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1
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Liu S, Chen H, Gagea M, Federico L, Zhang F, Gomez J, Do KA, Symmans WF, Hortobagyi GN, Mills GB, Gonzalez-Angulo AM, Tripathy D. ADAMs contribute to triple negative breast cancer via mTORC1 pathway: targeting ADAM-mTOR axis improves efficacy. Cancer Lett 2025; 626:217775. [PMID: 40339955 DOI: 10.1016/j.canlet.2025.217775] [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: 12/09/2024] [Revised: 04/28/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, and overexpression of all the individual ADAMs tested are correlated with poor patient survival, making it unlikely that targeting a single ADAM member would be effective. Reverse-phase protein array and multiplexed immunofluorescence revealed that ADAM10/15/17 expression was associated with activated mTOR signaling. Individual knockdown of ADAM10, ADAM15, or ADAM17 modestly reduced mTOR signaling, cellular proliferation and survival. However, the concurrent knockdown of the three ADAMs drastically decreased mTOR signaling and cellular aggressiveness. Consistently, combined targeting of ADAMs and mTOR increased inhibitory efficacy compared to monotherapy in ADAM-mTOR-activated tumor growth and invasion in vitro and in immunodeficient and immunocompetent mice. These results establish a functional link between ADAMs and activation of mTOR signaling, suggesting the ADAM-mTOR axis as a therapeutic target and biomarker for ADAM-enriched TNBC and, potentially, other tumor lineages with high ADAM activity.
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Affiliation(s)
| | - Huiqin Chen
- Department of Breast Medical Oncology, USA; Department of of Biostatistics, USA
| | - Mihai Gagea
- Department of Veterinary Medicine and Surgery, USA
| | | | | | | | | | - William F Symmans
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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2
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Wenta T, Nastaly P, Lipinska B, Manninen A. Remodeling of the extracellular matrix by serine proteases as a prerequisite for cancer initiation and progression. Matrix Biol 2024; 134:197-219. [PMID: 39500383 DOI: 10.1016/j.matbio.2024.10.007] [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: 04/30/2024] [Revised: 10/16/2024] [Accepted: 10/31/2024] [Indexed: 11/25/2024]
Abstract
The extracellular matrix (ECM) serves as a physical scaffold for tissues that is composed of structural proteins such as laminins, collagens, proteoglycans and fibronectin, forming a three dimensional network, and a wide variety of other matrix proteins with ECM-remodeling and signaling functions. The activity of ECM-associated signaling proteins is tightly regulated. Thus, the ECM serves as a reservoir for water and growth regulatory signals. The ECM architecture is dynamically modulated by multiple serine proteases that process both structural and signaling proteins to regulate physiological processes such as organogenesis and tissue homeostasis but they also contribute to pathological events, especially cancer progression. Here, we review the current literature regarding the role of ECM remodeling by serine proteases (KLKs, uPA, furin, HtrAs, granzymes, matriptase, hepsin) in tumorigenesis.
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Affiliation(s)
- Tomasz Wenta
- Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk, Poland.
| | - Paulina Nastaly
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland
| | - Barbara Lipinska
- Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk, Poland
| | - Aki Manninen
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.
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3
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Radisky ES. Extracellular proteolysis in cancer: Proteases, substrates, and mechanisms in tumor progression and metastasis. J Biol Chem 2024; 300:107347. [PMID: 38718867 PMCID: PMC11170211 DOI: 10.1016/j.jbc.2024.107347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/08/2024] [Accepted: 04/25/2024] [Indexed: 06/02/2024] Open
Abstract
A vast ensemble of extracellular proteins influences the development and progression of cancer, shaped and reshaped by a complex network of extracellular proteases. These proteases, belonging to the distinct classes of metalloproteases, serine proteases, cysteine proteases, and aspartic proteases, play a critical role in cancer. They often become dysregulated in cancer, with increases in pathological protease activity frequently driven by the loss of normal latency controls, diminished regulation by endogenous protease inhibitors, and changes in localization. Dysregulated proteases accelerate tumor progression and metastasis by degrading protein barriers within the extracellular matrix (ECM), stimulating tumor growth, reactivating dormant tumor cells, facilitating tumor cell escape from immune surveillance, and shifting stromal cells toward cancer-promoting behaviors through the precise proteolysis of specific substrates to alter their functions. These crucial substrates include ECM proteins and proteoglycans, soluble proteins secreted by tumor and stromal cells, and extracellular domains of cell surface proteins, including membrane receptors and adhesion proteins. The complexity of the extracellular protease web presents a significant challenge to untangle. Nevertheless, technological strides in proteomics, chemical biology, and the development of new probes and reagents are enabling progress and advancing our understanding of the pivotal importance of extracellular proteolysis in cancer.
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Affiliation(s)
- Evette S Radisky
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
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4
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Navasatli SA, Vahdati SN, Arjmand TF, Mohammadi far M, Behboudi H. New insight into the role of the ADAM protease family in breast carcinoma progression. Heliyon 2024; 10:e24805. [PMID: 38317965 PMCID: PMC10839977 DOI: 10.1016/j.heliyon.2024.e24805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 02/07/2024] Open
Abstract
Protease and adhesion molecules play a very emphasized role in the occurrence or progression of metastasis in many types of cancers. In this context, a molecule that contains both protease and adhesion functions play a crucial role in metastasis. ADAMs (a disintegrin and metalloprotease) are molecules with this special characteristic. Recently, a lot of attention has been attracted to various ADAM molecules and researchers have tried to elucidate the role of ADAMs in breast cancer occurrence and progression. Disrupting ADAMs protease and adhesion capabilities can lead to the discovery of worthy therapeutic targets in breast cancer treatment. In this review, we intend to discuss the mechanism of action of various ADAM molecules, their relation to pathogenic processes of breast cancer, and their potential as possible targets for breast cancer treatment.
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Affiliation(s)
- Sepideh Aliniaye Navasatli
- Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran
| | - Saeed Niazi Vahdati
- Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran
| | - Tahura Fayeghi Arjmand
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marjan Mohammadi far
- Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran
| | - Hossein Behboudi
- Department of Biology, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Tehran, Iran
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5
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Eugenín J, Eugenín-von Bernhardi L, von Bernhardi R. Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases. Front Mol Neurosci 2023; 16:1249320. [PMID: 37818457 PMCID: PMC10561274 DOI: 10.3389/fnmol.2023.1249320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/06/2023] [Indexed: 10/12/2023] Open
Abstract
The chemokine fractalkine (FKN, CX3CL1), a member of the CX3C subfamily, contributes to neuron-glia interaction and the regulation of microglial cell activation. Fractalkine is expressed by neurons as a membrane-bound protein (mCX3CL1) that can be cleaved by extracellular proteases generating several sCX3CL1 forms. sCX3CL1, containing the chemokine domain, and mCX3CL1 have high affinity by their unique receptor (CX3CR1) which, physiologically, is only found in microglia, a resident immune cell of the CNS. The activation of CX3CR1contributes to survival and maturation of the neural network during development, glutamatergic synaptic transmission, synaptic plasticity, cognition, neuropathic pain, and inflammatory regulation in the adult brain. Indeed, the various CX3CL1 forms appear in some cases to serve an anti-inflammatory role of microglia, whereas in others, they have a pro-inflammatory role, aggravating neurological disorders. In the last decade, evidence points to the fact that sCX3CL1 and mCX3CL1 exhibit selective and differential effects on their targets. Thus, the balance in their level and activity will impact on neuron-microglia interaction. This review is focused on the description of factors determining the emergence of distinct fractalkine forms, their age-dependent changes, and how they contribute to neuroinflammation and neurodegenerative diseases. Changes in the balance among various fractalkine forms may be one of the mechanisms on which converge aging, chronic CNS inflammation, and neurodegeneration.
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Affiliation(s)
- Jaime Eugenín
- Facultad de Química y Biología, Departamento de Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | | | - Rommy von Bernhardi
- Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Santiago, Chile
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6
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Rabinowitsch AI, Maretzky T, Weskamp G, Haxaire C, Tueshaus J, Lichtenthaler SF, Monette S, Blobel CP. Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice. J Cell Sci 2023; 136:jcs260910. [PMID: 37282854 PMCID: PMC10357010 DOI: 10.1242/jcs.260910] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/31/2023] [Indexed: 06/08/2023] Open
Abstract
Tylosis with oesophageal cancer (TOC) is a rare familial disorder caused by cytoplasmic mutations in inactive rhomboid 2 (iRhom2 or iR2, encoded by Rhbdf2). iR2 and the related iRhom1 (or iR1, encoded by Rhbdf1) are key regulators of the membrane-anchored metalloprotease ADAM17, which is required for activating EGFR ligands and for releasing pro-inflammatory cytokines such as TNFα (or TNF). A cytoplasmic deletion in iR2, including the TOC site, leads to curly coat or bare skin (cub) in mice, whereas a knock-in TOC mutation (toc) causes less severe alopecia and wavy fur. The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin (Areg) and Adam17, as loss of one allele of either gene rescues the fur phenotypes. Remarkably, we found that iR1-/- iR2cub/cub mice survived, despite a lack of mature ADAM17, whereas iR2cub/cub Adam17-/- mice died perinatally, suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity. The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner. Our findings provide new insights into the role of the cytoplasmic domain of iR2 in vivo, with implications for the treatment of TOC patients.
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Affiliation(s)
- Ariana I. Rabinowitsch
- Tri-Institutional MD/PhD Program, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, The Rockefeller University, New York, NY 10021, USA
- Program in Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Thorsten Maretzky
- Inflammation Program and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Gisela Weskamp
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Coline Haxaire
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Johanna Tueshaus
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
- Institute for Advanced Study, Technical University of Munich, 85748 Garching, Germany
| | - Stefan F. Lichtenthaler
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
- Institute for Advanced Study, Technical University of Munich, 85748 Garching, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
| | - Sébastien Monette
- Tri-Institutional Laboratory of Comparative Pathology, Hospital for Special Surgery, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY 10021, USA
| | - Carl P. Blobel
- Tri-Institutional MD/PhD Program, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, The Rockefeller University, New York, NY 10021, USA
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
- Institute for Advanced Study, Technical University of Munich, 85748 Garching, Germany
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA
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7
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Badenes M, Burbridge E, Oikonomidi I, Amin A, de Carvalho É, Kosack L, Mariano C, Domingos P, Faísca P, Adrain C. The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth. Life Sci Alliance 2023; 6:e202201644. [PMID: 36720499 PMCID: PMC9889915 DOI: 10.26508/lsa.202201644] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/22/2022] [Accepted: 01/03/2023] [Indexed: 02/02/2023] Open
Abstract
The metalloprotease ADAM17 is a sheddase of key molecules, including TNF and epidermal growth factor receptor ligands. ADAM17 exists within an assemblage, the "sheddase complex," containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology. The FERM domain-containing protein iTAP/Frmd8 is an iRhom-binding protein that prevents the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP/Frmd8 have not been addressed, we characterized the impact of iTAP/Frmd8 loss on ADAM17-associated phenotypes in mice. We show that iTAP/Frmd8 KO mice exhibit defects in inflammatory and intestinal epithelial barrier repair functions, but not the collateral defects associated with global ADAM17 loss. Furthermore, we show that iTAP/Frmd8 regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP/Frmd8 may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, while avoiding the collateral impact on the vital functions associated with the widespread inhibition of ADAM17.
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Affiliation(s)
- Marina Badenes
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Faculty of Veterinary Medicine, Lusofona University, Lisbon, Portugal
- Faculty of Veterinary Nursing, Polytechnic Institute of Lusofonia, Lisbon, Portugal
| | - Emma Burbridge
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | | | - Abdulbasit Amin
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria
| | - Érika de Carvalho
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Instituto de Tecnologia Química da Universidade Nova de Lisboa (ITQB-Nova), Oeiras, Portugal
| | | | | | - Pedro Domingos
- Instituto de Tecnologia Química da Universidade Nova de Lisboa (ITQB-Nova), Oeiras, Portugal
| | - Pedro Faísca
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Colin Adrain
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
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8
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Tang BY, Ge J, Wu Y, Wen J, Tang XH. The Role of ADAM17 in Inflammation-Related Atherosclerosis. J Cardiovasc Transl Res 2022; 15:1283-1296. [PMID: 35648358 DOI: 10.1007/s12265-022-10275-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 05/06/2022] [Indexed: 10/18/2022]
Abstract
Atherosclerosis is a chronic inflammatory disease that poses a huge economic burden due to its extremely poor prognosis. Therefore, it is necessary to explore potential mechanisms to improve the prevention and treatment of atherosclerosis. A disintegrin and metalloprotease 17 (ADAM17) is a cell membrane-bound protein that performs a range of functions through membrane protein shedding and intracellular signaling. ADAM17-mediated inflammation has been identified to be an important contributor to atherosclerosis; however, the specific relationship between its multiple regulatory roles and the pathogenesis of atherosclerosis remains unclear. Here, we reviewed the activation, function, and regulation of ADAM17, described in detail the role of ADAM17-mediated inflammatory damage in atherosclerosis, and discussed several controversial points. We hope that these insights into ADAM17 biology will lead to rational management of atherosclerosis. ADAM17 promotes vascular inflammation in endothelial cells, smooth muscle cells, and macrophages, and regulates the occurrence and development of atherosclerosis.
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Affiliation(s)
- Bai-Yi Tang
- Department of Cardiology, Third Xiang-Ya Hospital, Central South University, 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Jin Ge
- Department of Cardiology, Third Xiang-Ya Hospital, Central South University, 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Yang Wu
- Department of Cardiology, Third Hospital of Changsha, 176 W. Laodong Road, Changsha, 410015, Hunan, China
| | - Juan Wen
- Department of Cardiology, Third Xiang-Ya Hospital, Central South University, 138 Tongzipo Road, Changsha, 410013, Hunan, China.
| | - Xiao-Hong Tang
- Department of Cardiology, Third Xiang-Ya Hospital, Central South University, 138 Tongzipo Road, Changsha, 410013, Hunan, China.
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9
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Sieber B, Lu F, Stribbling SM, Grieve AG, Ryan AJ, Freeman M. iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells. J Cell Sci 2022; 135:jcs259949. [PMID: 35971826 PMCID: PMC9482348 DOI: 10.1242/jcs.259949] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/05/2022] [Indexed: 12/24/2022] Open
Abstract
Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer. Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhom proteins, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17. Here, we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 (also known as RHBDF2) to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing the cytoplasmic domain of iRhom2 as a central component of a positive feedback loop in lung cancer cells. This article has an associated First Person interview with the first authors of the paper.
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Affiliation(s)
- Boris Sieber
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Fangfang Lu
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | | | - Adam G. Grieve
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Anderson J. Ryan
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - Matthew Freeman
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
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10
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Fabbi M, Costa D, Russo D, Arenare L, Gaggero G, Signoriello S, Scambia G, Pisano C, Colombo N, Losito NS, Filaci G, Spina A, Califano D, Scognamiglio G, Gadducci A, Mezzanzanica D, Bagnoli M, Ferrini S, Canzonieri V, Chiodini P, Perrone F, Pignata S. Analysis of A Disintegrin and Metalloprotease 17 (ADAM17) Expression as a Prognostic Marker in Ovarian Cancer Patients Undergoing First-Line Treatment Plus Bevacizumab. Diagnostics (Basel) 2022; 12:diagnostics12092118. [PMID: 36140519 PMCID: PMC9498026 DOI: 10.3390/diagnostics12092118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/20/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
To find prognostic factors for advanced ovarian cancer patients undergoing first-line therapy with carboplatin, paclitaxel and bevacizumab, we investigated the expression of a disintegrin and metalloprotease 17 (ADAM17) in cancer tissues. ADAM17 has been involved in ovarian cancer development, progression and cell resistance to cisplatin. Tissue microarrays from 309 ovarian cancer patients enrolled in the MITO16A/MANGO-OV2 clinical trial were analyzed by immunohistochemistry for ADAM17 protein expression. Intensity and extent of staining were combined into a semi-quantitative visual grading system (H score) which was related to clinicopathological characteristics of cases and the clinical outcome of patients by univariate and multivariate Cox regression models. ADAM17 immunostaining was detected in most samples, mainly localized in the tumor cells, with variable intensity across the cohort. Kaplan–Meier survival curves, generated according to the best cut-off value for the ADAM17 H score, showed that high ADAM17 expression was associated with worse prognosis for PFS and OS. However, after the application of a shrinkage procedure to adjust for overfitting hazard ratio estimates, the ADAM17 value as prognostic factor was lost. As subgroup analysis suggested that ADAM17 expression could be prognostically relevant in cases with no residual disease at baseline, further studies in this patient category may be worth planning.
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Affiliation(s)
- Marina Fabbi
- UO Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence:
| | - Delfina Costa
- UO Oncologia Molecolare e Angiogenesi, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Daniela Russo
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Laura Arenare
- Clinical Trials Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Gabriele Gaggero
- UO Anatomia Patologica Ospedaliera, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Simona Signoriello
- Department of Mental Health and Public Medicine, Section of Statistics, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Giovanni Scambia
- Department of Women and Child Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Department of Life Science and Public Health, Catholic University of Sacred Heart, Largo Agostino Gemelli, 00168 Rome, Italy
| | - Carmela Pisano
- Urogynecological Medical Oncology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Nicoletta Colombo
- European Institute of Oncology IRCCS, University of Milan-Bicocca, 20126 Milan, Italy
| | - Nunzia Simona Losito
- Pathology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Gilberto Filaci
- UO Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Anna Spina
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Daniela Califano
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Giosuè Scognamiglio
- Pathology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Angiolo Gadducci
- Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, 56127 Pisa, Italy
| | - Delia Mezzanzanica
- Molecular Therapies Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Marina Bagnoli
- Molecular Therapies Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Silvano Ferrini
- UO Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Paolo Chiodini
- Department of Mental Health and Public Medicine, Section of Statistics, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Francesco Perrone
- Clinical Trials Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Sandro Pignata
- Urogynecological Medical Oncology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
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11
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Li H, Chang HM, Li S, Klausen C, Shi Z, Leung PC. Characterization of the roles of amphiregulin and transforming growth factor β1 in microvasculature-like formation in human granulosa-lutein cells. Front Cell Dev Biol 2022; 10:968166. [PMID: 36092732 PMCID: PMC9448859 DOI: 10.3389/fcell.2022.968166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022] Open
Abstract
Vascular endothelial-cadherin (VE-cadherin) is an essential component that regulates angiogenesis during corpus luteum formation. Amphiregulin (AREG) and transforming growth factor β1 (TGF-β1) are two intrafollicular factors that possess opposite functions in directing corpus luteum development and progesterone synthesis in human granulosa-lutein (hGL) cells. However, whether AREG or TGF-β1 regulates the VE-cadherin expression and subsequent angiogenesis in the human corpus luteum remains to be elucidated. Results showed that hGL cells cultured on Matrigel spontaneously formed capillary-like and sprout-like microvascular networks. Results of specific inhibitor treatment and small interfering RNA-mediated knockdown revealed that AREG promoteed microvascular-like formation in hGL cells by upregulating the VE-cadherin expression mediated by the epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathway. However, TGF-β1 suppressed microvascular-like formation in hGL cells by downregulating VE-cadherin expression mediated by the activin receptor-like kinase (ALK)5-Sma- and Mad-related protein (SMAD)2/3/4 signaling pathway. Collectively, this study provides important insights into the underlying molecular mechanisms by which TGF-β1 and AREG differentially regulate corpus luteum formation in human ovaries.
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Affiliation(s)
- Hui Li
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Key Laboratory of Animal Breeding and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Department of Obstetrics and Gynaecology, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Hsun-Ming Chang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
- *Correspondence: Hsun-Ming Chang, ; Peter C.K. Leung,
| | - Saijiao Li
- Department of Obstetrics and Gynaecology, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
- Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Christian Klausen
- Department of Obstetrics and Gynaecology, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Zhendan Shi
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Key Laboratory of Animal Breeding and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Peter C.K. Leung
- Department of Obstetrics and Gynaecology, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Hsun-Ming Chang, ; Peter C.K. Leung,
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12
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Gnosa S, Puig-Blasco L, Piotrowski KB, Freiberg ML, Savickas S, Madsen DH, Auf dem Keller U, Kronqvist P, Kveiborg M. ADAM17-mediated EGFR ligand shedding directs macrophage promoted cancer cell invasion. JCI Insight 2022; 7:155296. [PMID: 35998057 DOI: 10.1172/jci.insight.155296] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Macrophages in the tumor microenvironment have a significant impact on tumor progression. Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor progression. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of ADAM proteases, which are key mediators of cell-cell signaling, to the expression of pro-tumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several pro-tumorigenic markers in neighboring macrophages in vitro as well as in mouse models. Moreover, ADAM17-/- educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using mass spectrometry-based proteomics and ELISA, we identified HB-EGF and AREG, shed by ADAM17 in the cancer cells, as the implicated molecular mediators of macrophage education. Additionally, RNA-seq and ELISA experiments revealed that ADAM17-dependent HB-EGF-ligand release induces the expression and secretion of CXCL chemokines in macrophages, which in turn stimulates cancer cell invasion.In conclusion, we provide evidence that ADAM17 mediates a paracrine EGFR-ligand-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.
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Affiliation(s)
| | - Laia Puig-Blasco
- Biotech Research and Innovation Centre, Copenhagen University, Copenhagen, Denmark
| | | | - Marie L Freiberg
- Biotech Research and Innovation Centre, Copenhagen University, Copenhagen, Denmark
| | - Simonas Savickas
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Copenhagen, Denmark
| | - Daniel H Madsen
- Center for Cancer Immune Therapy (CCIT), Department of Haematology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Copenhagen, Denmark
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13
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Kawai T, Elliott KJ, Scalia R, Eguchi S. Contribution of ADAM17 and related ADAMs in cardiovascular diseases. Cell Mol Life Sci 2021; 78:4161-4187. [PMID: 33575814 PMCID: PMC9301870 DOI: 10.1007/s00018-021-03779-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/23/2020] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Abstract
A disintegrin and metalloproteases (ADAMs) are key mediators of cell signaling by ectodomain shedding of various growth factors, cytokines, receptors and adhesion molecules at the cellular membrane. ADAMs regulate cell proliferation, cell growth, inflammation, and other regular cellular processes. ADAM17, the most extensively studied ADAM family member, is also known as tumor necrosis factor (TNF)-α converting enzyme (TACE). ADAMs-mediated shedding of cytokines such as TNF-α orchestrates immune system or inflammatory cascades and ADAMs-mediated shedding of growth factors causes cell growth or proliferation by transactivation of the growth factor receptors including epidermal growth factor receptor. Therefore, increased ADAMs-mediated shedding can induce inflammation, tissue remodeling and dysfunction associated with various cardiovascular diseases such as hypertension and atherosclerosis, and ADAMs can be a potential therapeutic target in these diseases. In this review, we focus on the role of ADAMs in cardiovascular pathophysiology and cardiovascular diseases. The main aim of this review is to stimulate new interest in this area by highlighting remarkable evidence.
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Affiliation(s)
- Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Katherine J Elliott
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA.
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14
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Salcedo EC, Winter MB, Khuri N, Knudsen GM, Sali A, Craik CS. Global Protease Activity Profiling Identifies HER2-Driven Proteolysis in Breast Cancer. ACS Chem Biol 2021; 16:712-723. [PMID: 33765766 DOI: 10.1021/acschembio.0c01000] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Differential expression of extracellular proteases and endogenous protease inhibitors has been associated with distinct molecular subtypes of breast cancer. However, due to the tight post-translational regulation of protease activity, protease expression-level data alone are not sufficient to understand the role of proteases in malignant transformation. Therefore, we hypothesized that global profiles of extracellular protease activity could more completely reflect differences observed at the transcriptional level in breast cancer and that subtype-associated protease activity may be leveraged to identify specific proteases that play a functional role in cancer signaling. Here, we used a global peptide library-based approach to profile the activities of proteases within distinct breast cancer subtypes. Analysis of 3651 total peptide cleavages from a panel of well-characterized breast cancer cell lines demonstrated differences in proteolytic signatures between cell lines. Cell line clustering based on protease cleavages within the peptide library expanded upon the expected classification derived from transcriptional profiling. An isogenic cell line model developed to further interrogate proteolysis in the HER2 subtype revealed a proteolytic signature consistent with activation of TGF-β signaling. Specifically, we determined that a metalloprotease involved in TGF-β signaling, BMP1, was upregulated at both the protein (2-fold, P = 0.001) and activity (P = 0.0599) levels. Inhibition of BMP1 and HER2 suppressed invasion of HER2-expressing cells by 35% (P < 0.0001), compared to 15% (P = 0.0086) observed in cells where only HER2 was inhibited. In summary, through global identification of extracellular proteolysis in breast cancer cell lines, we demonstrate subtype-specific differences in protease activity and elucidate proteolysis associated with HER2-mediated signaling.
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15
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Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution. Molecules 2021; 26:molecules26040944. [PMID: 33579029 PMCID: PMC7916773 DOI: 10.3390/molecules26040944] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.
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16
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Bunker EN, Wheeler GE, Chapnick DA, Liu X. Suppression of α-catenin and adherens junctions enhances epithelial cell proliferation and motility via TACE-mediated TGF-α autocrine/paracrine signaling. Mol Biol Cell 2020; 32:348-361. [PMID: 33378218 PMCID: PMC8098817 DOI: 10.1091/mbc.e19-08-0474] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Sustained cell migration is essential for wound healing and cancer metastasis. The epidermal growth factor receptor (EGFR) signaling cascade is known to drive cell migration and proliferation. While the signal transduction downstream of EGFR has been extensively investigated, our knowledge of the initiation and maintenance of EGFR signaling during cell migration remains limited. The metalloprotease TACE (tumor necrosis factor alpha converting enzyme) is responsible for producing active EGFR family ligands in the via ligand shedding. Sustained TACE activity may perpetuate EGFR signaling and reduce a cell’s reliance on exogenous growth factors. Using a cultured keratinocyte model system, we show that depletion of α-catenin perturbs adherens junctions, enhances cell proliferation and motility, and decreases dependence on exogenous growth factors. We show that the underlying mechanism for these observed phenotypical changes depends on enhanced autocrine/paracrine release of the EGFR ligand transforming growth factor alpha in a TACE-dependent manner. We demonstrate that proliferating keratinocyte epithelial cell clusters display waves of oscillatory extracellular signal–regulated kinase (ERK) activity, which can be eliminated by TACE knockout, suggesting that these waves of oscillatory ERK activity depend on autocrine/paracrine signals produced by TACE. These results provide new insights into the regulatory role of adherens junctions in initiating and maintaining autocrine/paracrine signaling with relevance to wound healing and cellular transformation.
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Affiliation(s)
- Eric N Bunker
- Department of Biochemistry, University of Colorado, Boulder, CO 80303
| | - Graycen E Wheeler
- Department of Biochemistry, University of Colorado, Boulder, CO 80303
| | | | - Xuedong Liu
- Department of Biochemistry, University of Colorado, Boulder, CO 80303
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17
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Yu WH, Wu E, Li Y, Hou HH, Yu SSC, Huang PT, Kuo WH, Qi D, Yu CJ. Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells. iScience 2020; 23:101600. [PMID: 33089100 PMCID: PMC7559243 DOI: 10.1016/j.isci.2020.101600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/21/2020] [Accepted: 09/18/2020] [Indexed: 01/11/2023] Open
Abstract
The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking of p53 in gefitinib-resistant lung CSCs. The nucleolus colocalizations of p53, MUC-1 C-ter, MMP-7 and nucleolin were observed in the CD34+ CXADR+ CD44v3+ gefitinib-resistant EGFRL858R/T790M CSC colonies. MUC-1 C-ter induced a unique porous bulky-ball-shaped, cagelike nucleolus that functions as a nucleus molecular “garage” for potent tumor suppressor, p53. Nucleolus could also facilitate the novel sub-nucleus compartment for proteolytic processing p53 by MMP-7 to generate a 35 kDa fragment. Moreover, we show that salinomycin, an anti-CSC agent, disrupts nucleolus by inducing nucleoplasm translocation of p53 and sensitizing CSC to chemotherapy drugs. Thus, this study highlights the MMP-7-MUC-1-p53 axis in nucleolus as a potential therapeutic target for anti-CSCs to resolve the chemotherapy-resistance dilemma.
MMP-7 cleaves the SEA domain of MUC-1 and releases MUC-1 C-ter MUC-1 C-ter mediates bulky-ball-like nucleolus assembly trapping p53 in nucleolus MMP-7 cleaves p53 to 35 kDa fragments in the nucleolus of gefitinib-resistant CSCs Salinomycin induces p53 nucleoplasm translocation sensitizing CSCs to gefitinib
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Affiliation(s)
- Wei-Hsuan Yu
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.,Molecular Image Center, College of Medicine. National Taiwan University, Taipei 10051, Taiwan
| | - Erxi Wu
- Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 76508, USA.,Colleges of Medicine and Pharmacy, Texas A&M University, Health Science Center, College Station, TX 77843, USA.,Livestrong Cancer Institutes and Department of Oncology, Dell Medical School, the University of Texas at Austin, Austin, TX 78712, USA
| | - Yongqing Li
- Department of Surgery, University of Michigan Health Systems North Campus Research Complex, Ann Arbor, MI 48109, USA
| | - Hsin-Han Hou
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Shuan-Su C Yu
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Po-Tsang Huang
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Wen-Hung Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei 10048, Taiwan
| | - Dan Qi
- Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 76508, USA
| | - Chong-Jen Yu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan
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18
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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: 22] [Impact Index Per Article: 4.4] [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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19
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Schumacher N, Rose-John S, Schmidt-Arras D. ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation. Int J Mol Sci 2020; 21:ijms21145133. [PMID: 32698506 PMCID: PMC7404302 DOI: 10.3390/ijms21145133] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also termed ectodomain shedding. Members of the family of A disintegrin and metalloproteases (ADAM) are major mediators of ectodomain shedding and therefore initiators of paracrine signal transduction. In this review, we summarize the current knowledge on how ADAM proteases on tumour cells but also on cells of the tumour micro-environment contribute to the formation of gastrointestinal tumours, and discuss how these processes can be exploited pharmacologically.
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20
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Lipphardt M, Song JW, Goligorsky MS. Sirtuin 1 and endothelial glycocalyx. Pflugers Arch 2020; 472:991-1002. [PMID: 32494847 PMCID: PMC7376508 DOI: 10.1007/s00424-020-02407-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/21/2020] [Accepted: 05/22/2020] [Indexed: 02/08/2023]
Abstract
Sirtuin1 deficiency or reduced activity comprises one of the hallmarks of diseases as diverse as chronic cardiovascular, renal, and metabolic, some malignancies, and infections, as well as aging-associated diseases. In a mouse model of endothelium-limited defect in sirtuin 1 deacetylase activity, we found a dramatic reduction in the volume of endothelial glycocalyx. This was associated with the surge in the levels of one of key scaffolding heparan sulfate proteoglycans of endothelial glycocalyx, syndecan-4, and specifically, its extracellular domain (ectodomain). We found that the defect in endothelial sirtuin 1 deacetylase activity is associated with (a) elevated basal and stimulated levels of superoxide generation (via the FoxO1 over-acetylation mechanism) and (b) increased nuclear translocation of NF-kB (via p65 over-acetylation mechanism). These findings laid the foundation for the proposed novel function of sirtuin 1, namely, the maintenance of endothelial glycocalyx, particularly manifest in conditions associated with sirtuin 1 depletion. In the forthcoming review, we summarize the emerging conceptual framework of the enhanced glycocalyx degradation in the states of defective endothelial sirtuin 1 function, thus explaining a broad footprint of the syndrome of endothelial dysfunction, from impaired flow-induced nitric oxide production, deterrent leukocytes infiltration, increased endothelial permeability, coagulation, and pro-inflammatory changes to development of microvascular rarefaction and progression of an underlying disease.
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Affiliation(s)
- Mark Lipphardt
- Renal Research Institute, New York Medical College at the Touro University, Valhalla, NY, USA. .,Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Robert-Koch-Straße 40, 37075, Göttingen, Germany.
| | - Jong Wook Song
- Renal Research Institute, New York Medical College at the Touro University, Valhalla, NY, USA.,Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Michael S Goligorsky
- Renal Research Institute, New York Medical College at the Touro University, Valhalla, NY, USA
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21
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Giotopoulou GA, Stathopoulos GT. Effects of Inhaled Tobacco Smoke on the Pulmonary Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1225:53-69. [PMID: 32030647 DOI: 10.1007/978-3-030-35727-6_4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tobacco smoke is a multicomponent mixture of chemical, organic, and inorganic compounds, as well as additive substances and radioactive materials. Many studies have proved the carcinogenicity of various of these compounds through the induction of DNA adducts, mutational potential, epigenetic changes, gene fusions, and chromosomal events. The tumor microenvironment plays an important role in malignant tumor formation and progression through the regulation of expression of key molecules which mediate the recruitment of immune cells to the tumor site and subsequently regulate tumor growth and metastasis. In this chapter, we discuss the effects of inhaled tobacco smoke in the tumor microenvironment of the respiratory tract. The mechanisms underlying these effects as well as their link with tumor progression are analyzed.
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Affiliation(s)
- Georgia A Giotopoulou
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany.
- Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras, Rio, Greece.
| | - Georgios T Stathopoulos
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany
- Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras, Rio, Greece
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22
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Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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23
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Camodeca C, Cuffaro D, Nuti E, Rossello A. ADAM Metalloproteinases as Potential Drug Targets. Curr Med Chem 2019; 26:2661-2689. [PMID: 29589526 DOI: 10.2174/0929867325666180326164104] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 03/12/2018] [Accepted: 03/12/2018] [Indexed: 01/01/2023]
Abstract
The ADAMs, together with ADAMTSs and snake venom metalloproteases (SVMPs), are members of the Adamalysin family. Differences in structural organization, functions and localization are known and their domains, catalytic or non-catalytic, show key roles in the substrate recognition and protease activity. Some ADAMs, as membrane-bound enzymes, show sheddase activity. Sheddases are key to modulation of functional proteins such as the tumor necrosis factor, growth factors, cytokines and their receptors, adhesion proteins, signaling molecules and stress molecules involved in immunity. These activities take part in the regulation of several physiological and pathological processes including inflammation, tumor growth, metastatic progression and infectious diseases. On these bases, some ADAMs are currently investigated as drug targets to develop new alternative therapies in many fields of medicine. This review will be focused on these aspects.
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Affiliation(s)
- Caterina Camodeca
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
| | - Doretta Cuffaro
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
| | - Elisa Nuti
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
| | - Armando Rossello
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
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Huang J, Pan Y, Hu G, Sun W, Jiang L, Wang P, Ding X. SRC fine-tunes ADAM10 shedding activity to promote pituitary adenoma cell progression. FEBS J 2019; 287:190-204. [PMID: 31365784 DOI: 10.1111/febs.15026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/20/2019] [Accepted: 07/29/2019] [Indexed: 12/30/2022]
Abstract
A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a metalloproteinase known to modulate the progression of several types of tumor. However, the role played by ADAM10 in pituitary adenomas is currently unknown, and what factors orchestrate the activation of ADAM10 in this kind of tumor is also unclear. Here, we found that SRC kinase is an ADAM10-interacting partner and that SRC kinase activity is required for this interaction. As a new positive regulator promoting the shedding activity of ADAM10, SRC could compete with calmodulin 1 (CALM1) for ADAM10 binding in a mutually exclusive manner. Strikingly, the interaction between ADAM10 and CALM1 is regulated by SRC activity. Furthermore, we proved that the cytoplasmic region of ADAM10 is required for the shedding activity of ADAM10 upon SRC activation. As a proof-of-concept, we discovered that the combination of ADAM10 and SRC inhibitors can inhibit cell proliferation and migration to a great extent. Thus, our findings shed light on a novel therapeutic strategy to block the tumorigenesis and migration of pituitary adenoma.
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Affiliation(s)
- Jinxiang Huang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yuan Pan
- Department of Neurosurgery, No.971 Hospital of People's Liberation Army Navy, Qingdao, Shandong, China
| | - Guohan Hu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Sun
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lei Jiang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Peng Wang
- Department of Radiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xuehua Ding
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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25
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Saad MI, Rose-John S, Jenkins BJ. ADAM17: An Emerging Therapeutic Target for Lung Cancer. Cancers (Basel) 2019; 11:E1218. [PMID: 31438559 PMCID: PMC6769596 DOI: 10.3390/cancers11091218] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/07/2019] [Accepted: 08/17/2019] [Indexed: 12/23/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). KRAS mutations are a major driver of LAC, and are closely related to cigarette smoking, unlike mutations in the epidermal growth factor receptor (EGFR) which arise in never-smokers. Although the past two decades have seen fundamental progress in the treatment and diagnosis of NSCLC, NSCLC still is predominantly diagnosed at an advanced stage when therapeutic interventions are mostly palliative. A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-α (TNFα)-converting enzyme (TACE), is responsible for the protease-driven shedding of more than 70 membrane-tethered cytokines, growth factors and cell surface receptors. Among these, the soluble interleukin-6 receptor (sIL-6R), which drives pro-inflammatory and pro-tumourigenic IL-6 trans-signaling, along with several EGFR family ligands, are the best characterised. This large repertoire of substrates processed by ADAM17 places it as a pivotal orchestrator of a myriad of physiological and pathological processes associated with the initiation and/or progression of cancer, such as cell proliferation, survival, regeneration, differentiation and inflammation. In this review, we discuss recent research implicating ADAM17 as a key player in the development of LAC, and highlight the potential of ADAM17 inhibition as a promising therapeutic strategy to tackle this deadly malignancy.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University, D-24098 Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
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Xia C, Zhang D, Li Y, Chen J, Zhou H, Nie L, Sun Y, Guo S, Cao J, Zhou F, Li J. Inhibition of hepatocellular carcinoma cell proliferation, migration, and invasion by a disintegrin and metalloproteinase-17 inhibitor TNF484. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2019; 24:26. [PMID: 31007696 PMCID: PMC6450222 DOI: 10.4103/jrms.jrms_129_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 04/30/2018] [Accepted: 07/16/2018] [Indexed: 11/04/2022]
Abstract
Background The aim of this study was to test the effect of TNF484 on cell proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. Materials and Methods Various doses (0, 1, 10, 50, and 100 nM) of TNF484 were applied to the HepG2 and Bel7402 cells, and cell proliferation was measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay after 72 h. Cell migration rate was measured using the xCELLigence system, and the cell invasion ability was examined by the three-dimensional spheroid BME cell invasion assay. The expression level of ADAM17 was also measured with RT-PCR. Results With the treatment of TNF484, the cell proliferation of HepG2 and Bel7402 cells was inhibited in a dose-dependent manner. Moreover, under TNF484 treatment, the cell migration rate as well as cell invasion ability of the HepG2 and Bel7402 cells were suppressed. Conclusion TNF484 could inhibit the cell proliferation, migration, and invasion of some HCC cell lines, making it a potential therapeutic option for liver cancer treatment.
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Affiliation(s)
- Changhong Xia
- Department of Ultrasound, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Dongsheng Zhang
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Yanmei Li
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Jie Chen
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Haibo Zhou
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Long Nie
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Yanyan Sun
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Siyan Guo
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Jianbiao Cao
- Department of Liver Disease, Army General Hospital of PLA, Beijing, China
| | - Fangzheng Zhou
- Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Junlai Li
- Department of Ultrasound, Chinese People's Liberation Army General Hospital, Beijing, China
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Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics. Int J Mol Sci 2018; 19:ijms19124111. [PMID: 30567378 PMCID: PMC6321118 DOI: 10.3390/ijms19124111] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 12/14/2018] [Accepted: 12/17/2018] [Indexed: 12/20/2022] Open
Abstract
Signaling of the receptor tyrosine kinase Axl and its ligand Gas6 is crucially involved in the development of liver fibrosis and hepatocellular carcinoma (HCC) by activation of hepatic stellate cells and modulation of hepatocyte differentiation. Shedding of Axl’s ectodomain leads to the release of soluble Axl (sAxl), which is increased in advanced fibrosis and in early-to-late stage HCC in the presence and absence of cirrhosis. Here, we focus on the dynamics of Axl receptor shedding and delineate possible scenarios how Axl signaling might act as driver of fibrosis progression and HCC development. Based on experimental and clinical data, we discuss the consequences of modifying Axl signaling by sAxl cleavage, as well as cellular strategies to escape from antagonizing effects of Axl shedding by the involvement of the hepatic microenvironment. We emphasize a correlation between free Gas6 and free sAxl levels favoring abundant Gas6/Axl signaling in advanced fibrosis and HCC. The raised scenario provides a solid basis for theranostics allowing the use of sAxl as an accurate diagnostic biomarker of liver cirrhosis and HCC, as well as Axl receptor signaling for therapeutic intervention in stratified HCC patients.
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Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. Cancer Lett 2018; 433:165-175. [DOI: 10.1016/j.canlet.2018.06.040] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 01/02/2023]
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Tyrinova T, Leplina O, Mishinov S, Tikhonova M, Kalinovskiy A, Chernov S, Dolgova E, Stupak V, Voronina E, Bogachev S, Shevela E, Ostanin A, Chernykh E. Defective Dendritic Cell Cytotoxic Activity of High-Grade Glioma Patients' Results from the Low Expression of Membrane TNFα and Can Be Corrected In Vitro by Treatment with Recombinant IL-2 or Exogenic Double-Stranded DNA. J Interferon Cytokine Res 2018; 38:298-310. [PMID: 29932796 DOI: 10.1089/jir.2017.0084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Besides initiation of tumor-specific T cell immunity, dendritic cells (DCs) are endowed with tumoricidal activity. Previously, we showed that monocyte-derived DCs of high-grade glioma patients generated in the presence of interferon alpha (IFNα) (IFN-DCs) have impaired cytotoxic activity against tumor necrosis factor alpha (TNFα)-sensitive HEp-2 tumor cells. Herein, we demonstrate that decreased transmembrane TNFα (tmTNFα) expression, but not soluble TNFα (sTNFα) production by high-grade glioma patient IFN-DCs, determines the defective tumoricidal activity against TNFα-sensitive HEp-2 cells. Blocking TNFα-converting enzyme or stimulation of patient IFN-DCs with rIL-2 or dsDNA enhances tmTNFα expression on IFN-DCs and significantly increases their cytotoxicity. Decreased tmTNFα expression on patient IFN-DCs is not caused by downregulation of pNFκB. Neither rIL-2 nor dsDNA upregulates tmTNFα expression on patient IFN-DCs via an increase of pNFκB. The current study shows an important role of tmTNFα as mediator of IFN-DC tumoricidal activity and as molecular target for the restoration of defective DC killer activity in high-grade glioma patients.
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Affiliation(s)
- Tamara Tyrinova
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Olga Leplina
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Sergey Mishinov
- 2 Department of Neurosurgery, Novosibirsk Research Institute of Traumatology and Orthopedics named after Ya.L. Zivian , Novosibirsk, Russia
| | - Marina Tikhonova
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Anton Kalinovskiy
- 3 Department of Neurosurgery, Federal Neurosurgical Center , Novosibirsk, Russia
| | - Sergey Chernov
- 3 Department of Neurosurgery, Federal Neurosurgical Center , Novosibirsk, Russia
| | - Evgeniya Dolgova
- 4 Laboratory of Induced Cellular Processes, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk, Russia
| | - Vyacheslav Stupak
- 2 Department of Neurosurgery, Novosibirsk Research Institute of Traumatology and Orthopedics named after Ya.L. Zivian , Novosibirsk, Russia
| | - Evgeniya Voronina
- 5 Laboratory of Morphological and Molecular Biology Techniques, Regional Center of High Medical Technologies , Novosibirsk, Russia
| | - Sergey Bogachev
- 4 Laboratory of Induced Cellular Processes, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk, Russia
| | - Ekaterina Shevela
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Alexander Ostanin
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Elena Chernykh
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
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Hwang SM, Kim HJ, Kim SM, Jung Y, Park SW, Chung IY. Lysophosphatidylserine receptor P2Y10: A G protein-coupled receptor that mediates eosinophil degranulation. Clin Exp Allergy 2018; 48:990-999. [PMID: 29700886 DOI: 10.1111/cea.13162] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 04/13/2018] [Accepted: 04/16/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND P2Y10, along with GPR34 and GPR174, is a G protein-coupled receptor that is activated by an endogenous lipid mediator lysophosphatidylserine (LysoPS). Its expression pattern and its function are completely unknown. We have previously shown that P2Y10 is one of the highly up-regulated genes at the late differentiation stage during in vitro eosinophilopoiesis. OBJECTIVE We explored the expression and functions of P2Y10 in human cord blood (CB)-derived and peripheral blood (PB) eosinophils. METHODS Real-time PCR, FACS, Western blot, ELISA, and chemotaxis assays were performed to determine the expression and function of P2Y10. RESULTS As CB cells differentiated towards eosinophils, P2Y10 mRNA and protein were abundantly expressed. P2Y10 was the most highly expressed in the granulocytes from PB, to a lesser extent in monocytes, and least in lymphocytes. Further fractionation of granulocytes revealed that eosinophils express P2Y10 much more strongly than do neutrophils. PB eosinophils solely expressed P2Y10 among the three LysoPS receptors, while PB neutrophils expressed the three at comparable levels. LysoPS activated both CB and PB eosinophils to induce a robust ERK phosphorylation. Importantly, LysoPS was capable of triggering degranulation of ECP in PB eosinophils. This response was significantly reduced by pharmacological inhibitors of TNF-alpha-converting enzyme (TACE), epidermal growth factor receptor (EGFR), and ERK1/2, which were known to be required in P2Y10-mediated signalling pathways. However, LysoPS had no effect on chemotaxis, differentiation, or eosinophil survival. CONCLUSIONS AND CLINICAL RELEVANCE LysoPS provokes eosinophil degranulation through P2Y10. Therefore, P2Y10 is a potential therapeutic target to control eosinophil-associated diseases.
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Affiliation(s)
- S M Hwang
- Department of Bionano Technology, Hanyang University, Ansan, Gyeonggi-do, Korea
| | - H J Kim
- Department of Bionano Technology, Hanyang University, Ansan, Gyeonggi-do, Korea
| | - S M Kim
- Department of Bionano Technology, Hanyang University, Ansan, Gyeonggi-do, Korea
| | - Y Jung
- Department of Microbiology, School of Medicine, Gachon University, Incheon, Korea
| | - S W Park
- Graduate School of Medicine, Soonchunhyang University Hospital, Bucheon, Gyeonggi-do, Korea
| | - I Y Chung
- Department of Bionano Technology, Hanyang University, Ansan, Gyeonggi-do, Korea.,Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Korea
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Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer. Oncotarget 2018; 7:58244-58260. [PMID: 27542270 PMCID: PMC5295428 DOI: 10.18632/oncotarget.11309] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 07/27/2016] [Indexed: 11/25/2022] Open
Abstract
Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45-, showed a high tumorigenicity compared to non-CD24+CD90+CD45- cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45- TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45- cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45- cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas.
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Escalona RM, Chan E, Kannourakis G, Findlay JK, Ahmed N. The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression. Int J Mol Sci 2018; 19:E450. [PMID: 29393911 PMCID: PMC5855672 DOI: 10.3390/ijms19020450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 01/23/2018] [Accepted: 01/24/2018] [Indexed: 02/07/2023] Open
Abstract
Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients.
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Affiliation(s)
- Ruth M Escalona
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
- The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia.
| | - Emily Chan
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia.
- Federation University Australia, Ballarat, VIC 3010, Australia.
| | - Jock K Findlay
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
- The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
| | - Nuzhat Ahmed
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
- The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia.
- Federation University Australia, Ballarat, VIC 3010, Australia.
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Hong SW, Hur W, Choi JE, Kim JH, Hwang D, Yoon SK. Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation. Oncotarget 2018; 7:23482-97. [PMID: 26993601 PMCID: PMC5029641 DOI: 10.18632/oncotarget.8112] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 02/28/2016] [Indexed: 12/29/2022] Open
Abstract
We investigated the biological role of CD133-expressing liver cancer stem cells (CSCs) enriched after irradiation of Huh7 cells in cell invasion and migration. We also explored whether a disintegrin and metalloproteinase-17 (ADAM17) influences the metastatic potential of CSC-enriched hepatocellular carcinoma (HCC) cells after irradiation. A CD133-expressing Huh7 cell subpopulation showed greater resistance to sublethal irradiation and specifically enhanced cell invasion and migration capabilities. We also demonstrated that the radiation-induced MMP-2 and MMP-9 enzyme activities as well as the secretion of vascular endothelial growth factor were increased more predominantly in Huh7CD133+ cell subpopulations than Huh7CD133− cell subpopulations. Furthermore, we showed that silencing ADAM17 significantly inhibited the migration and invasiveness of enriched Huh7CD133+ cells after irradiation; moreover, Notch signaling was significantly reduced in irradiated CD133-expressing liver CSCs following stable knockdown of the ADAM17 gene. In conclusion, our findings indicate that CD133-expressing liver CSCs have considerable metastatic capabilities after irradiation of HCC cells, and their metastatic capabilities might be maintained by ADAM17. Therefore, suppression of ADAM17 shows promise for improving the efficiency of current radiotherapies and reducing the metastatic potential of liver CSCs during HCC treatment.
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Affiliation(s)
- Sung Woo Hong
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Wonhee Hur
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Eun Choi
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung-Hee Kim
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Daehee Hwang
- Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Hong SW, Hur W, Choi JE, Kim JH, Hwang D, Yoon SK. Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation. Oncotarget 2018. [PMID: 26993601 DOI: 0.18632/oncotarget.8112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
We investigated the biological role of CD133-expressing liver cancer stem cells (CSCs) enriched after irradiation of Huh7 cells in cell invasion and migration. We also explored whether a disintegrin and metalloproteinase-17 (ADAM17) influences the metastatic potential of CSC-enriched hepatocellular carcinoma (HCC) cells after irradiation. A CD133-expressing Huh7 cell subpopulation showed greater resistance to sublethal irradiation and specifically enhanced cell invasion and migration capabilities. We also demonstrated that the radiation-induced MMP-2 and MMP-9 enzyme activities as well as the secretion of vascular endothelial growth factor were increased more predominantly in Huh7CD133+ cell subpopulations than Huh7CD133- cell subpopulations. Furthermore, we showed that silencing ADAM17 significantly inhibited the migration and invasiveness of enriched Huh7CD133+ cells after irradiation; moreover, Notch signaling was significantly reduced in irradiated CD133-expressing liver CSCs following stable knockdown of the ADAM17 gene. In conclusion, our findings indicate that CD133-expressing liver CSCs have considerable metastatic capabilities after irradiation of HCC cells, and their metastatic capabilities might be maintained by ADAM17. Therefore, suppression of ADAM17 shows promise for improving the efficiency of current radiotherapies and reducing the metastatic potential of liver CSCs during HCC treatment.
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Affiliation(s)
- Sung Woo Hong
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Wonhee Hur
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Eun Choi
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung-Hee Kim
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Daehee Hwang
- Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Wilson JL, Kefaloyianni E, Stopfer L, Harrison C, Sabbisetti VS, Fraenkel E, Lauffenburger DA, Herrlich A. Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding. Mol Cancer Res 2018; 16:147-161. [PMID: 29018056 PMCID: PMC5859574 DOI: 10.1158/1541-7786.mcr-17-0140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 08/16/2017] [Accepted: 10/04/2017] [Indexed: 11/16/2022]
Abstract
Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFκB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFκB regulatory functions. Inflammatory regulators thus also govern cancer cell growth-promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer.Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers. Mol Cancer Res; 16(1); 147-61. ©2017 AACR.
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Affiliation(s)
- Jennifer L Wilson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Eirini Kefaloyianni
- Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri
| | - Lauren Stopfer
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Christina Harrison
- Department of Biology, University of Massachusetts, Boston, Massachusetts
| | | | - Ernest Fraenkel
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
| | - Andreas Herrlich
- Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri.
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Ye J, Yuen SM, Murphy G, Xie R, Kwok HF. Anti-tumor effects of a 'human & mouse cross-reactive' anti-ADAM17 antibody in a pancreatic cancer model in vivo. Eur J Pharm Sci 2017; 110:62-69. [PMID: 28554668 DOI: 10.1016/j.ejps.2017.05.057] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/24/2017] [Accepted: 05/25/2017] [Indexed: 12/30/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors. Mouse genetic studies have demonstrated that ADAM17 is required for PDAC development. In this study, we evaluated the anti-tumor effects of A9(B8) IgG - the first specific 'human and mouse cross-reactive' ADAM17 inhibitory antibody on pancreatic malignant transformation. We found that inhibition of ADAM17 with A9(B8) IgG efficiently suppressed the shedding of ADAM17 substrates both in vivo and in vitro. Furthermore, we demonstrated that administration of A9(B8) IgG significantly suppressed motility in human pancreatic cancer cells and also significantly delayed tumorigenesis in the Pdx1Cre;KrasG12D;Trp53fl/+PDAC mouse model. Inhibition of ADAM17 with A9(B8) IgG particularly affected the progression of pre-invasive pancreatic lesions to advanced PDAC in mice. Taken together, the preclinical data presented here will provide a starting point for clinical applications of ADAM17 targeted therapy.
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Affiliation(s)
- Jie Ye
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau
| | - Shun Ming Yuen
- Histopathology Core, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau
| | - Gillian Murphy
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Ruiyu Xie
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau.
| | - Hang Fai Kwok
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau; Histopathology Core, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau.
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Shen H, Li L, Zhou S, Yu D, Yang S, Chen X, Wang D, Zhong S, Zhao J, Tang J. The role of ADAM17 in tumorigenesis and progression of breast cancer. Tumour Biol 2016; 37:15359–15370. [PMID: 27658778 DOI: 10.1007/s13277-016-5418-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 09/15/2016] [Indexed: 12/22/2022] Open
Abstract
A disintegrin and metalloproteinase (ADAM) family members are known to process the target membrane-bound molecules through the quick induction of their protease activities under interaction with other molecules, which have diverse roles in tissue morphogenesis and pathophysiological remodeling. Among these, ADAM17 is a membrane-bound protease that sheds the extracellular domain of various receptors or its ligands from the cell membrane and subsequently activates downstream signaling transduction pathways. Importantly, breast cancer remains a mainspring of cancer-induced death in women, and numerous regulatory pathways have been implicated in the formation of breast cancer. Substantial evidence has demonstrated that an obvious increased in ADAM17 cell surface expression has been discovered in breast cancer and was shown to be associated with mammary tumorigenesis, invasiveness, and drug resistance. Over the last decades, it has received more than its share of attention that ADAM17 plays a potential role in breast cancer, including cell proliferation, invasion, angiogenesis, apoptosis, and trastuzumab resistance. In our review, we discuss the mechanisms through which ADAM17 acts on breast cancer tumorigenesis and progression. Thus, this will provide further impetus for exploiting ADAM17 as a new target for breast cancer treatment.
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Affiliation(s)
- Hongyu Shen
- The Fourth Clinical School of Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
| | - Liangpeng Li
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Changle Road 68, Nanjing, Jiangsu, 210006, China
| | - Siying Zhou
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
- Nanjing University of Traditional Chinese Medicine, Xianlin Road 138, Nanjing, Jiangsu, 210023, China
| | - Dandan Yu
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
| | - Sujin Yang
- The Fourth Clinical School of Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
| | - Xiu Chen
- The Fourth Clinical School of Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
| | - Dandan Wang
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
| | - Shanliang Zhong
- Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China
| | - Jianhua Zhao
- Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China.
| | - Jinhai Tang
- The Fourth Clinical School of Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China.
- Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu, 210009, China.
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Chen J, Zeng F, Forrester SJ, Eguchi S, Zhang MZ, Harris RC. Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease. Physiol Rev 2016; 96:1025-1069. [DOI: 10.1152/physrev.00030.2015] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.
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Affiliation(s)
- Jianchun Chen
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Fenghua Zeng
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Steven J. Forrester
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Satoru Eguchi
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Ming-Zhi Zhang
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Raymond C. Harris
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα. Sci Rep 2016; 6:27342. [PMID: 27264103 PMCID: PMC4893610 DOI: 10.1038/srep27342] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/16/2016] [Indexed: 12/17/2022] Open
Abstract
Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes.
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Sharma A, Bender S, Zimmermann M, Riesterer O, Broggini-Tenzer A, Pruschy MN. Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non-Small Cell Lung Cancer. Clin Cancer Res 2016; 22:4428-39. [PMID: 27076628 DOI: 10.1158/1078-0432.ccr-15-2449] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 04/04/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE Ionizing radiation (IR) induces intracellular signaling processes as part of a treatment-induced stress response. Here we investigate IR-induced ADAM17 activation and the role of ADAM17-shed factors for radiation resistance in non-small cell lung cancer. EXPERIMENTAL DESIGN Large-scale secretome profiling was performed using antibody arrays. Secretion kinetics of ADAM17 substrates was determined using ELISA across multiple in vitro and in vivo models of non-small cell lung cancer. Clonogenic survival and tumor xenograft assays were performed to determine radiosensitization by ADAM17 inhibition. RESULTS On the basis of a large-scale secretome screening, we investigated secretion of auto- or paracrine factors in non-small cell lung cancer in response to irradiation and discovered the ADAM17 network as a crucial mediator of resistance to IR. Irradiation induced a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which resulted in enhanced ADAM17 activity in vitro and in vivo Genetic or pharmacologic targeting of ADAM17 suppressed IR-induced shedding of secreted factors, downregulated ErbB signaling in otherwise cetuximab-resistant target cells, and enhanced IR-induced cytotoxicity. The combined treatment modality of IR with the ADAM17 inhibitor TMI-005 resulted in a supra-additive antitumor response in vivo demonstrating the potential of ADAM17 targeting in combination with radiotherapy. CONCLUSIONS Radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of non-small cell lung cancer. Clin Cancer Res; 22(17); 4428-39. ©2016 AACR.
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Affiliation(s)
- Ashish Sharma
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland
| | - Sabine Bender
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland
| | - Martina Zimmermann
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland
| | - Oliver Riesterer
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland
| | - Angela Broggini-Tenzer
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland
| | - Martin N Pruschy
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.
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Abstract
Hepatocellular carcinoma (HCC) is a major health problem. In human hepatocarcinogenesis, the balance between cell death and proliferation is deregulated, tipping the scales for a situation where antiapoptotic signals are overpowering the death-triggering stimuli. HCC cells harbor a wide variety of mutations that alter the regulation of apoptosis and hence the response to chemotherapeutical drugs, making them resistant to the proapoptotic signals. Considering all these modifications found in HCC cells, therapeutic approaches need to be carefully studied in order to specifically target the antiapoptotic signals. This review deals with the recent relevant contributions reporting molecular alterations for HCC that lead to a deregulation of apoptosis, as well as the challenge of death-inducing chemotherapeutics in current HCC treatment.
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Affiliation(s)
- Joaquim Moreno-Càceres
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Isabel Fabregat
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Department of Physiological Sciences II, University of Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Department of Physiological Sciences II, University of Barcelona, Spain
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42
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Leung CH, Liu LJ, Lu L, He B, Kwong DWJ, Wong CY, Ma DL. A metal-based tumour necrosis factor-alpha converting enzyme inhibitor. Chem Commun (Camb) 2015; 51:3973-6. [PMID: 25610924 DOI: 10.1039/c4cc09251a] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We report herein a novel iridium(III) complex 1 as an antitumour necrosis factor agent and the first metal-based inhibitor of TACE enzymatic activity. Complex 1 inhibited TNF-α secretion and p38 phosphorylation in human monocytic THP-1 cells.
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Affiliation(s)
- Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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43
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Mullooly M, McGowan PM, Kennedy SA, Madden SF, Crown J, O' Donovan N, Duffy MJ. ADAM10: a new player in breast cancer progression? Br J Cancer 2015; 113:945-51. [PMID: 26284334 PMCID: PMC4578086 DOI: 10.1038/bjc.2015.288] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Revised: 07/07/2015] [Accepted: 07/11/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. As cleavage of several of these proteins has been implicated in cancer formation and progression, we hypothesised that ADAM10 is also involved in these processes. METHODS ADAM10 expression was decreased by RNA interference and the effects of this on cell numbers, invasion and migration were determined. We also examined the effect of ADAM10 inhibition on breast cancer cell line invasion and migration. RESULTS Using the triple-negative (TN) breast cancer cell lines, BT20, MDA-MB-231 and the non-TN cell line MDA-MB-453, knockdown of ADAM10 expression significantly decreased in vitro migration (P<0.01; for each cell line). Similarly, treatment with the ADAM10-selective inhibitor GI254023X reduced migration in the three cell lines (for BT20, P<0.001; for MDA-MB-231, P=0.005; for MDA-MB-453, P=0.023). In contrast, neither knockdown of ADAM10 nor treatment with the ADAM10-selective inhibitor GI254023X significantly affected cell numbers. Using extracts of primary breast cancers, higher levels of ADAM10 were found more frequently in high-grade vs low-grade tumours (P<0.001) and in oestrogen receptor (ER)-negative compared with ER-positive tumours (P=0.005). Analysis of pooled publicly available data sets found that high levels of ADAM10 mRNA were associated with adverse outcome in patients with the basal subtype of breast cancer. CONCLUSIONS Based on our combined cell line and breast cancer extract data, we conclude that ADAM10 is likely to be involved in breast cancer progression, especially in the basal subtype.
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Affiliation(s)
- Maeve Mullooly
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,Education and Research Centre, St. Vincent's University Hospital, Dublin, Ireland
| | - Patricia M McGowan
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,Education and Research Centre, St. Vincent's University Hospital, Dublin, Ireland
| | - Susan A Kennedy
- Systems Biology Ireland, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Stephen F Madden
- National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland
| | - John Crown
- National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.,Department of Medical Oncology, St. Vincent's University Hospital, Dublin, Ireland
| | - Norma O' Donovan
- National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland
| | - Michael J Duffy
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,UCD Clinical Research Centre, St. Vincent's University Hospital, Dublin, Ireland
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Dombernowsky SL, Samsøe-Petersen J, Petersen CH, Instrell R, Hedegaard AMB, Thomas L, Atkins KM, Auclair S, Albrechtsen R, Mygind KJ, Fröhlich C, Howell M, Parker P, Thomas G, Kveiborg M. The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. Nat Commun 2015; 6:7518. [PMID: 26108729 PMCID: PMC4481878 DOI: 10.1038/ncomms8518] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 05/16/2015] [Indexed: 01/07/2023] Open
Abstract
The metalloproteinase ADAM17 activates ErbB signalling by releasing ligands from the cell surface, a key step underlying epithelial development, growth and tumour progression. However, mechanisms acutely controlling ADAM17 cell-surface availability to modulate the extent of ErbB ligand release are poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases. PACS-2 co-localizes with ADAM17 on early endosomes and PACS-2 knockdown decreases the recycling and stability of internalized ADAM17. Hence, PACS-2 sustains ADAM17 cell-surface activity by diverting ADAM17 away from degradative pathways. Interestingly, Pacs2-deficient mice display significantly reduced levels of phosphorylated EGFR and intestinal proliferation. We suggest that this mechanism controlling ADAM17 cell-surface availability and EGFR signalling may play a role in intestinal homeostasis, with potential implications for cancer biology.
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Affiliation(s)
- Sarah Louise Dombernowsky
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Jacob Samsøe-Petersen
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Camilla Hansson Petersen
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Rachael Instrell
- High Throughput Screening Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
| | - Anne-Mette Bornhardt Hedegaard
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Laurel Thomas
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technolohy Drive, Pittsburgh, PA 15219, USA
| | - Katelyn Mae Atkins
- Department of Cell and Developmental Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Sylvain Auclair
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technolohy Drive, Pittsburgh, PA 15219, USA
| | - Reidar Albrechtsen
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Kasper Johansen Mygind
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Camilla Fröhlich
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Michael Howell
- High Throughput Screening Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
| | - Peter Parker
- Protein Phosphorylation Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
- Division of Cancer Studies, King’s College London, New Hunts House, Guy’s Campus, London SE1 1UL, UK
| | - Gary Thomas
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technolohy Drive, Pittsburgh, PA 15219, USA
- Department of Cell and Developmental Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Marie Kveiborg
- Department of Biomedical Sciences & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
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45
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Caiazza F, McGowan PM, Mullooly M, Murray A, Synnott N, O'Donovan N, Flanagan L, Tape CJ, Murphy G, Crown J, Duffy MJ. Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer cells. Br J Cancer 2015; 112:1895-903. [PMID: 26010411 PMCID: PMC4580380 DOI: 10.1038/bjc.2015.163] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/30/2015] [Accepted: 04/08/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best-validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFα, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC. METHODS We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines. RESULTS D1(A12) was found to significantly inhibit the release of TGFα, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three-dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells. CONCLUSION Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells.
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Affiliation(s)
- F Caiazza
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - P M McGowan
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - M Mullooly
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - A Murray
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - N Synnott
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - N O'Donovan
- National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland
| | - L Flanagan
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - C J Tape
- Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
- Cell Communication Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK
| | - G Murphy
- Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
| | - J Crown
- Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland
| | - M J Duffy
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
- UCD Clinical Research Centre, St Vincent's University Hospital, Dublin, Ireland
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46
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Prognostic significance of ADAM17 expression in patients with gastric cancer who underwent curative gastrectomy. Clin Transl Oncol 2015; 17:604-11. [DOI: 10.1007/s12094-015-1283-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/06/2015] [Indexed: 11/25/2022]
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47
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Brune K, Frank J, Schwingshackl A, Finigan J, Sidhaye VK. Pulmonary epithelial barrier function: some new players and mechanisms. Am J Physiol Lung Cell Mol Physiol 2015; 308:L731-45. [PMID: 25637609 DOI: 10.1152/ajplung.00309.2014] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 01/27/2015] [Indexed: 12/20/2022] Open
Abstract
The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the initial responses of the lung to both infectious and noninfectious stimuli. One mechanism by which the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review, we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli. This review is a summary of talks presented during a symposium in Experimental Biology geared toward novel and less recognized methods of epithelial barrier regulation. First, we will discuss mechanisms of dynamic regulation of cell-cell contacts in the context of repetitive exposure to inhaled infectious and noninfectious insults. In the second section, we will briefly discuss mechanisms of transcellular ion homeostasis specifically focused on the role of claudins and paracellular ion-channel regulation in chronic barrier dysfunction. In the next section, we will address transcellular ion transport and highlight the role of Trek-1 in epithelial responses to lung injury. In the final section, we will outline the role of epithelial growth receptor in barrier regulation in baseline, acute lung injury, and airway disease. We will then end with a summary of mechanisms of epithelial control as well as discuss emerging paradigms of the epithelium role in shifting between a structural element that maintains tight cell-cell adhesion to a cell that initiates and participates in immune responses.
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Affiliation(s)
- Kieran Brune
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
| | - James Frank
- The Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco VA Medical Center, and NCIRE/Veterans Health Research Institute, San Francisco, California
| | - Andreas Schwingshackl
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - James Finigan
- Division of Oncology, Cancer Center, National Jewish Health, Denver, Colorado
| | - Venkataramana K Sidhaye
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland;
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Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors: suggestion of combination therapy. Neoplasia 2015; 16:301-18. [PMID: 24862757 DOI: 10.1016/j.neo.2014.03.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 03/10/2014] [Accepted: 03/11/2014] [Indexed: 12/14/2022] Open
Abstract
The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies.
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Liu LJ, Leung KH, Lin S, Chan DSH, Susanti D, Rao W, Chan PWH, Ma DL, Leung CH. Pharmacophore modeling for the identification of small-molecule inhibitors of TACE. Methods 2015; 71:92-7. [DOI: 10.1016/j.ymeth.2014.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/02/2014] [Accepted: 09/14/2014] [Indexed: 01/27/2023] Open
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Li G, Forest F, Feng G, Gentil-Perret A, Péoc'h M, Cottier M, Mottet N. A novel marker ADAM17 for clear cell renal cell carcinomas: Implication for patients’ prognosis. Urol Oncol 2014; 32:1272-6. [DOI: 10.1016/j.urolonc.2014.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 05/22/2014] [Accepted: 05/23/2014] [Indexed: 01/23/2023]
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