M. Nerves and Pancreatic Cancer: New Insights into a Dangerous Relationship. Cancers (Basel) 2019; 11:E893. [PMID: 31248001 PMCID: PMC6678884 DOI: 10.3390/cancers11070893] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer-particularly in pancreatic ductal adenocarcinoma (PDAC)-PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously ("present" or "absent"). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.
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Affiliation(s)
- Giulia Gasparini
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Marta Pellegatta
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Stefano Crippa
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
| | - Marco Schiavo Lena
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Giulio Belfiori
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Claudio Doglioni
- Vita Salute San Raffaele University, 20132 Milan, Italy.
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Carla Taveggia
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Massimo Falconi
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
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26
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Syrkina MS, Vassetzky YS, Rubtsov MA. MUC1 Story: Great Expectations, Disappointments and the Renaissance. Curr Med Chem 2019; 26:554-563. [PMID: 28820070 DOI: 10.2174/0929867324666170817151954] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 07/03/2017] [Accepted: 07/03/2017] [Indexed: 11/22/2022]
Abstract
In the course of studying human mucin MUC1, the attitude towards this molecule has been changing time and again. Initially, the list of presumable functions of MUC1 was restricted to protecting and lubricating epithelium. To date, it is assumed to play an important role in cell signaling as well as in all stages of oncogenesis, from malignant cell transformation to tumor dissemination. The story of MUC1 is full of hopes and disappointments. However, the scientific interest to MUC1 has never waned, and the more profoundly it has been investigated, the clearer its hidden potential turned to be disclosed. The therapeutic potential of mucin MUC1 has already been noted by various scientific groups at the early stages of research. Over forty years ago, the first insights into MUC1 functions became a strong ground for considering this molecule as potential target for anticancer therapy. Therefore, this direction of research has always been of particular interest and practical importance. More than 200 papers on MUC1 were published in 2016; the majority of them are dedicated to MUC1-related anticancer diagnostics and therapeutics. Here we review the history of MUC1 studies from the very first attempts to reveal its functions to the ongoing renaissance.
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Affiliation(s)
- Marina S Syrkina
- Department of Molecular Biology, Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.,LIA LFR2O (LIA French-Russian Cancer Research laboratory) Villejuif, France - Moscow, Russian Federation.,Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Yegor S Vassetzky
- LIA LFR2O (LIA French-Russian Cancer Research laboratory) Villejuif, France - Moscow, Russian Federation.,UMR8126, Université Paris Sud - Paris Saclay, CNRS, Institut Gustave Roussy, 94805 Villejuif, France.,A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.,Koltzov Institute of Developmental Biology, Moscow, Russian Federation
| | - Mikhail A Rubtsov
- Department of Molecular Biology, Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.,LIA LFR2O (LIA French-Russian Cancer Research laboratory) Villejuif, France - Moscow, Russian Federation.,Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation.,Department of Biochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
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27
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Sliker BH, Goetz BT, Peters HL, Poelaert BJ, Borgstahl GEO, Solheim JC. Beta 2-microglobulin regulates amyloid precursor-like protein 2 expression and the migration of pancreatic cancer cells. Cancer Biol Ther 2019; 20:931-940. [PMID: 30810435 DOI: 10.1080/15384047.2019.1580414] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Beta 2-microglobulin (β2m) is a component of the major histocompatibility complex (MHC) class I molecule, which presents tumor antigens to T lymphocytes to trigger cancer cell destruction. Notably, β2m has been reported as persistently expressed, rather than down regulated, in some tumor types. For renal cell and oral squamous cell carcinomas, β2m expression has been linked to increased migratory capabilities. The migratory ability of pancreatic cancer cells contributes to their metastatic tendencies and lethal nature. Therefore, in this study, we examined the impact of β2m on pancreatic cancer cell migration. We found that β2m protein is amply expressed in several human pancreatic cancer cell lines (S2-013, PANC-1, and MIA PaCa-2). Reducing β2m expression by short interfering RNA (siRNA) transfection significantly slowed the migration of the PANC-1 and S2-013 cancer cell lines, but increased the migration of the MIA PaCa-2 cell line. The amyloid precursor-like protein 2 (APLP2) has been documented as contributing to pancreatic cancer cell migration, invasiveness, and metastasis. We have previously shown that β2m/HLA class I/peptide complexes associate with APLP2 in S2-013 cells, and in this study we also detected their association in PANC-1 cells but not MIA PaCa-2 cells. In addition, siRNA down regulation of β2m expression diminished the expression of APLP2 in S2-013 and PANC-1 but heightened the level of APLP2 in MIA PaCa-2 cells, consistent with our migration data and co-immunoprecipitation data. Thus, our findings indicate that β2m regulates pancreatic cancer cell migration, and furthermore suggest that APLP2 is an intermediary in this process.
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Affiliation(s)
- Bailee H Sliker
- a Eppley Institute for Research in Cancer and Allied Diseases , University of Nebraska Medical Center , Omaha , NE , USA.,b Fred and Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA
| | - Benjamin T Goetz
- a Eppley Institute for Research in Cancer and Allied Diseases , University of Nebraska Medical Center , Omaha , NE , USA.,b Fred and Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA
| | - Haley L Peters
- a Eppley Institute for Research in Cancer and Allied Diseases , University of Nebraska Medical Center , Omaha , NE , USA.,b Fred and Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA
| | - Brittany J Poelaert
- a Eppley Institute for Research in Cancer and Allied Diseases , University of Nebraska Medical Center , Omaha , NE , USA.,b Fred and Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA
| | - Gloria E O Borgstahl
- a Eppley Institute for Research in Cancer and Allied Diseases , University of Nebraska Medical Center , Omaha , NE , USA.,b Fred and Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.,c Department of Biochemistry and Molecular Biology , University of Nebraska Medical Center , Omaha , NE , USA.,d Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , NE , USA
| | - Joyce C Solheim
- a Eppley Institute for Research in Cancer and Allied Diseases , University of Nebraska Medical Center , Omaha , NE , USA.,b Fred and Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.,c Department of Biochemistry and Molecular Biology , University of Nebraska Medical Center , Omaha , NE , USA.,e Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA
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28
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Baindara P, Korpole S, Grover V. Bacteriocins: perspective for the development of novel anticancer drugs. Appl Microbiol Biotechnol 2018; 102:10393-10408. [PMID: 30338356 DOI: 10.1007/s00253-018-9420-8] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/26/2018] [Accepted: 09/26/2018] [Indexed: 11/26/2022]
Abstract
Antimicrobial peptides (AMPs) from prokaryotic source also known as bacteriocins are ribosomally synthesized by bacteria belonging to different eubacterial taxonomic branches. Most of these AMPs are low molecular weight cationic membrane active peptides that disrupt membrane by forming pores in target cell membranes resulting in cell death. While these peptides known to exhibit broad-spectrum antimicrobial activity, including antibacterial and antifungal, they displayed minimal cytotoxicity to the host cells. Their antimicrobial efficacy has been demonstrated in vivo using diverse animal infection models. Therefore, we have discussed some of the promising peptides for their ability towards potential therapeutic applications. Further, some of these bacteriocins have also been reported to exhibit significant biological activity against various types of cancer cells in different experimental studies. In fact, differential cytotoxicity towards cancer cells as compared to normal cells by certain bacteriocins directs for a much focused research to utilize these compounds as novel therapeutic agents. In this review, bacteriocins that demonstrated antitumor activity against diverse cancer cell lines have been discussed emphasizing their biochemical features, selectivity against extra targets and molecular mechanisms of action.
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Affiliation(s)
- Piyush Baindara
- MTCC and Gene Bank, CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh, India
| | - Suresh Korpole
- MTCC and Gene Bank, CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh, India
| | - Vishakha Grover
- Dr. HS Judge Dental Institute and Hospital, Punjab University, Sector 25, Chandigarh, 160014, India.
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29
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Aronson MR, Simonson AW, Orchard LM, Llinás M, Medina SH. Lipopeptisomes: Anticancer peptide-assembled particles for fusolytic oncotherapy. Acta Biomater 2018; 80:269-277. [PMID: 30240951 DOI: 10.1016/j.actbio.2018.09.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/28/2018] [Accepted: 09/17/2018] [Indexed: 12/31/2022]
Abstract
Anticancer peptides (ACPs) are cationic amphiphiles that preferentially kill cancer cells through folding-dependent membrane disruption. Although ACPs represent attractive therapeutic candidates, particularly against drug-resistant cancers, their successful translation into clinical practice has gone unrealized due to their poor bioavailability, serum instability and, most importantly, severe hemolytic toxicity. Here, we exploit the membrane-specific interactions of ACPs to prepare a new class of peptide-lipid particle, we term a lipopeptisome (LP). This design sequesters loaded ACPs within a lipid lamellar corona to avoid contact with red blood cells and healthy tissues, while affording potent lytic destruction of cancer cells following LP-membrane fusion. Biophysical studies show ACPs rapidly fold at, and integrate into, liposomal membranes to form stable LPs with high loading efficiencies (>80%). Rational design of the particles to possess lipid combinations mimicking that of the aberrant cancer cell outer leaflet allows LPs to rapidly fuse with tumor cell membranes and afford localized assembly of loaded ACPs within the bilayer. This leads to preferential fusolytic killing of cancer cells with minimal collateral toxicity towards non-cancerous cells and erythrocytes, thereby imparting clinically relevant therapeutic indices to otherwise toxic ACPs. Thus, integration of ACPs into self-assembled LPs represents a new delivery strategy to improve the therapeutic utility of oncolytic agents, and suggests this technology may be added to targeted combinatorial approaches in precision medicine. STATEMENT OF SIGNIFICANCE: Despite their significant clinical potential, the therapeutic utility of many ACPs has been limited by their collateral hemolysis during administration. Leveraging the membrane-specific interactions of ACPs, here we prepare self-assembled peptide-lipid nanoparticles, or 'lipopeptisomes' (LPs), capable of preferentially fusing with and lysing cancer cell membranes. Key to this fusolytic action is the construction of LPs from lipids simulating the cancer cell outer leaflet. This design recruits the oncolytic peptide payload into the carrier lamella and allows for selective destruction of cancer cells without disrupting healthy cells. Consequently, LPs impart clinically relevant therapeutic indexes to previously toxic ACPs, and thus open new opportunities to improve the clinical translation of oncolytics challenged by narrow therapeutic windows.
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Affiliation(s)
- Matthew R Aronson
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
| | - Andrew W Simonson
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
| | - Lindsey M Orchard
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Manuel Llinás
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA
| | - Scott H Medina
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
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30
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Chang T, Manabe Y, Fujimoto Y, Ohshima S, Kametani Y, Kabayama K, Nimura Y, Lin C, Fukase K. Syntheses and Immunological Evaluation of Self‐Adjuvanting Clustered
N
‐Acetyl and
N
‐Propionyl Sialyl‐Tn Combined with a T‐helper Cell Epitope as Antitumor Vaccine Candidates. Angew Chem Int Ed Engl 2018. [DOI: 10.1002/ange.201804437] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Tsung‐Che Chang
- Department of ChemistryGraduate School of ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
| | - Yoshiyuki Manabe
- Department of ChemistryGraduate School of ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
- Core for Medicine and Science Collaborative Research and EducationProject Research Center for Fundamental ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
| | - Yukari Fujimoto
- Department of ChemistryFaculty of Science and TechnologyKeio University 3-14-1 Hiyoshi Kohoku-ku Yokohama, Kanagawa 223-8522 Japan
| | - Shino Ohshima
- Faculty of MedicineSchool of MedicineTokai University 143 Shimokasuya, Isehara-shi Kanagawa 259-1193 Japan
| | - Yoshie Kametani
- Faculty of MedicineSchool of MedicineTokai University 143 Shimokasuya, Isehara-shi Kanagawa 259-1193 Japan
| | - Kazuya Kabayama
- Department of ChemistryGraduate School of ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
- Core for Medicine and Science Collaborative Research and EducationProject Research Center for Fundamental ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
| | - Yuka Nimura
- Department of ChemistryGraduate School of ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
| | - Chun‐Cheng Lin
- Department of ChemistryNational Tsing Hua University 101 Sec. 2, Kuang Fu Rd. Hsinchu 30013 Taiwan
| | - Koichi Fukase
- Department of ChemistryGraduate School of ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
- Core for Medicine and Science Collaborative Research and EducationProject Research Center for Fundamental ScienceOsaka University 1-1 Machikaneyama, Toyonaka Osaka 560-0043 Japan
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31
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Chang TC, Manabe Y, Fujimoto Y, Ohshima S, Kametani Y, Kabayama K, Nimura Y, Lin CC, Fukase K. Syntheses and Immunological Evaluation of Self-Adjuvanting Clustered N-Acetyl and N-Propionyl Sialyl-Tn Combined with a T-helper Cell Epitope as Antitumor Vaccine Candidates. Angew Chem Int Ed Engl 2018; 57:8219-8224. [PMID: 29768704 DOI: 10.1002/anie.201804437] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/14/2018] [Indexed: 01/08/2023]
Abstract
Sialyl-Tn (STn) is a tumor-associated carbohydrate antigen (TACA) rarely observed on healthy tissues. We synthesized two fully synthetic N-acetyl and N-propionyl STn trimer (triSTn) vaccines possessing a T-helper epitope and a TLR2 agonist, since the clustered STn antigens are highly expressed on many cancer cells. Immunization of both vaccines in mice induced the anti-triSTn IgG antibodies, which recognized triSTn-expressing cell lines PANC-1 and HepG2. The N-propionyl triSTn vaccine induced the triSTn-specific IgGs, while IgGs induced by the N-acetyl triSTn vaccine were less specific. These results illustrated that N-propionyl triSTn is a valuable unnatural TACA for anticancer vaccines.
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Affiliation(s)
- Tsung-Che Chang
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Yoshiyuki Manabe
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.,Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Yukari Fujimoto
- Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Shino Ohshima
- Faculty of Medicine, School of Medicine, Tokai University, 143 Shimokasuya, Isehara-shi, Kanagawa, 259-1193, Japan
| | - Yoshie Kametani
- Faculty of Medicine, School of Medicine, Tokai University, 143 Shimokasuya, Isehara-shi, Kanagawa, 259-1193, Japan
| | - Kazuya Kabayama
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.,Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Yuka Nimura
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Chun-Cheng Lin
- Department of Chemistry, National Tsing Hua University, 101 Sec. 2, Kuang Fu Rd., Hsinchu, 30013, Taiwan
| | - Koichi Fukase
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.,Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
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32
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Wu ST, Fowler AJ, Garmon CB, Fessler AB, Ogle JD, Grover KR, Allen BC, Williams CD, Zhou R, Yazdanifar M, Ogle CA, Mukherjee P. Treatment of pancreatic ductal adenocarcinoma with tumor antigen specific-targeted delivery of paclitaxel loaded PLGA nanoparticles. BMC Cancer 2018; 18:457. [PMID: 29685122 PMCID: PMC5914049 DOI: 10.1186/s12885-018-4393-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 04/17/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDA) remains the most aggressive cancers with a 5-year survival below 10%. Systemic delivery of chemotherapy drugs has severe side effects in patients with PDA and does not significantly improve overall survival rate. It is highly desirable to advance the therapeutic efficacy of chemotherapeutic drugs by targeting their delivery and increasing accumulation at the tumor site. MUC1 is a membrane-tethered glycoprotein that is aberrantly overexpressed in > 80% of PDA thus making it an attractive antigenic target. METHODS Poly lactic-co-glycolic acid nanoparticles (PLGA NPs) conjugated to a tumor specific MUC1 antibody, TAB004, was used as a nanocarrier for targeted delivery into human PDA cell lines in vitro and in PDA tumors in vivo. The PLGA NPs were loaded with fluorescent imaging agents, fluorescein diacetate (FDA) and Nile Red (NR) or isocyanine green (ICG) for in vitro and in vivo imaging respectively or with a chemotherapeutic drug, paclitaxel (PTX) for in vitro cytotoxicity assays. Confocal microscopy was used to visualize internalization of the nanocarrier in vitro in PDA cells with high and low MUC1 expression. The in vivo imaging system (IVIS) was used to visualize in vivo tumor targeting of the nanocarrier. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was used to determine in vitro cell survival of cells treated with PTX-loaded nanocarrier. One-sided t-test comparing treatment groups at each concentration and two-way ANOVAs comparing internalization of antibody and PLGA nanoparticles. RESULTS In vitro, TAB004-conjugated ICG-nanocarriers were significantly better at internalizing in PDA cells than its non-conjugated counterpart. Similarly, TAB004-conjugated PTX-nanocarriers were significantly more cytotoxic in vitro against PDA cells than its non-conjugated counterpart. In vivo, TAB004-conjugated ICG-nanocarriers showed increased accumulation in the PDA tumor compared to the non-conjugated nanocarrier while sparing normal organs. CONCLUSIONS The study provides promising data for future development of a novel MUC1-targeted nanocarrier for direct delivery of imaging agents or drugs into the tumor microenvironment.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/chemistry
- Antineoplastic Agents, Immunological/pharmacokinetics
- Biomarkers, Tumor
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cell Survival
- Disease Models, Animal
- Drug Liberation
- Endocytosis
- Female
- Gene Expression
- Humans
- Mice
- Molecular Targeted Therapy
- Mucin-1/immunology
- Nanoparticles/chemistry
- Nanoparticles/ultrastructure
- Paclitaxel/administration & dosage
- Paclitaxel/chemistry
- Paclitaxel/pharmacokinetics
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/pathology
- Polyethylene Glycols/chemistry
- Polylactic Acid-Polyglycolic Acid Copolymer
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Shu-ta Wu
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Anthony J. Fowler
- Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Corey B. Garmon
- Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Adam B. Fessler
- Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Joshua D. Ogle
- Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Kajal R. Grover
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Bailey C. Allen
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Chandra D. Williams
- Department of Animal Laboratory Resources, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Ru Zhou
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Mahboubeh Yazdanifar
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Craig A. Ogle
- Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Pinku Mukherjee
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223 USA
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33
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Pearce OMT. Cancer glycan epitopes: biosynthesis, structure and function. Glycobiology 2018; 28:670-696. [DOI: 10.1093/glycob/cwy023] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 03/09/2018] [Indexed: 12/13/2022] Open
Affiliation(s)
- Oliver M T Pearce
- Centre for Cancer & Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
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Wu ST, Williams CD, Grover PA, Moore LJ, Mukherjee P. Early detection of pancreatic cancer in mouse models using a novel antibody, TAB004. PLoS One 2018; 13:e0193260. [PMID: 29462213 PMCID: PMC5819830 DOI: 10.1371/journal.pone.0193260] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 02/07/2018] [Indexed: 01/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is the fourth-leading cause of cancer death in the United States with a 5-year overall survival rate of 8% for all stages combined. But this decreases to 3% for the majority of patients that present with stage IV PDA at time of diagnosis. The lack of distinct early symptoms for PDA is one of the primary reasons for the late diagnosis. Common symptoms like weight loss, abdominal and back pains, and jaundice are often mistaken for symptoms of other issues and do not appear until the cancer has progressed to a late stage. Thus the development of novel imaging platforms for PDA is crucial for the early detection of the disease. MUC1 is a tumor-associated antigen (tMUC1) expressed on 80% of PDA. The goal of this study was to determine the targeting and detection capabilities of a tMUC1 specific antibody, TAB004. TAB004 antibody conjugated to a near infrared fluorescent probe was injected intraperitoneally into immune competent orthotopic and spontaneous models of PDA. Results show that fluorophore conjugated TAB004 specifically targets a) 1 week old small tumor in the pancreas in an orthotopic PDA model and b) very early pre-neoplastic lesions (PanIN lesions) that develop in the spontaneous PDA model before progression to adenocarcinoma. Thus, TAB004 is a promising antibody to deliver imaging agents directly to the pancreatic tumor microenvironment, significantly affecting early detection of PDA.
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Affiliation(s)
- Shu-ta Wu
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America
| | - Chandra D. Williams
- Department of Animal Laboratory Resources, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America
| | - Priyanka A. Grover
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America
| | - Laura J. Moore
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America
| | - Pinku Mukherjee
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America
- * E-mail:
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Balmaña M, Duran A, Gomes C, Llop E, López-Martos R, Ortiz MR, Barrabés S, Reis CA, Peracaula R. Analysis of sialyl-Lewis x on MUC5AC and MUC1 mucins in pancreatic cancer tissues. Int J Biol Macromol 2018; 112:33-45. [PMID: 29408556 DOI: 10.1016/j.ijbiomac.2018.01.148] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 01/18/2018] [Accepted: 01/21/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic adenocarcinoma (PDAC) lacks efficient biomarkers. Mucins are glycoproteins that can carry aberrant glycosylation in cancer. Our objective was to identify cancer-related glycan epitopes on MUC1 and MUC5AC mucins in PDAC as potential biomarkers. We have analysed the tumour-associated carbohydrate antigens sialyl-Lewis x (SLex) and sialyl-Tn (STn) on MUC1 and MUC5AC in PDAC tissues. The selected cohort for this study consisted of twenty-one PDAC tissues positive for SLex antigen and three normal pancreas specimens as controls. STn expression was shown in 76% of the PDAC tissues. MUC1 and MUC5AC were detected in 90% of PDAC tissues. We performed in situ proximity ligation assay combining antibodies against mucins and glycan epitopes to identify specific mucin glycoforms. MUC1-SLex and MUC5AC-SLex were found in 68% and 84% respectively, of the mucin expressing PDAC tissues, while STn hardly colocalized with any of the evaluated mucins. Further analysis by Western blot of MUC5AC and SLex in eight PDAC tissue lysates showed that six out of eight cases were positive for both markers. Moreover, immunoprecipitation of MUC5AC from positive PDAC tissues and subsequent SLex immunodetection confirmed the presence of SLex on MUC5AC. Altogether, MUC5AC-SLex glycoform is present in PDAC and can be regarded as potential biomarker.
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Affiliation(s)
- Meritxell Balmaña
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain; Instituto de Investigação e Inovação em Saúde, I3S, Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Porto, Portugal
| | - Adrià Duran
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain
| | - Catarina Gomes
- Instituto de Investigação e Inovação em Saúde, I3S, Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Porto, Portugal
| | - Esther Llop
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain
| | - Raquel López-Martos
- Department of Anatomic Pathology, Dr. Trueta University Hospital, Girona, Spain
| | - M Rosa Ortiz
- Department of Anatomic Pathology, Dr. Trueta University Hospital, Girona, Spain
| | - Sílvia Barrabés
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain
| | - Celso A Reis
- Instituto de Investigação e Inovação em Saúde, I3S, Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Porto, Portugal; Medical Faculty, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar - ICBAS, University of Porto, Porto, Portugal.
| | - Rosa Peracaula
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain.
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Hanson RL, Brown RB, Steele MM, Grandgenett PM, Grunkemeyer JA, Hollingsworth MA. Identification of FRA-1 as a novel player in pancreatic cancer in cooperation with a MUC1: ERK signaling axis. Oncotarget 2018; 7:39996-40011. [PMID: 27220889 PMCID: PMC5129987 DOI: 10.18632/oncotarget.9557] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 05/10/2016] [Indexed: 11/25/2022] Open
Abstract
The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases.
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Affiliation(s)
- Ryan L Hanson
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Roger B Brown
- University of New Mexico, Albuquerque, NM 87131, USA
| | - Maria M Steele
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - James A Grunkemeyer
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Hori SI, Herrera A, Rossi JJ, Zhou J. Current Advances in Aptamers for Cancer Diagnosis and Therapy. Cancers (Basel) 2018; 10:cancers10010009. [PMID: 29301363 PMCID: PMC5789359 DOI: 10.3390/cancers10010009] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 12/22/2017] [Accepted: 12/26/2017] [Indexed: 12/24/2022] Open
Abstract
Nucleic acid aptamers are single-stranded oligonucleotides that interact with target molecules with high affinity and specificity in unique three-dimensional structures. Aptamers are generally isolated by a simple selection process called systematic evolution of ligands by exponential enrichment (SELEX) and then can be chemically synthesized and modified. Because of their high affinity and specificity, aptamers are promising agents for biomarker discovery, as well as cancer diagnosis and therapy. In this review, we present recent progress and challenges in aptamer and SELEX technology and highlight some representative applications of aptamers in cancer therapy.
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Affiliation(s)
- Shin-Ichiro Hori
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
- Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
| | - Alberto Herrera
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
| | - John J Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
| | - Jiehua Zhou
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
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Rothan HA, Ambikabothy J, Ramasamy TS, Rashid NN, Yusof R. A Preliminary Study in Search of Potential Peptide Candidates for a Combinational Therapy with Cancer Chemotherapy Drug. Int J Pept Res Ther 2017. [DOI: 10.1007/s10989-017-9646-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Idowu T, Samadder P, Arthur G, Schweizer F. Amphiphilic Modulation of Glycosylated Antitumor Ether Lipids Results in a Potent Triamino Scaffold against Epithelial Cancer Cell Lines and BT474 Cancer Stem Cells. J Med Chem 2017; 60:9724-9738. [DOI: 10.1021/acs.jmedchem.7b01198] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Temilolu Idowu
- Department
of Chemistry, Faculty of Science, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada
| | - Pranati Samadder
- Department
of Biochemistry and Medical Genetics, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada
| | - Gilbert Arthur
- Department
of Biochemistry and Medical Genetics, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada
| | - Frank Schweizer
- Department
of Chemistry, Faculty of Science, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada
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40
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Kuzmin DV, Emelianova AA, Kalashnikova MB, Panteleev PV, Balandin SV, Serebrovskaya EO, Belogurova-Ovchinnikova OY, Ovchinnikova TV. Comparative in vitro study on cytotoxicity of recombinant β-hairpin peptides. Chem Biol Drug Des 2017; 91:294-303. [PMID: 28815904 DOI: 10.1111/cbdd.13081] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 07/19/2017] [Accepted: 07/27/2017] [Indexed: 02/06/2023]
Abstract
Natural antimicrobial peptides (AMPs) are important components of the innate immune system with a wide spectrum of biological activity. In this study, we investigated the cytotoxic effect of three recombinant β-hairpin cationic AMPs: arenicin-1 from the polychaeta Arenicola marina, tachyplesin I from the horseshoe crab Tachypleus tridentatus, and gomesin from the spider Acanthoscurria gomesiana. All the three β-hairpin AMPs were overexpressed in Escherichia coli. Different cell lines were incubated with various concentrations of the investigated AMPs in order to evaluate their cytotoxic activity. Double staining with subsequent flow cytometric analysis was used to determine the predominant way of cell death mediated by each AMP. Hemolytic activity of the peptides was tested against fresh human red blood cells. Our results indicated that all the three AMPs exhibited significant cytotoxic effect against cancer cells that varied depending on the cell line type and, in most cases, on the presence of serum components. Flow cytometric analysis implicitly indicated that tachyplesin I mostly promoted late apoptosis/necrosis, while arenicin-1 and gomesin induced early apoptosis under the same conditions. Tachyplesin I proved to be the most promising therapeutic candidate as it displayed the highest specific cytotoxicity against cancer cell lines, independent of the serum presence.
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Affiliation(s)
- Denis V Kuzmin
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Anna A Emelianova
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Mariana B Kalashnikova
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Pavel V Panteleev
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Sergey V Balandin
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Ekaterina O Serebrovskaya
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | | | - Tatiana V Ovchinnikova
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
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41
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Shinagawa T, Hoshino H, Taga M, Sakai Y, Imamura Y, Yokoyama O, Kobayashi M. Clinicopathological implications to micropapillary bladder urothelial carcinoma of the presence of sialyl Lewis X-decorated mucin 1 in stroma-facing membranes. Urol Oncol 2017; 35:606.e17-606.e23. [PMID: 28666720 DOI: 10.1016/j.urolonc.2017.06.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/01/2017] [Accepted: 06/01/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Bladder urothelial carcinoma (UC) comprises more than 90% of all bladder cancers. Among several UC variants, micropapillary UC (MPUC) is a rare one with high potential for lymphovascular invasion and subsequent lymph node metastasis. Histologically, MPUC is characterized by the presence of small papillary carcinoma cell clusters surrounded by lacunar spaces. Immunohistochemically, the outer circumference of these clusters, that is, the stroma-facing membrane of carcinoma cells, is reportedly almost invariably positive for mucin 1 (MUC1) protein and to a lesser extent for sialyl Lewis X (sLeX) carbohydrates; however, the clinicopathological implications of these expression patterns have not been fully investigated. MATERIALS AND METHODS We performed immunohistochemical analysis of MPUC (n = 11) and conventional UC (n = 57) for MUC1 and sLeX to determine whether these factors immunolocalized. Dual immunofluorescence staining was also carried out to assess MUC1 and sLeX colocalization. We also performed Western blot analysis of Chinese hamster ovary cells misexpressing both recombinant epitope-tagged MUC1 and glycosyltransferases enabling sLeX biosynthesis. RESULTS MPUC samples preferentially exhibited both MUC1 protein and sLeX carbohydrate expression on the stroma-facing membrane of carcinoma cells. Based on univariate analysis, MUC1 expression in that pattern was positively correlated with tumor extension, lymphovascular invasion, lymph node metastasis, disease stage, and relatively poor patient prognosis. A comparable sLeX expression pattern also correlated positively with tumor extension and nodal metastasis. Based on multivariate analysis, localization of MUC1 and sLeX on the stroma-facing side of the membrane was positively correlated with lymph node metastasis. CONCLUSIONS Overall, our immunofluorescence findings as well as immunoprecipitation analyses of Chinese hamster ovary cell transfectants strongly suggest that MUC1 is a potential scaffold protein for sLeX carbohydrates in MPUC. Both MUC1 and sLeX may cooperatively contribute to MPUC histogenesis and clinicopathological characteristics.
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Affiliation(s)
- Tomochika Shinagawa
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Department of Urology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Hitomi Hoshino
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Minekatsu Taga
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Department of Urology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Yasuhiro Sakai
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Yoshiaki Imamura
- Division of Surgical Pathology, University of Fukui Hospital, Eiheiji, Japan
| | - Osamu Yokoyama
- Department of Urology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Motohiro Kobayashi
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
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Syrkina MS, Maslakova AA, Potashnikova DM, Veiko VP, Vassetzky YS, Rubtsov MA. Dual Role of the Extracellular Domain of Human Mucin MUC1 in Metastasis. J Cell Biochem 2017; 118:4002-4011. [PMID: 28407289 DOI: 10.1002/jcb.26056] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022]
Abstract
Human mucin MUC1 plays an important role in cancer development. The increased level of this molecule expression during cancer cell progression induces metastasis and is associated with poor prognosis for patients. There is a large body of experimental data on the role of various functional domains of human mucin MUC1 in metastasis. While, the cytoplasmic domain determined to play a definitive role, the influence of extracellular domain on cancer cell invasiveness still remains unclear. The present paper reveals that the extracellular domain of MUC1 molecule consists of two functional subdomains-the region of tandem repeats (TR) and the region of irregular repeats (IR). We demonstrate the ability of each of these subdomains to alter the invasiveness of cancer cells. The presence of the MUC1 molecules containing TR subdomain (MUC1-TR) on the surface of low-invasive cancer cells leads to the increase in their transendothelial migration potency, while the addition of the IR subdomain to the MUC1-TR molecule (MUC1-IR-TR) restores their natural low invasiveness. J. Cell. Biochem. 118: 4002-4011, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- M S Syrkina
- Faculty of Biology, Department of Molecular Biology, M.V. Lomonosov Moscow State University, Moscow, Russia.,LIA 1066 French-Russian Joint Cancer Research Laboratory, Villejuif, France
| | - A A Maslakova
- Faculty of Biology, Department of Human and Animal Physiology, M.V. Lomonosov Moscow State University, Moscow, Russia
| | - D M Potashnikova
- Faculty of Biology, Department of Cell Biology and Histology, M.V. Lomonosov Moscow State University, Moscow, Russia
| | - V P Veiko
- Bach Institute of Biochemistry, Biotechnology Research Center, Russian Academy of Sciences, Moscow, Russia
| | - Y S Vassetzky
- LIA 1066 French-Russian Joint Cancer Research Laboratory, Villejuif, France.,UMR8126, Université Paris Sud-Paris Saclay, CNRS, Institut Gustave Roussy, Villejuif, France.,A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russia.,Koltzov Institute of Developmental Biology, Moscow, Russia
| | - M A Rubtsov
- Faculty of Biology, Department of Molecular Biology, M.V. Lomonosov Moscow State University, Moscow, Russia.,LIA 1066 French-Russian Joint Cancer Research Laboratory, Villejuif, France.,Department of Biochemistry/Strategic Management, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers. BIOLOGY 2017; 6:biology6010016. [PMID: 28241499 PMCID: PMC5372009 DOI: 10.3390/biology6010016] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/17/2017] [Accepted: 02/20/2017] [Indexed: 12/20/2022]
Abstract
The tetrasaccharide structures Siaα2,3Galβ1,3(Fucα1,4)GlcNAc and Siaα2,3Galβ1,4(Fucα1,3)GlcNAc constitute the epitopes of the carbohydrate antigens sialyl-Lewis a (sLea) and sialyl-Lewis x (sLex), respectively, and are the minimal requirement for selectin binding to their counter-receptors. Interaction of sLex expressed on the cell surface of leucocytes with E-selectin on endothelial cells allows their arrest and promotes their extravasation. Similarly, the rolling of cancer cells ectopically expressing the selectin ligands on endothelial cells is potentially a crucial step favoring the metastatic process. In this review, we focus on the biosynthetic steps giving rise to selectin ligand expression in cell lines and native tissues of gastrointestinal origin, trying to understand whether and how they are deregulated in cancer. We also discuss the use of such molecules in the diagnosis of gastrointestinal cancers, particularly in light of recent data questioning the ability of colon cancers to express sLea and the possible use of circulating sLex in the early detection of pancreatic cancer. Finally, we reviewed the data dealing with the mechanisms that link selectin ligand expression in gastrointestinal cells to cancer malignancy. This promising research field seems to require additional data on native patient tissues to reach more definitive conclusions.
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44
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Strzelecka P, Czaplinska D, Sadej R, Wardowska A, Pikula M, Lesner A. Simplified, serine-rich theta-defensin analogues as antitumour peptides. Chem Biol Drug Des 2017; 90:52-63. [PMID: 28004513 DOI: 10.1111/cbdd.12927] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 12/05/2016] [Accepted: 12/10/2016] [Indexed: 01/15/2023]
Abstract
θ-defensins belong to the family of host defence peptides. They are the only known example of cyclic polypeptides in animal proteomes. This study presents the synthesis of simplified θ-defensin analogues with pairs of cysteine replaced either by alanine, leucine or serine residues. Cytotoxicity tests were performed on human mammary epithelial (HB2) and breast cancer (SKBR3, MDA-MB-231) cell lines to determine whether peptides are selectively targeting cancer cells. The effect of these peptides was also evaluated in 3D Matrigel cultures, which are based on extracellular matrix components and therefore closely represent in vivo conditions. Finally, to determine whether analogues are able to sensitize MDA-MB-231 triple-negative breast cancer cells to chemotherapeutics, we co-administrated peptides with cisplatin or doxorubicin hydrochloride also in 3D Matrigel cultures. Additionally, cytotoxicity towards peripheral blood mononuclear cells and haemolytic effect were examined for a chosen representative of synthesized compounds. The results showed that positively charged serine-containing θ-defensin derivatives were more cytotoxic towards breast cancer cells (SKBR3, MDA-MB-231) than towards mammary epithelial cells (HB2). Analogues enhanced the effect of cisplatin and doxorubicin hydrochloride on triple-negative breast cancer cell line (MDA-MB-231).
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Affiliation(s)
- Paulina Strzelecka
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
| | - Dominika Czaplinska
- Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland
| | - Rafal Sadej
- Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland
| | - Anna Wardowska
- Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Michal Pikula
- Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Adam Lesner
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
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van Putten JPM, Strijbis K. Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer. J Innate Immun 2017; 9:281-299. [PMID: 28052300 DOI: 10.1159/000453594] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Accepted: 11/19/2016] [Indexed: 12/18/2022] Open
Abstract
Mucosal surfaces line our body cavities and provide the interaction surface between commensal and pathogenic microbiota and the host. The barrier function of the mucosal layer is largely maintained by gel-forming mucin proteins that are secreted by goblet cells. In addition, mucosal epithelial cells express cell-bound mucins that have both barrier and signaling functions. The family of transmembrane mucins consists of diverse members that share a few characteristics. The highly glycosylated extracellular mucin domains inhibit invasion by pathogenic bacteria and can form a tight mesh structure that protects cells in harmful conditions. The intracellular tails of transmembrane mucins can be phosphorylated and connect to signaling pathways that regulate inflammation, cell-cell interactions, differentiation, and apoptosis. Transmembrane mucins play important roles in preventing infection at mucosal surfaces, but are also renowned for their contributions to the development, progression, and metastasis of adenocarcinomas. In general, transmembrane mucins seem to have evolved to monitor and repair damaged epithelia, but these functions can be highjacked by cancer cells to yield a survival advantage. This review presents an overview of the current knowledge of the functions of transmembrane mucins in inflammatory processes and carcinogenesis in order to better understand the diverse functions of these multifunctional proteins.
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Affiliation(s)
- Jos P M van Putten
- Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands
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Thind K, Padrnos LJ, Ramanathan RK, Borad MJ. Immunotherapy in pancreatic cancer treatment: a new frontier. Therap Adv Gastroenterol 2017; 10:168-194. [PMID: 28286568 PMCID: PMC5330603 DOI: 10.1177/1756283x16667909] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy. Novel therapies targeting the tumor microenvironment with an aim to decrease this resistance, improve immune tolerance and increase the efficacy of the current treatment have shown some promising preliminary results in preclinical and clinical trials. We review the current advances in the field of immunotherapy and their effectiveness as a potential treatment strategy in the pancreatic cancer.
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Affiliation(s)
- Komal Thind
- Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH, USA
| | - Leslie J. Padrnos
- Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | - Mitesh J. Borad
- Division of Hematology/Oncology, Mayo Clinic Arizona, 5777 E. Mayo Boulevard, Phoenix, AZ 85054, USA
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Hoshino H, Ohta M, Ito M, Uchimura K, Sakai Y, Uehara T, Low S, Fukushima M, Kobayashi M. Apical membrane expression of distinct sulfated glycans represents a novel marker of cholangiolocellular carcinoma. J Transl Med 2016; 96:1246-1255. [PMID: 27748735 DOI: 10.1038/labinvest.2016.104] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 08/25/2016] [Accepted: 08/30/2016] [Indexed: 12/31/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver neoplasm, followed by hepatocellular carcinoma. ICC can be further subclassified as (i) perihilar and (ii) peripheral types, the latter histologically resembling small-sized intrahepatic bile ducts, such as interlobular bile ducts, cholangioles/ductules and the canals of Hering. Cholangiolocellular carcinoma (CoCC), now classified by the World Health Organization as a subtype of combined hepatocellular-cholangiocarcinoma, is currently regarded as a subtype of peripheral-type ICC. The present study was undertaken to determine whether sulfated glycans recognized by the MECA-79 monoclonal antibody could serve as a CoCC marker. Using immunohistochemistry, we show that MECA-79 sulfated glycans are preferentially expressed at the apical membrane of cholangiocytes found in small-sized intrahepatic bile ducts in normal liver and in canalicular structures formed in CoCC. We also report that apical membrane MECA-79 sulfated glycan expression colocalizes with that of mucin 1 (MUC1) core proteins. We also present immunoblotting of Chinese hamster ovary cells overexpressing FLAG-tagged MUC1 to show that MUC1 serves as a MECA-79 scaffold. Furthermore, we report that SSP-25 human ICC cells overexpressing N-acetylglucosamine-6-O-sulfotransferase 2 (GlcNAc6ST-2), but not GlcNAc6ST-1, exhibit membrane expression of MECA-79 sulfated glycans, suggesting that GlcNAc6ST-2 catalyzes MECA-79 epitope biosynthesis in cholangiocytes. Moreover, both wild-type and GlcNAc6ST-1 knockout mice exhibit apical membrane MECA-79 expression in small-sized intrahepatic bile ducts, namely interlobular bile ducts, whereas MECA-79 expression was completely absent in comparable tissues from GlcNAc6ST-1 and GlcNAc6ST-2 double knockout mice. These data collectively indicate that apical membrane localization of MUC1 proteins decorated with GlcNAc6ST-2-dependent MECA-79 sulfated glycans may mark cholangiocytes with cholangiolar/ductular differentiation and could serve as a useful CoCC marker.
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MESH Headings
- Animals
- Antigens, Surface/biosynthesis
- Antigens, Surface/chemistry
- Antigens, Surface/metabolism
- Antigens, Tumor-Associated, Carbohydrate/biosynthesis
- Bile Duct Neoplasms/metabolism
- Bile Duct Neoplasms/pathology
- Bile Ducts, Intrahepatic/metabolism
- Bile Ducts, Intrahepatic/pathology
- Biomarkers, Tumor/metabolism
- CHO Cells
- Cell Line, Tumor
- Cell Membrane/metabolism
- Cell Membrane/pathology
- Cell Polarity
- Cholangiocarcinoma/metabolism
- Cholangiocarcinoma/pathology
- Cricetinae
- Cricetulus
- Humans
- Isoenzymes/genetics
- Isoenzymes/metabolism
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Membrane Proteins/biosynthesis
- Membrane Proteins/chemistry
- Mice, Knockout
- Mucin-1/genetics
- Mucin-1/metabolism
- Polysaccharides/biosynthesis
- Polysaccharides/metabolism
- Protein Transport
- Recombinant Proteins/metabolism
- Sulfotransferases/genetics
- Sulfotransferases/metabolism
- Sulfuric Acid Esters/metabolism
- Carbohydrate Sulfotransferases
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Affiliation(s)
- Hitomi Hoshino
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Makoto Ohta
- Department of Pathology, Fukui Red Cross Hospital, Fukui, Japan
| | - Makoto Ito
- Department of Pathology and Laboratory Medicine, Kariya Toyota General Hospital, Kariya, Japan
| | - Kenji Uchimura
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Sakai
- Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shulin Low
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Mana Fukushima
- Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Motohiro Kobayashi
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
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Moschovis D, Bamias G, Delladetsima I. Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol 2016; 8:725-734. [PMID: 27795812 PMCID: PMC5064050 DOI: 10.4251/wjgo.v8.i10.725] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/19/2016] [Accepted: 08/16/2016] [Indexed: 02/05/2023] Open
Abstract
Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.
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MUC1 (VPM654 and EPR1023) Expression in Mucosa of Fallopian Tubes With Ectopic Pregnancy is Altered. Appl Immunohistochem Mol Morphol 2016; 24:569-74. [DOI: 10.1097/pai.0000000000000233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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50
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Cao H, Fang X, Li H, Li H, Kong J. Ultrasensitive detection of mucin 1 biomarker by immuno-loop-mediated isothermal amplification. Talanta 2016; 164:588-592. [PMID: 28107977 DOI: 10.1016/j.talanta.2016.07.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/24/2016] [Accepted: 07/04/2016] [Indexed: 02/07/2023]
Abstract
Mucin 1 (MUC-1), a glycoprotein over-expressed on most malignant epithelial cell surfaces, such as colorectal, lung, prostate, pancreatic, ovarian, and bladder carcinomas, has been confirmed as a useful biomarker for the diagnosis of early cancers. Therefore, it is very important for early cancer diagnoses to develop the sensitive and specific detection approach of MUC-1. In this paper, we report a novel technique of aptamer-based Immuno-Loop-Mediated Isothermal Amplification (Im-LAMP) for the quantitative detection of MUC-1 by MUC-1 aptamer with high affinity for MUC-1. The cycle time is linearly dependent on the logarithm (log) of the concentration of mucin 1 ranging from 1.0 pM to 1.0 aM. We call this technique Im-LAMP, which is a novel method for the detection of low-abundance proteins with high sensitivity (a low detection limit of 120 MUC-1 molecules by calculation)and specificity. Finally, this approach is also successfully applied in the analysis of human blood serum samples. It also lays the foundation for the early diagnosis of different types of low-abundance cancer biomarkers.
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Affiliation(s)
- Hongmei Cao
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China
| | - Xueen Fang
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China.
| | - Haipeng Li
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China
| | - Hua Li
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China
| | - Jilie Kong
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China.
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