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Sekar S, Srikanth S, Mukherjee AG, Gopalakrishnan AV, Wanjari UR, Vellingiri B, Renu K, Madhyastha H. Biogenesis and functional implications of extracellular vesicles in cancer metastasis. Clin Transl Oncol 2024:10.1007/s12094-024-03815-8. [PMID: 39704958 DOI: 10.1007/s12094-024-03815-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/23/2024] [Indexed: 12/21/2024]
Abstract
Extracellular vesicles (EVs) play a crucial role in the complex process of cancer metastasis by facilitating cellular communication and influencing the microenvironment to promote the spread and establishment of cancer cells in distant locations. This paper explores the process of EV biogenesis, explaining their various sources that range from endosomal compartments to plasma membrane shedding. It also discusses the complex mechanisms that control the sorting of cargo within EVs, determining their chemical makeup. We investigate the several functions of EVs in promoting the spread of cancer to other parts of the body. These functions include influencing the immune system, creating environments that support the formation of metastases before they occur, and aiding in the transformation of cells from an epithelial to a mesenchymal state. Moreover, we explore the practical consequences of EV cargo, such as nucleic acids, proteins, and lipids, in influencing the spread of cancer cells, from the beginning of invasion to the creation of secondary tumor sites. Examining recent progress in the field of EV-based diagnostics and treatments, we explore the potential of EVs as highly promising biomarkers for predicting the course of cancer and as targets for therapeutic intervention. This review aims to provide a complete understanding of the biology of EVs in the context of cancer metastasis. By unravelling the nuances of EV biology, it seeks to pave the way for new tactics in cancer detection, treatment, and management.
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Affiliation(s)
- Sneha Sekar
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Sandhya Srikanth
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda, Punjab, 151401, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, 600077, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
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Vasishta S, Ammankallu S, Umakanth S, Keshava Prasad TS, Joshi MB. DNA methyltransferase isoforms regulate endothelial cell exosome proteome composition. Biochimie 2024; 223:98-115. [PMID: 38735570 DOI: 10.1016/j.biochi.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 03/31/2024] [Accepted: 05/06/2024] [Indexed: 05/14/2024]
Abstract
Extrinsic and intrinsic pathological stimuli in vascular disorders induce DNA methylation based epigenetic reprogramming in endothelial cells, which leads to perturbed gene expression and subsequently results in endothelial dysfunction (ED). ED is also characterized by release of exosomes with altered proteome leading to paracrine interactions in vasculature and subsequently contributing to manifestation, progression and severity of vascular complications. However, epigenetic regulation of exosome proteome is not known. Hence, our present study aimed to understand influence of DNA methylation on exosome proteome composition and their influence on endothelial cell (EC) function. DNMT isoforms (DNMT1, DNMT3A, and DNMT3B) were overexpressed using lentivirus in ECs. Exosomes were isolated and characterized from ECs overexpressing DNMT isoforms and C57BL/6 mice plasma treated with 5-aza-2'-deoxycytidine. 3D spheroid assay was performed to understand the influence of exosomes derived from cells overexpressing DNMTs on EC functions. Further, the exosomes were subjected to TMT labelled proteomics analysis followed by validation. 3D spheroid assay showed increase in the pro-angiogenic activity in response to exosomes derived from DNMT overexpressing cells which was impeded by inclusion of 5-aza-2'-deoxycytidine. Our results showed that exosome proteome and PTMs were significantly modulated and were associated with dysregulation of vascular homeostasis, metabolism, inflammation and endothelial cell functions. In vitro and in vivo validation showed elevated DNMT1 and TGF-β1 exosome proteins due to DNMT1 and DNMT3A overexpression, but not DNMT3B which was mitigated by 5-aza-2'-deoxycytidine indicating epigenetic regulation. Further, exosomes induced ED as evidenced by reduced expression of phospho-eNOSser1177. Our study unveils epigenetically regulated exosome proteins, aiding management of vascular complications.
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Affiliation(s)
- Sampara Vasishta
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Shruthi Ammankallu
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575020, Karnataka, India
| | | | | | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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3
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Kumar S, Senapati S, Chang HC. Extracellular vesicle and lipoprotein diagnostics (ExoLP-Dx) with membrane sensor: A robust microfluidic platform to overcome heterogeneity. BIOMICROFLUIDICS 2024; 18:041301. [PMID: 39056024 PMCID: PMC11272220 DOI: 10.1063/5.0218986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024]
Abstract
The physiological origins and functions of extracellular vesicles (EVs) and lipoproteins (LPs) propel advancements in precision medicine by offering non-invasive diagnostic and therapeutic prospects for cancers, cardiovascular, and neurodegenerative diseases. However, EV/LP diagnostics (ExoLP-Dx) face considerable challenges. Their intrinsic heterogeneity, spanning biogenesis pathways, surface protein composition, and concentration metrics complicate traditional diagnostic approaches. Commonly used methods such as nanoparticle tracking analysis, enzyme-linked immunosorbent assay, and nuclear magnetic resonance do not provide any information about their proteomic subfractions, including active proteins/enzymes involved in essential pathways/functions. Size constraints limit the efficacy of flow cytometry for small EVs and LPs, while ultracentrifugation isolation is hampered by co-elution with non-target entities. In this perspective, we propose a charge-based electrokinetic membrane sensor, with silica nanoparticle reporters providing salient features, that can overcome the interference, long incubation time, sensitivity, and normalization issues of ExoLP-Dx from raw plasma without needing sample pretreatment/isolation. A universal EV/LP standard curve is obtained despite their heterogeneities.
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Affiliation(s)
- Sonu Kumar
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Satyajyoti Senapati
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Hsueh-Chia Chang
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana 46556, USA
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4
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Martin P, Kurth EA, Budean D, Momplaisir N, Qu E, Simien JM, Orellana GE, Brautigam CA, Smrcka AV, Haglund E. Biophysical characterization of the CXC chemokine receptor 2 ligands. PLoS One 2024; 19:e0298418. [PMID: 38625857 PMCID: PMC11020491 DOI: 10.1371/journal.pone.0298418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/24/2024] [Indexed: 04/18/2024] Open
Abstract
The chemokines of the immune system act as first responders by operating as chemoattractants, directing immune cells to specific locations of inflamed tissues. This promiscuous network is comprised of 50 ligands and 18 receptors where the ligands may interact with the receptors in various oligomeric states i.e., monomers, homodimers, and heterodimers. Chemokine receptors are G-protein coupled receptors (GPCRs) present in the membrane of immune cells. The migration of immune cells occurs in response to a concentration gradient of the ligands. Chemotaxis of neutrophils is directed by CXC-ligand (CXCL) activation of the membrane bound CXC chemokine receptor 2 (CXCR2). CXCR2 plays an important role in human health and is linked to disorders such as autoimmune disorders, inflammation, and cancer. Yet, despite their important role, little is known about the biophysical characteristics controlling ligand:ligand and ligand:receptor interaction essential for biological activity. In this work, we study the homodimers of three of the CXCR2 cognate ligands, CXCL1, CXCL5, and CXCL8. The ligands share high structural integrity but a low sequence identity. We show that the sequence diversity has evolved different binding affinities and stabilities for the CXC-ligands resulting in diverse agonist/antagonist behavior. Furthermore, CXC-ligands fold through a three-state mechanism, populating a folded monomeric state before associating into an active dimer.
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Affiliation(s)
- Patrick Martin
- Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
| | - Emily A. Kurth
- Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
| | - David Budean
- Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
| | - Nathalie Momplaisir
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Elaine Qu
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Jennifer M. Simien
- Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
| | - Grace E. Orellana
- Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
| | - Chad A. Brautigam
- Department of Biophysics and the Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Alan V. Smrcka
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Ellinor Haglund
- Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America
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Das K, Mukherjee T, Shankar P. The Role of Extracellular Vesicles in the Pathogenesis of Hematological Malignancies: Interaction with Tumor Microenvironment; a Potential Biomarker and Targeted Therapy. Biomolecules 2023; 13:897. [PMID: 37371477 DOI: 10.3390/biom13060897] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/21/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
The tumor microenvironment (TME) plays an important role in the development and progression of hematological malignancies. In recent years, studies have focused on understanding how tumor cells communicate within the TME. In addition to several factors, such as growth factors, cytokines, extracellular matrix (ECM) molecules, etc., a growing body of evidence has indicated that extracellular vesicles (EVs) play a crucial role in the communication of tumor cells within the TME, thereby contributing to the pathogenesis of hematological malignancies. The present review focuses on how EVs derived from tumor cells interact with the cells in the TME, such as immune cells, stromal cells, endothelial cells, and ECM components, and vice versa, in the context of various hematological malignancies. EVs recovered from the body fluids of cancer patients often carry the bioactive molecules of the originating cells and hence can be considered new predictive biomarkers for specific types of cancer, thereby also acting as potential therapeutic targets. Here, we discuss how EVs influence hematological tumor progression via tumor-host crosstalk and their use as biomarkers for hematological malignancies, thereby benefiting the development of potential therapeutic targets.
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Affiliation(s)
- Kaushik Das
- Department of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USA
| | - Tanmoy Mukherjee
- Department of Pulmonary Immunology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USA
| | - Prem Shankar
- Department of Pulmonary Immunology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USA
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Jackson HK, Mitoko C, Linke F, Macarthur D, Kerr ID, Coyle B. Extracellular Vesicles Potentiate Medulloblastoma Metastasis in an EMMPRIN and MMP-2 Dependent Manner. Cancers (Basel) 2023; 15:cancers15092601. [PMID: 37174066 PMCID: PMC10177484 DOI: 10.3390/cancers15092601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/19/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
Extracellular vesicles (EVs) have emerged as pivotal mediators of communication in the tumour microenvironment. More specifically, nanosized extracellular vesicles termed exosomes have been shown to contribute to the establishment of a premetastatic niche. Here, we sought to determine what role exosomes play in medulloblastoma (MB) progression and elucidate the underlying mechanisms. Metastatic MB cells (D458 and CHLA-01R) were found to secrete markedly more exosomes compared to their nonmetastatic, primary counterparts (D425 and CHLA-01). In addition, metastatic cell-derived exosomes significantly enhanced the migration and invasiveness of primary MB cells in transwell migration assays. Protease microarray analysis identified that matrix metalloproteinase-2 (MMP-2) was enriched in metastatic cells, and zymography and flow cytometry assays of metastatic exosomes demonstrated higher levels of functionally active MMP-2 on their external surface. Stable genetic knockdown of MMP-2 or extracellular matrix metalloproteinase inducer (EMMPRIN) in metastatic MB cells resulted in the loss of this promigratory effect. Analysis of serial patient cerebrospinal fluid (CSF) samples showed an increase in MMP-2 activity in three out of four patients as the tumour progressed. This study demonstrates the importance of EMMPRIN and MMP-2-associated exosomes in creating a favourable environment to drive medulloblastoma metastasis via extracellular matrix signalling.
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Affiliation(s)
- Hannah K Jackson
- Children's Brain Tumour Research Centre, School of Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK
| | - Christine Mitoko
- Children's Brain Tumour Research Centre, School of Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
| | - Franziska Linke
- Children's Brain Tumour Research Centre, School of Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
- Department of Experimental Urology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Donald Macarthur
- Department of Neurosurgery, Nottingham University Hospital, Nottingham NG7 2UH, UK
| | - Ian D Kerr
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Beth Coyle
- Children's Brain Tumour Research Centre, School of Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
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7
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Patel NJ, Ashraf A, Chung EJ. Extracellular Vesicles as Regulators of the Extracellular Matrix. Bioengineering (Basel) 2023; 10:136. [PMID: 36829629 PMCID: PMC9952427 DOI: 10.3390/bioengineering10020136] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Extracellular vesicles (EVs) are small membrane-bound vesicles secreted into the extracellular space by all cell types. EVs transfer their cargo which includes nucleic acids, proteins, and lipids to facilitate cell-to-cell communication. As EVs are released and move from parent to recipient cell, EVs interact with the extracellular matrix (ECM) which acts as a physical scaffold for the organization and function of cells. Recent work has shown that EVs can modulate and act as regulators of the ECM. This review will first discuss EV biogenesis and the mechanism by which EVs are transported through the ECM. Additionally, we discuss how EVs contribute as structural components of the matrix and as components that aid in the degradation of the ECM. Lastly, the role of EVs in influencing recipient cells to remodel the ECM in both pathological and therapeutic contexts is examined.
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Affiliation(s)
- Neil J. Patel
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Anisa Ashraf
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
- Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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8
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Leal-Orta E, Ramirez-Ricardo J, Garcia-Hernandez A, Cortes-Reynosa P, Salazar EP. Extracellular vesicles from MDA-MB-231 breast cancer cells stimulated with insulin-like growth factor 1 mediate an epithelial-mesenchymal transition process in MCF10A mammary epithelial cells. J Cell Commun Signal 2022; 16:531-546. [PMID: 34309795 PMCID: PMC9733745 DOI: 10.1007/s12079-021-00638-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 07/19/2021] [Indexed: 12/24/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) plays an important role in function and development of the mammary gland. However, high levels of IGF-1 has been associated with an increased risk of breast cancer development. Epithelial-mesenchymal transition (EMT) is a process where epithelial cells lose their epithelial characteristics and acquire a mesenchymal phenotype, which is considered one of the most important mechanisms in cancer initiation and promotion of metastasis. Extracellular vesicles (EVs) are released into the extracellular space by different cell types, which mediate intercellular communication and play an important role in different physiological and pathological processes, such as cancer. In this study, we demonstrate that EVs from MDA-MB-231 breast cancer cells stimulated with IGF-1 (IGF-1 EVs) decrease the levels of E-cadherin, increase the expression of vimentin and N-cadherin and stimulate the secretion of metalloproteinase-9 in mammary non-tumorigenic epithelial cells MCF10A. IGF-1 EVs also induce the expression of Snail1, Twist1 and Sip1, which are transcription factors involved in EMT. Moreover, IGF-1 EVs induce activation of ERK1/2, Akt1 and Akt2, migration and invasion. In summary, we demonstrate, for the first time, that IGF-1 EVs induce an EMT process in mammary non-tumorigenic epithelial cells MCF10A.
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Affiliation(s)
- Elizabeth Leal-Orta
- grid.512574.0Departamento de Biologia Celular, Cinvestav-IPN, 07360 Mexico City, Mexico
| | | | | | - Pedro Cortes-Reynosa
- grid.512574.0Departamento de Biologia Celular, Cinvestav-IPN, 07360 Mexico City, Mexico
| | - Eduardo Perez Salazar
- grid.512574.0Departamento de Biologia Celular, Cinvestav-IPN, 07360 Mexico City, Mexico
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9
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Plant-derived extracellular vesicles as oral drug delivery carriers. J Control Release 2022; 350:389-400. [PMID: 36037973 DOI: 10.1016/j.jconrel.2022.08.046] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/21/2022]
Abstract
Oral administration is one of the most convenient and widely utilized methods of drug administration. However, many drugs were difficult to be administered orally due to their poor oral bioavailability. Designing a safe and effective oral drug delivery system is one of the basic strategies to overcome the poor oral bioavailability. Plant-derived extracellular vesicles (PDEVs) were found in a variety of plants and have similar physical and chemical properties to mammalian EVs. It has been proved that PDEVs can effectively encapsulate hydrophilic and hydrophobic drugs, remain stable in harsh gastrointestinal environments, and cross biological barriers to reach target tissues. Furthermore, the biological activity of PDEVs enables it to play a synergistic therapeutic role with drugs. In addition, the safety and high yield of PDEVs indicate their potential as oral drug carriers. In this review, we introduce the biogenesis, isolation, characterization and drug delivery methods of PDEVs, describe their stability, transport, delivery and therapeutic applications. Finally, the potential and challenges of PDEVs as drug carriers are discussed.
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10
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Rodrigues-Junior DM, Tsirigoti C, Lim SK, Heldin CH, Moustakas A. Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer. Front Cell Dev Biol 2022; 10:849938. [PMID: 35493080 PMCID: PMC9043557 DOI: 10.3389/fcell.2022.849938] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the TGF-β pathway have been reported as constituents in the cargo of extracellular vesicles (EVs). EVs are secreted vesicles delimited by a lipid bilayer and play critical functions in intercellular communication, including regulation of the tumor microenvironment and cancer development. Thus, this review aims at summarizing the impact of EVs on TGF-β signaling by focusing on mechanisms by which EV cargo can influence tumorigenesis, metastatic spread, immune evasion and response to anti-cancer treatment. Moreover, we emphasize the potential of TGF-β-related molecules present in circulating EVs as useful biomarkers of prognosis, diagnosis, and prediction of response to treatment in cancer patients.
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Affiliation(s)
| | - Chrysoula Tsirigoti
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (A*-STAR), Singapore, Singapore
| | - Carl-Henrik Heldin
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- *Correspondence: Aristidis Moustakas,
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11
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Ren HL, Wen GM, Zhao ZY, Liu DH, Xia P. Can CD147 work as a therapeutic target for tumors through COVID-19 infection? Int J Med Sci 2022; 19:2087-2092. [PMID: 36483594 PMCID: PMC9724241 DOI: 10.7150/ijms.79162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/10/2022] [Indexed: 11/24/2022] Open
Abstract
In this review, we discussed an interesting case infected with "COVID-19" (Corona Virus Disease 2019). The patients with Hodgkin's lymphoma recovered after infection with COVID-19. It may be that COVID-19 activates the patient's immune system, or it may be a coincidence. COVID-19 spike protein can interact with CD147 and use it as an entry to invade host cells. CD147 is a partner of SLC3A2, which is the chaperone subunit of cystine/glutamate reverse transporter (system XC). The catalytic subunit of system XC is SLC7A11. SLC7A11 mediated cysteine uptake plays a key role in ferroptosis. Through literature review and data analysis, we suggest that CD147, as a new potential COVID-19 infection entry, may also lead to ferroptosis of host cells. Our hypothesis is that spike protein of COVID-19 induced ferroptosis in host cells via CD147/SLC3A2/SLC7A11 complex. This is another explanation for the cancer patient recovered after COVID-19 infection.
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Affiliation(s)
- Hao-Lin Ren
- Department of Radiology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Gui-Min Wen
- Department of Basic Nursing, College of Nursing, Jinzhou Medical University, Jinzhou, Liaoning, P.R. China
| | - Zhen-Ying Zhao
- Department of Pharmacy, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Da-Hua Liu
- Biological Anthropology Institute, College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning, P.R. China
| | - Pu Xia
- Biological Anthropology Institute, College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning, P.R. China
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12
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Espejo C, Wilson R, Willms E, Ruiz-Aravena M, Pye RJ, Jones ME, Hill AF, Woods GM, Lyons AB. Extracellular vesicle proteomes of two transmissible cancers of Tasmanian devils reveal tenascin-C as a serum-based differential diagnostic biomarker. Cell Mol Life Sci 2021; 78:7537-7555. [PMID: 34655299 PMCID: PMC11073120 DOI: 10.1007/s00018-021-03955-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/26/2021] [Accepted: 09/28/2021] [Indexed: 12/15/2022]
Abstract
The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition-mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial-mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers' EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.
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Affiliation(s)
- Camila Espejo
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia.
| | - Richard Wilson
- Central Science Laboratory, University of Tasmania, Hobart, TAS, 7005, Australia
| | - Eduard Willms
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia
| | - Manuel Ruiz-Aravena
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA
- School of Natural Sciences, University of Tasmania, Hobart, TAS, 7001, Australia
| | - Ruth J Pye
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia
| | - Menna E Jones
- School of Natural Sciences, University of Tasmania, Hobart, TAS, 7001, Australia
| | - Andrew F Hill
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia
| | - Gregory M Woods
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia
| | - A Bruce Lyons
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia
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13
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Kaddour H, Tranquille M, Okeoma CM. The Past, the Present, and the Future of the Size Exclusion Chromatography in Extracellular Vesicles Separation. Viruses 2021; 13:2272. [PMID: 34835078 PMCID: PMC8618570 DOI: 10.3390/v13112272] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/02/2021] [Accepted: 11/02/2021] [Indexed: 01/13/2023] Open
Abstract
Extracellular vesicles (EVs) are cell-derived membranous particles secreted by all cell types (including virus infected and uninfected cells) into the extracellular milieu. EVs carry, protect, and transport a wide array of bioactive cargoes to recipient/target cells. EVs regulate physiological and pathophysiological processes in recipient cells and are important in therapeutics/drug delivery. Despite these great attributes of EVs, an efficient protocol for EV separation from biofluids is lacking. Numerous techniques have been adapted for the separation of EVs with size exclusion chromatography (SEC)-based methods being the most promising. Here, we review the SEC protocols used for EV separation, and discuss opportunities for significant improvements, such as the development of novel particle purification liquid chromatography (PPLC) system capable of tandem purification and characterization of biological and synthetic particles with near-single vesicle resolution. Finally, we identify future perspectives and current issues to make PPLC a tool capable of providing a unified, automated, adaptable, yet simple and affordable particle separation resource.
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Affiliation(s)
- Hussein Kaddour
- Department of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA
| | - Malik Tranquille
- Department of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
| | - Chioma M. Okeoma
- Department of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
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14
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Ramachandran S, Verma AK, Dev K, Goyal Y, Bhatt D, Alsahli MA, Rahmani AH, Almatroudi A, Almatroodi SA, Alrumaihi F, Khan NA. Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5563746. [PMID: 34336101 PMCID: PMC8313354 DOI: 10.1155/2021/5563746] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/23/2021] [Accepted: 06/28/2021] [Indexed: 12/14/2022]
Abstract
With over a million deaths every year around the world, lung cancer is found to be the most recurrent cancer among all types. Nonsmall cell lung carcinoma (NSCLC) amounts to about 85% of the entire cases. The other 15% owes it to small cell lung carcinoma (SCLC). Despite decades of research, the prognosis for NSCLC patients is poorly understood with treatment options limited. First, this article emphasises on the part that tumour microenvironment (TME) and its constituents play in lung cancer progression. This review also highlights the inflammatory (pro- or anti-) roles of different cytokines (ILs, TGF-β, and TNF-α) and chemokine (CC, CXC, C, and CX3C) families in the lung TME, provoking tumour growth and subsequent metastasis. The write-up also pinpoints recent developments in the field of chemokine biology. Additionally, it covers the role of extracellular vesicles (EVs), as alternate carriers of cytokines and chemokines. This allows the cytokines/chemokines to modulate the EVs for their secretion, trafficking, and aid in cancer proliferation. In the end, this review also stresses on the role of these factors as prognostic biomarkers for lung immunotherapy, apart from focusing on inflammatory actions of these chemoattractants.
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Affiliation(s)
- Sowmya Ramachandran
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Main Campus, Penang, Malaysia
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Amit K Verma
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Yamini Goyal
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Deepti Bhatt
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Saleh A Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Naushad Ahmad Khan
- Department of Biochemistry, Faculty of Medical Sciences, Alatoo International University, Bishkek, Kyrgyzstan
- Department of Trauma and Surgery, Hamad Medical Corporation, Doha, Qatar
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15
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Wu Y, Brennan K, Fernández AB, Mc Gee MM. Cyclophilin A regulates secretion of tumour-derived extracellular vesicles. Transl Oncol 2021; 14:101112. [PMID: 33984826 PMCID: PMC8131927 DOI: 10.1016/j.tranon.2021.101112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 01/06/2023] Open
Abstract
Blood cancer EVs stimulate pro-inflammatory immune signals. Cyclophilin A is a core EV protein and is localised in high density blood cancer derived EVs. Cyclophilin A regulates biogenesis and/or release of EVs with a diameter of 100 to 200 nm. Extracellular Vesicles (EVs) are a heterogenous population of particles that play an important role in cell-cell communication in physiological and pathophysiological situations. In this study we reveal that the peptidyl prolyl isomerase Cyclophilin A (CypA) is enriched in cancer-derived EVs from a range of haematopoietic malignancies. CypA-enriched blood cancer EVs were taken up by normal monocytes independent of EV surface trypsin-sensitive proteins and potently stimulated pro-inflammatory MMP9 and IL-6 secretion. Further characterisation revealed that CypA is intravesicular, however, it is not present in all EVs derived from the haematopoietic cells, instead, it is predominantly located in high density EVs with a range of 1.15–1.18 g/ml. Furthermore, loss of CypA expression in haematological cancer cells attenuates high density EV-induced pro-inflammatory MMP9 and IL-6 secretion from monocytes. Mechanistically, we reveal that homozygous loss or siRNA knockdown of CypA expression significantly reduced the secretion of EVs in the range of 100–200 nm from blood cancer cells under normal and hypoxic conditions. Overall, this work reveals a novel role for CypA in cancer cell EV biogenesis.
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Affiliation(s)
- Yunjie Wu
- UCD School of Biomolecular & Biomedical Science, Conway Institute, University College Dublin (UCD), Belfield, Dublin 4, Ireland
| | - Kieran Brennan
- UCD School of Biomolecular & Biomedical Science, Conway Institute, University College Dublin (UCD), Belfield, Dublin 4, Ireland
| | - Alfonso Blanco Fernández
- Flow Cytometry Core Technology, Conway Institute, University College Dublin (UCD), Belfield, Dublin 4, Ireland
| | - Margaret M Mc Gee
- UCD School of Biomolecular & Biomedical Science, Conway Institute, University College Dublin (UCD), Belfield, Dublin 4, Ireland.
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16
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Park KC, Dharmasivam M, Richardson DR. The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity. Int J Mol Sci 2020; 21:E6805. [PMID: 32948029 PMCID: PMC7555822 DOI: 10.3390/ijms21186805] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 12/21/2022] Open
Abstract
The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase-a prostate-specific antigen-in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.
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Affiliation(s)
- Kyung Chan Park
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building, University of Sydney, Sydney 2006, Australia; (K.C.P.); (M.D.)
| | - Mahendiran Dharmasivam
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building, University of Sydney, Sydney 2006, Australia; (K.C.P.); (M.D.)
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute of Drug Discovery, Griffith University, Nathan, Brisbane 4111, Australia
| | - Des R. Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building, University of Sydney, Sydney 2006, Australia; (K.C.P.); (M.D.)
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute of Drug Discovery, Griffith University, Nathan, Brisbane 4111, Australia
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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17
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Carnino JM, Ni K, Jin Y. Post-translational Modification Regulates Formation and Cargo-Loading of Extracellular Vesicles. Front Immunol 2020; 11:948. [PMID: 32528471 PMCID: PMC7257894 DOI: 10.3389/fimmu.2020.00948] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/22/2020] [Indexed: 12/25/2022] Open
Abstract
Accumulating evidence suggests that post-translational modifications (PTMs) regulate the selective encapsulation of non-coding RNA molecules into extracellular vesicles (EVs) and contribute to the downstream functions of EVs or EV-cargo non-coding RNAs. EVs are a newly studied mechanism of intercellular communication that involves the transfer of molecules, including but not limited to proteins, lipids, and non-coding RNAs, to induce functional changes in the recipient cells. In this present mini-review, we focus on the PTM-regulated protein and non-coding RNA selection into eukaryotic EVs.
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Affiliation(s)
- Jonathan M Carnino
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, MA, United States
| | - Kareemah Ni
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, MA, United States
| | - Yang Jin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, MA, United States
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18
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Weng Y, Chen T, Ren J, Lu D, Liu X, Lin S, Xu C, Lou J, Chen X, Tang L. The Association Between Extracellular Matrix Metalloproteinase Inducer Polymorphisms and Coronary Heart Disease: A Potential Way to Predict Disease. DNA Cell Biol 2020; 39:244-254. [PMID: 31928425 DOI: 10.1089/dna.2019.5015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Extracellular matrix metalloproteinase inducer (EMMPRIN) had been reported to be involved in the occurrence and development of coronary heart disease (CHD) in previous studies. This study aimed to investigate whether single nucleotide polymorphisms of EMMPRIN and matrix metalloproteinase-9 (MMP-9) contributed to the onset and severity of CHD. One thousand seventy patients suspected to have CHD were enrolled into the study. Each patient had undergone coronary angiogram, and the severity of coronary artery stenosis was assessed by Gensini score. Eight hundred twelve patients were confirmed to have CHD, while 258 patients were selected as non-CHD control. All patients were genotyped for five EMMPRIN polymorphisms (rs8259, rs28915400, rs4919859, rs6758, and rs8637) and one MMP-9 polymorphism (rs3918242) by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. EMMPRIN polymorphism rs8259 and MMP-9 polymorphism rs3918242 were found to be associated with CHD (rs8259: AT vs. AA, adjusted odds ratio [OR] = 2.038, adjusted 95% confidence interval [CI] = 1.080-3.847, p = 0.028; rs3918242: CT vs. CC, adjusted OR = 0.607, adjusted 95% CI = 0.403-0.916, p = 0.017, TT vs. CC, adjusted OR = 2.559, adjusted 95% CI = 1.326-4.975, p = 0.006). No crossover effects were observed although a single environmental or genetic factor had an impact on the occurrence of CHD. The value of the Gensini score revealed that severity of CHD decreased in the rs3918242 CT carriers in both the male and female population. Our study suggested that EMMPRIN rs8259 and MMP-9 rs3918242 polymorphisms may contribute to pathological process of CHD. It could play a critical role in the prediction of CHD.
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Affiliation(s)
- Yingzheng Weng
- Department of Cardiology, Zhejiang Hospital, Hangzhou, China
| | - Tingting Chen
- Department of Cardiology, Taizhou Hospital, Taizhou, China.,Department of Medicine, The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Jianfei Ren
- Department of Internal Medicine, Lihuili Hospital Affiliated Ningbo University, Ningbo, China
| | - Difan Lu
- Department of Medicine, The Second College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaowei Liu
- Department of Cardiology, Zhejiang Hospital, Hangzhou, China
| | - Senna Lin
- Department of Cardiology, Zhejiang Hospital, Hangzhou, China
| | - Chenkai Xu
- Department of Cardiology, Zhejiang Hospital, Hangzhou, China
| | - Jiangjie Lou
- Department of Cardiology, Zhejiang Hospital, Hangzhou, China
| | - Xiaofeng Chen
- Department of Cardiology, Taizhou Hospital, Taizhou, China.,Department of Medicine, The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China.,Department of Medicine, The Second College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lijiang Tang
- Department of Cardiology, Zhejiang Hospital, Hangzhou, China.,Department of Cardiology, Taizhou Hospital, Taizhou, China.,Department of Medicine, The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China.,Department of Medicine, The Second College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
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19
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Abstract
Extracellular vesicles (EVs) are nano-membrane vesicles containing exosomes and microvesicles, and are released by almost all types of cells. They can carry lipids, proteins, mRNAs, and miRNAs to enable intercellular communication between cells either locally or distantly without direct cell-to-cell contact. Cancer-derived EVs are known to facilitate tumor progression and metastasis by preparing premetastatic niches. Here, we define a strategy to label cancer derived EVs with Renilla luciferase for noninvasive bioluminescence imaging (BLI) and monitoring of intravenously administered EVs in vivo.
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20
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Yunusova NV, Tugutova EA, Tamkovich SN, Kondakova IV. [The role of exosomal tetraspanins and proteases in tumor progression]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2019; 64:123-133. [PMID: 29723143 DOI: 10.18097/pbmc20186402123] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Major (CD9, CD63, CD81) and others (CD82, CD151, Tspan8) tetraspanins are widely represented in exosomes, where they interact with various proteins and form functional tetraspanin complexes. Tetraspanin complexes include proteases. Tetraspanin-associated exosomal proteases (ADAM proteases, MMPs, EMMPRIN) play an important role in the processes of cell motility, migration, invasion and formation of metastases. Also, a significant contribution to tumor progression is made by proteases that are not associated with tetraspanins. They destabilize intercellular contacts, promote migration and invasion of tumor cells, participate in the regulation of the expression IGF-I, VEGF and transcription factors activation/deactivation. The role of other proteases of exosomes in the processes of tumor progression is being clarified.
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Affiliation(s)
- N V Yunusova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia; Siberian State Medical University, Tomsk, Russia
| | - E A Tugutova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - S N Tamkovich
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia; Novosibirsk State Medical University, Novosibirsk, Russia
| | - I V Kondakova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
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21
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Kumar D, Vetrivel U, Parameswaran S, Subramanian KK. Structural insights on druggable hotspots in CD147: A bull's eye view. Life Sci 2019; 224:76-87. [DOI: 10.1016/j.lfs.2019.03.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/11/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022]
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22
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Extracellular Vesicles and Matrix Remodeling Enzymes: The Emerging Roles in Extracellular Matrix Remodeling, Progression of Diseases and Tissue Repair. Cells 2018; 7:cells7100167. [PMID: 30322133 PMCID: PMC6210724 DOI: 10.3390/cells7100167] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 09/17/2018] [Accepted: 10/12/2018] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs) are membrane enclosed micro- and nano-sized vesicles that are secreted from almost every species, ranging from prokaryotes to eukaryotes, and from almost every cell type studied so far. EVs contain repertoire of bioactive molecules such as proteins (including enzymes and transcriptional factors), lipids, carbohydrates and nucleic acids including DNA, coding and non-coding RNAs. The secreted EVs are taken up by neighboring cells where they release their content in recipient cells, or can sail through body fluids to reach distant organs. Since EVs transport bioactive cargo between cells, they have emerged as novel mediators of extra- and intercellular activities in local microenvironment and inter-organ communications distantly. Herein, we review the activities of EV-associated matrix-remodeling enzymes such as matrix metalloproteinases, heparanases, hyaluronidases, aggrecanases, and their regulators such as extracellular matrix metalloproteinase inducers and tissue inhibitors of metalloproteinases as novel means of matrix remodeling in physiological and pathological conditions. We discuss how such EVs act as novel mediators of extracellular matrix degradation to prepare a permissive environment for various pathological conditions such as cancer, cardiovascular diseases, arthritis and metabolic diseases. Additionally, the roles of EV-mediated matrix remodeling in tissue repair and their potential applications as organ therapies have been reviewed. Collectively, this knowledge could benefit the development of new approaches for tissue engineering.
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23
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A Multiwell-Based Detection Platform with Integrated PDMS Concentrators for Rapid Multiplexed Enzymatic Assays. Sci Rep 2018; 8:10772. [PMID: 30018340 PMCID: PMC6050343 DOI: 10.1038/s41598-018-29065-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 07/05/2018] [Indexed: 02/05/2023] Open
Abstract
We report an integrated system for accelerating assays with concentrators in a standard 12-well plate (ISAAC-12) and demonstrate its versatility for rapid detection of matrix metalloproteinase (MMP)-9 expression in the cell culture supernatant of breast cancer cell line MDA-MB-231 by accelerating the enzymatic reaction and end-point signal intensity via electrokinetic preconcentration. Using direct printing of a conductive ion-permselective polymer on a polydimethylsiloxane (PDMS) channel, the new microfluidic concentrator chip can be built without modifying the underlying substrate. Through this decoupling fabrication strategy, our microfluidic concentrator chip can easily be integrated with a standard multiwell plate, the de facto laboratory standard platform for high-throughput assays, simply by reversible bonding on the bottom of each well. It increases the reaction rate of enzymatic assays by concentrating the enzyme and the reaction product inside each well simultaneously for rapid multiplexed detection.
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24
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Muhsin-Sharafaldine MR, McLellan AD. Apoptotic vesicles: deathly players in cancer-associated coagulation. Immunol Cell Biol 2018; 96:723-732. [PMID: 29738615 DOI: 10.1111/imcb.12162] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/01/2018] [Accepted: 05/02/2018] [Indexed: 12/27/2022]
Abstract
Although cancer is associated with coagulation disorders, it is still unclear how the combination of tumor cell and host factors enhance the hypercoagulable state of cancer patients. Emerging evidence points to a central role for tumor endosomal and plasma membrane-derived vesicular components in the pathogenesis of cancer-related thrombosis. In particular, tumor cell membranes and extracellular vesicles (EV) harbor lipids and proteinaceous coagulation factors able to initiate multiple points within the coagulation matrix. The impact of chemotherapy upon a host already burdened with a hypercoagulable state increases the risk of pathological coagulation. We argue that chemotherapy-induced EV harbor the most active components for cancer related thrombosis and discuss how membrane components of the host and tumor act to initiate coagulation to enhance thrombotic risk in cancer patients.
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25
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Roy L, Bobbs A, Sattler R, Kurkewich JL, Dausinas PB, Nallathamby P, Cowden Dahl KD. CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche. CANCER GROWTH AND METASTASIS 2018; 11:1179064418767882. [PMID: 29662326 PMCID: PMC5894897 DOI: 10.1177/1179064418767882] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 03/09/2018] [Indexed: 12/25/2022]
Abstract
Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.
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Affiliation(s)
- Lynn Roy
- Harper Cancer Research Institute, South Bend, IN, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA
| | - Alexander Bobbs
- Harper Cancer Research Institute, South Bend, IN, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA
| | - Rachel Sattler
- Harper Cancer Research Institute, South Bend, IN, USA.,Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| | - Jeffrey L Kurkewich
- Harper Cancer Research Institute, South Bend, IN, USA.,Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Paige B Dausinas
- Harper Cancer Research Institute, South Bend, IN, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA
| | - Prakash Nallathamby
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, USA
| | - Karen D Cowden Dahl
- Harper Cancer Research Institute, South Bend, IN, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA.,Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, USA.,Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
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26
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Kendrick AA, Schafer J, Dzieciatkowska M, Nemkov T, D'Alessandro A, Neelakantan D, Ford HL, Pearson CG, Weekes CD, Hansen KC, Eisenmesser EZ. CD147: a small molecule transporter ancillary protein at the crossroad of multiple hallmarks of cancer and metabolic reprogramming. Oncotarget 2018; 8:6742-6762. [PMID: 28039486 PMCID: PMC5341751 DOI: 10.18632/oncotarget.14272] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/30/2016] [Indexed: 02/07/2023] Open
Abstract
Increased expression of CD147 in pancreatic cancer has been proposed to play a critical role in cancer progression via CD147 chaperone function for lactate monocarboxylate transporters (MCTs). Here, we show for the first time that CD147 interacts with membrane transporters beyond MCTs and exhibits a protective role for several of its interacting partners. CD147 prevents its interacting partner's proteasome-dependent degradation and incorrect plasma membrane localization through the CD147 transmembrane (TM) region. The interactions with transmembrane small molecule and ion transporters identified here indicate a central role of CD147 in pancreatic cancer metabolic reprogramming, particularly with respect to amino acid anabolism and calcium signaling. Importantly, CD147 genetic ablation prevents pancreatic cancer cell proliferation and tumor growth in vitro and in vivo in conjunction with metabolic rewiring towards amino acid anabolism, thus paving the way for future combined pharmacological treatments.
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Affiliation(s)
- Agnieszka A Kendrick
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
| | - Johnathon Schafer
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
| | - Monika Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
| | - Travis Nemkov
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
| | - Deepika Neelakantan
- Department of Pharmacology, School of Medicine, University of Colorado Denver, CO, USA
| | - Heide L Ford
- Department of Pharmacology, School of Medicine, University of Colorado Denver, CO, USA
| | - Chad G Pearson
- Department of Cell and Developmental Biology, School of Medicine, University of Colorado Denver, CO, USA
| | - Colin D Weekes
- Division of Oncology, Department of Medicine, University of Colorado Denver, CO, USA
| | - Kirk C Hansen
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
| | - Elan Z Eisenmesser
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA
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Wu K, Xing F, Wu SY, Watabe K. Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside. Biochim Biophys Acta Rev Cancer 2017; 1868:538-563. [PMID: 29054476 DOI: 10.1016/j.bbcan.2017.10.001] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/13/2017] [Accepted: 10/13/2017] [Indexed: 12/16/2022]
Abstract
Extracellular vesicles (EVs) have emerged as important players of cancer initiation and progression through cell-cell communication. They have been recognized as critical mediators of extracellular communications, which promote transformation, growth invasion, and drug-resistance of cancer cells. Interestingly, the secretion and uptake of EVs are regulated in a more controlled manner than previously anticipated. EVs are classified into three groups, (i) exosomes, (ii) microvesicles (MVs), and (iii) apoptotic bodies (ABs), based on their sizes and origins, and novel technologies to isolate and distinguish these EVs are evolving. The biologically functional molecules harbored in these EVs, including nucleic acids, lipids, and proteins, have been shown to induce key signaling pathways in both tumor and tumor microenvironment (TME) cells for exacerbating tumor development. While tumor cell-derived EVs are capable of reprogramming stromal cells to generate a proper tumor cell niche, stromal-derived EVs profoundly affect the growth, resistance, and stem cell properties of tumor cells. This review summarizes and discusses these reciprocal communications through EVs in different types of cancers. Further understanding of the pathophysiological roles of different EVs in tumor progression is expected to lead to the discovery of novel biomarkers in liquid biopsy and development of tumor specific therapeutics. This review will also discuss the translational aspects of EVs and therapeutic opportunities of utilizing EVs in different cancer types.
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Affiliation(s)
- Kerui Wu
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Fei Xing
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Shih-Ying Wu
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Kounosuke Watabe
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
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Caivano A, La Rocca F, Laurenzana I, Trino S, De Luca L, Lamorte D, Del Vecchio L, Musto P. Extracellular Vesicles in Hematological Malignancies: From Biology to Therapy. Int J Mol Sci 2017; 18:E1183. [PMID: 28574430 PMCID: PMC5486006 DOI: 10.3390/ijms18061183] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/29/2017] [Accepted: 05/30/2017] [Indexed: 12/22/2022] Open
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of particles, between 15 nanometers and 10 microns in diameter, released by almost all cell types in physiological and pathological conditions, including tumors. EVs have recently emerged as particularly interesting informative vehicles, so that they could be considered a true "cell biopsy". Indeed, EV cargo, including proteins, lipids, and nucleic acids, generally reflects the nature and status of the origin cells. In some cases, EVs are enriched of peculiar molecular cargo, thus suggesting at least a degree of specific cellular packaging. EVs are identified as important and critical players in intercellular communications in short and long distance interplays. Here, we examine the physiological role of EVs and their activity in cross-talk between bone marrow microenvironment and neoplastic cells in hematological malignancies (HMs). In these diseases, HM EVs can modify tumor and bone marrow microenvironment, making the latter "stronger" in supporting malignancy, inducing drug resistance, and suppressing the immune system. Moreover, EVs are abundant in biologic fluids and protect their molecular cargo against degradation. For these and other "natural" characteristics, EVs could be potential biomarkers in a context of HM liquid biopsy and therapeutic tools. These aspects will be also analyzed in this review.
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Affiliation(s)
- Antonella Caivano
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 858028 Rionero in Vulture, Italy.
| | - Francesco La Rocca
- Laboratory of Clinical Research and Advanced Diagnostics, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy.
| | - Ilaria Laurenzana
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 858028 Rionero in Vulture, Italy.
| | - Stefania Trino
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 858028 Rionero in Vulture, Italy.
| | - Luciana De Luca
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 858028 Rionero in Vulture, Italy.
| | - Daniela Lamorte
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 858028 Rionero in Vulture, Italy.
| | - Luigi Del Vecchio
- CEINGE-Biotecnologie Avanzate scarl, Federico II University, 80138 Naples, Italy.
- Department of Molecular Medicine and Medical Biotechnologies, Federico II University, 80138 Naples, Italy.
| | - Pellegrino Musto
- Scientific Direction, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy.
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Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2016; 17:376. [PMID: 26985892 PMCID: PMC4813235 DOI: 10.3390/ijms17030376] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 03/01/2016] [Accepted: 03/02/2016] [Indexed: 12/14/2022] Open
Abstract
In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting.
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30
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Xie M, He C, Wei S. [Relationship between Expression of TGF-β1, Smad2, Smad4 and Prognosis
of Patients with Resected Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2016; 18:543-8. [PMID: 26383977 PMCID: PMC6000115 DOI: 10.3779/j.issn.1009-3419.2015.09.03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND AND OBJECTIVE It has been proven that any changes of transforming growth factor β (TGF-β)-Smad signal transduction pathway will lead to abnormalities of signal transmission and the out of control during cell growth and differentiation, resulting in cancer development. The aim of this study is to investigate the prognostic values of TGF-β1, Smad2 and Smad4 in resected non-small cell lung cancer (NSCLC). METHODS The expression of TGF-β1, Smad2, and Smad4 was evaluated by immunohistochemistry in 85 patients with NSCLC. The relationships among the expression of these proteins, clinicopathological factors, and prognosis were also analyzed. RESULTS TGF-β1 positive expression was significantly correlated with the late stage and lymph node involvement. No significant association existed between the expression of Smad2 and the clinicopathological characteristics. The lack of Smad4 expression was associated with the advanced tumor stage (P=0.014). Multivariate analysis indicated that lymph node involvement (P=0.001) was an independent prognostic factor in the 85 NSCLC patients. The positive expression levels of TGF-β1 (P=0.032) and N stage (P=0.028) were demonstrated to be independent risk factors for survival among 47 lung adenocarcinoma patients. Adenocarcinoma patients with TGF-β1 positive expression demonstrated an unfavorable survival outcome (P=0.0376). CONCLUSIONS TGF-β1 may be an independent predictor of survival in resected lung adenocarcinoma patients.
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Affiliation(s)
- Mian Xie
- China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University,
Guangzhou 510120, China
| | - Chaosheng He
- China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University,
Guangzhou 510120, China
| | - Shenhai Wei
- China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University,
Guangzhou 510120, China
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31
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Muramatsu T. Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners. J Biochem 2015; 159:481-90. [PMID: 26684586 PMCID: PMC4846773 DOI: 10.1093/jb/mvv127] [Citation(s) in RCA: 195] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 11/30/2015] [Indexed: 12/31/2022] Open
Abstract
Basigin, also called CD147 or EMMPRIN, is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. Basigin has isoforms; the common form (basigin or basigin-2) has two immunoglobulin domains, and the extended form (basigin-1) has three. Basigin is the receptor for cyclophilins, S100A9 and platelet glycoprotein VI, whereas basigin-1 serves as the receptor for the rod-derived cone viability factor. Basigin tightly associates with monocarboxylate transporters and is essential for their cell surface translocation and activities. In the same membrane plane, basigin also associates with other proteins including GLUT1, CD44 and CD98. The carbohydrate portion of basigin is recognized by lectins, such as galectin-3 and E-selectin. These molecular recognitions form the basis for the role of basigin in the transport of nutrients, migration of inflammatory leukocytes and induction of matrix metalloproteinases. Basigin is important in vision, spermatogenesis and other physiological phenomena, and plays significant roles in the pathogenesis of numerous diseases, including cancer. Basigin is also the receptor for an invasive protein RH5, which is present in malaria parasites.
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Affiliation(s)
- Takashi Muramatsu
- Professor Emeritus, Nagoya University, 1204 Hirabariminami 2, Tenpaku, Nagoya 468-0020, Japan
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32
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Wu X, Qiao B, Liu Q, Zhang W. Upregulation of extracellular matrix metalloproteinase inducer promotes hypoxia-induced epithelial-mesenchymal transition in esophageal cancer. Mol Med Rep 2015; 12:7419-24. [PMID: 26458866 DOI: 10.3892/mmr.2015.4410] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 07/17/2015] [Indexed: 01/12/2023] Open
Abstract
Extracellular matrix metalloproteinase inducer (EMMPRIN) exerts important roles in tumor progression, including angiogenesis, metastasis and therapy resistance. The epithelial‑mesenchymal transition (EMT), which is induced by hypoxia, is an important process in cancer metastasis. However, the association between hypoxia and EMMPRIN remains to be elucidated in esophageal cancer. The expression of EMMPRIN was determined by western blotting and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and EMT markers were analyzed by western blotting, RT‑qPCR and immunofluoresence. The migration and invasion of cells was investigated by Transwell assay. The results indicated that the expression levels of EMMPRIN in esophageal cancer cells were markedly higher compared with those in normal esophageal cells. EMMPRIN was able to promote esophageal cancer cell migration and invasion under both hypoxic or normoxic conditions, as demonstrated by the migration and invasion assay. The expression levels of E‑cadherin were reduced, and those of snail family zinc finger 1, fibronectin, α‑smooth muscle actin and fibroblast secretory protein 1 increased in esophageal cancer cells following treatment with human recombinant EMMPRIN under hypoxic conditions. The mRNA expression levels of the EMT markers were similar to those of the protein expression levels. Furthermore, the results demonstrated that EMMPRIN was regulated by hypoxia‑inducible factor (HIF)‑1α. These data suggested that EMMPRIN promoted metastasis and the EMT in esophageal cancer cells by regulating HIF-1α.
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Affiliation(s)
- Xiaopeng Wu
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Bin Qiao
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Qin Liu
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Weiguo Zhang
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
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Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1863:438-448. [PMID: 26278055 DOI: 10.1016/j.bbamcr.2015.08.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 08/08/2015] [Accepted: 08/10/2015] [Indexed: 12/15/2022]
Abstract
Various, diverse molecules contribute to the tumor microenvironment and influence invasion and metastasis. In this review, the roles of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) in the tumor microenvironment and sensitivity to therapy will be discussed. The lipocalin family of proteins has many important functions. For example when NGAL forms a complex with MMP-9 it increases its stability which is important in cancer metastasis. Small hydrophobic molecules are bound by NGAL which can alter their entry into and efflux from cells. Iron transport and storage are also influenced by NGAL activity. Regulation of iron levels is important for survival in the tumor microenvironment as well as metastasis. Innate immunity is also regulated by NGAL as it can have bacteriostatic properties. NGAL and MMP-9 expression may also affect the sensitivity of cancer cells to chemotherapy as well as targeted therapy. Thus NGAL and MMP-9 play important roles in key processes involved in metastasis as well as response to therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
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34
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Pais V, Pais ES. Intercellular communication by extracellular vesicles with emphasis on the roles of cordocytes in the human brain. An ultrastructural study. Ultrastruct Pathol 2015; 39:177-86. [PMID: 25569160 DOI: 10.3109/01913123.2014.981327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We describe in this work the presence of extracellular vesicles (EVs) along different cell types, especially cordocytes, in various clinical conditions of the human brain (atherothrombotic disease, cerebral tumors, hygroma durae matris, intracerebral cysts, Moyamoya disease and parenchymatous hematoma) using transmission electron microscopy (TEM). EVs, illustrated as exosomes and microvesicles, were causally related to cell-to-cell communication, and other vital functions of resident cells around the brain parenchyma, either around the cortical vessels or into the subarachnoid space and the reticular arachnoid. Our direct demonstration by TEM of these information transporters in all locations and situations where the cordocytes play coordinating and regulating roles, producing and delivering a significant number of EVs to their targets, remains to be better documented in future studies. This first study on this topic showed clearly that EVs can be important modulators of cell functions with roles in cell activation, differentiation, phenotypic change, cancer progression, from precursor/stem cells to tumoral phenotypes, because EVs are released en masse during key interactions and certain moments.
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Affiliation(s)
- Viorel Pais
- Independent Researcher , Bucharest , Romania and
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35
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Menck K, Scharf C, Bleckmann A, Dyck L, Rost U, Wenzel D, Dhople VM, Siam L, Pukrop T, Binder C, Klemm F. Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN. J Mol Cell Biol 2014; 7:143-53. [PMID: 25503107 PMCID: PMC4401212 DOI: 10.1093/jmcb/mju047] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 10/11/2014] [Indexed: 12/13/2022] Open
Abstract
Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN.
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Affiliation(s)
- Kerstin Menck
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Christian Scharf
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medicine Greifswald, Walther-Rathenau-Str. 43-45, 17475 Greifswald, Germany Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487 Greifswald, Germany
| | - Annalen Bleckmann
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Lydia Dyck
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Ulrike Rost
- Institute for Organic and Biomolecular Chemistry, University of Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
| | - Dirk Wenzel
- Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
| | - Vishnu M Dhople
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487 Greifswald, Germany
| | - Laila Siam
- Department of Neurosurgery, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Tobias Pukrop
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Claudia Binder
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Florian Klemm
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany Present address: Sloan Kettering Institute, Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 417 E 68th St., Z-1306, New York, NY 10065, USA
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Xiong L, Edwards CK, Zhou L. The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature. Int J Mol Sci 2014; 15:17411-41. [PMID: 25268615 PMCID: PMC4227170 DOI: 10.3390/ijms151017411] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/08/2014] [Accepted: 09/16/2014] [Indexed: 02/05/2023] Open
Abstract
CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions. CD147 is also important to many organ systems. This review will provide a detailed overview of the discovery, characterization, molecular structure, diverse biological functions and regulatory mechanisms of CD147 in human physiological and pathological processes. In particular, recent studies have demonstrated the potential application of CD147 not only as a phenotypic marker of activated regulatory T cells but also as a potential diagnostic marker for early-stage disease. Moreover, CD147 is recognized as an effective therapeutic target for hepatocellular carcinoma (HCC) and other cancers, and exciting clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies.
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Affiliation(s)
- Lijuan Xiong
- Central Laboratory, Navy General Hospital, Beijing 100048, China.
| | - Carl K Edwards
- National Key Laboratory of Biotherapy and Cancer Research (NKLB), West China Hospital and Medical School, Sichuan University, Chengdu 610041, China.
| | - Lijun Zhou
- Central Laboratory, Navy General Hospital, Beijing 100048, China.
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Djaldetti M, Bessler H. Modulators affecting the immune dialogue between human immune and colon cancer cells. World J Gastrointest Oncol 2014; 6:129-38. [PMID: 24834143 PMCID: PMC4021329 DOI: 10.4251/wjgo.v6.i5.129] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 01/03/2014] [Accepted: 04/11/2014] [Indexed: 02/05/2023] Open
Abstract
The link between chronic inflammation and colorectal cancer has been well established. The events proceeding along tumorigenesis are complicated and involve cells activated at the cancer microenvironment, tumor infiltrating polymorphonuclears, immune cells including lymphocyte subtypes and peripheral blood mononuclear cells (PBMC), as well as tumor-associated macrophages. The immune cells generate inflammatory cytokines, several of them playing a crucial role in tumorigenesis. Additional factors, such as gene expression regulated by cytokines, assembling of tumor growth- and transforming factors, accelerated angiogenesis, delayed apoptosis, contribute all to initiation, development and migration of tumor cells. Oxygen radical species originating from the inflammatory area promote cell mutation and cancer proliferation. Tumor cells may over-express pro-inflammatory mediators that in turn activate immune cells for inflammatory cytokines production. Consequently, an immune dialogue emerges between immune and cancer cells orchestrated through a number of activated molecular pathways. Cytokines, encompassing migration inhibitory factor, transforming growth factor beta 1, tumor necrosis factor-α, Interleukin (IL)-6, IL-10, IL-12, IL-17, IL-23 have been reported to be involved in human cancer development. Some cytokines, namely IL-5, IL-6, IL-10, IL-22 and growth factors promote tumor development and metastasis, and inhibit apoptosis via activation of signal transducer activator transcription-3 transcription factor. Colon cancer environment comprises mesenchymal, endothelial and immune cells. Assessment of the interaction between components in the tumor environment and malignant cells requires a reconsideration of a few topics elucidating the role of chronic inflammation in carcinogenesis, the function of the immune cells expressed by inflammatory cytokine production, the immunomodulation of cancer cells and the existence of a cross-talk between immune and malignant cells leading to a balance in cytokine production. It is conceivable that the prevalence of anti-inflammatory cytokine production by PBMC in the affected colonic mucosa will contribute to the delay, or even to halt down malignant expansion. Targeting the interplay between immune and cancer cells by mediators capable to alter cytokine secretion toward increased anti-inflammatory cytokine release by PBMC and tumor associated macrophages, may serve as an additional strategy for treatment of malignant diseases. This review will focus on the inflammatory events preceding tumorigenesis in general, and on a number of modulators capable to affect colon cancer cell-induced production of inflammatory cytokines by PBMC through alteration of the immune cross-talk between PBMC and cancer cells.
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38
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Lee HD, Kim YH, Kim DS. Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking. Eur J Immunol 2014; 44:1156-69. [DOI: 10.1002/eji.201343660] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 11/08/2013] [Accepted: 12/09/2013] [Indexed: 12/30/2022]
Affiliation(s)
- Hee Doo Lee
- Department of Biochemistry; College of Life Science and Biotechnology; Yonsei University; Seoul Korea
| | - Yeon Hyang Kim
- Department of Biochemistry; College of Life Science and Biotechnology; Yonsei University; Seoul Korea
| | - Doo-Sik Kim
- Department of Biochemistry; College of Life Science and Biotechnology; Yonsei University; Seoul Korea
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