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Alsubaie FS, Neufeld Z. Modelling the effect of cell motility on mixing and invasion in epithelial monolayers. J Biol Phys 2024; 50:291-306. [PMID: 39031299 PMCID: PMC11490479 DOI: 10.1007/s10867-024-09660-8] [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: 01/18/2024] [Accepted: 06/22/2024] [Indexed: 07/22/2024] Open
Abstract
Collective cell invasion underlies several biological processes such as wound healing, embryonic development, and cancerous invasion. Here, we investigate the impact of cell motility on invasion in epithelial monolayers and its coupling to cellular mechanical properties, such as cell-cell adhesion and cortex contractility. We develop a two-dimensional computational model for cells with active motility based on the cellular Potts model, which predicts that the cellular invasion speed is mainly determined by active cell motility and is independent of the biological and mechanical properties of the cells. We also find that, in general, motile cells out-compete and invade non-motile cells, however, this can be reversed by differential cell proliferation. Stable coexistence of motile and static cell types is also possible for certain parameter regimes.
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Affiliation(s)
- Faris Saad Alsubaie
- School of Mathematics and Physics, The University of Queensland, St Lucia, Brisbane, 4072, Queensland, Australia
| | - Zoltan Neufeld
- School of Mathematics and Physics, The University of Queensland, St Lucia, Brisbane, 4072, Queensland, Australia.
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2
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Modelling of Tissue Invasion in Epithelial Monolayers. Life (Basel) 2023; 13:life13020427. [PMID: 36836784 PMCID: PMC9964186 DOI: 10.3390/life13020427] [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: 11/24/2022] [Revised: 01/20/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Mathematical and computational models are used to describe biomechanical processes in multicellular systems. Here, we develop a model to analyse how two types of epithelial cell layers interact during tissue invasion depending on their cellular properties, i.e., simulating cancer cells expanding into a region of normal cells. We model the tissue invasion process using the cellular Potts model and implement our two-dimensional computational simulations in the software package CompuCell3D. The model predicts that differences in mechanical properties of cells can lead to tissue invasion, even if the division rates and death rates of the two cell types are the same. We also show how the invasion speed varies depending on the cell division and death rates and the mechanical properties of the cells.
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3
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Xing D, Zuo W, Chen J, Ma B, Cheng X, Zhou X, Qian Y. Spatial Delivery of Triple Functional Nanoparticles via an Extracellular Matrix-Mimicking Coaxial Scaffold Synergistically Enhancing Bone Regeneration. ACS APPLIED MATERIALS & INTERFACES 2022; 14:37380-37395. [PMID: 35946874 DOI: 10.1021/acsami.2c08784] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
It remains a major challenge to simultaneously achieve bone regeneration and prevent infection in the complex microenvironment of repairing bone defects. Here, we developed a novel ECM-mimicking scaffold by coaxial electrospinning to be endowed with multibiological functions. Lysophosphatidic acid (LPA) and zinc oxide (ZnO) nanoparticles were loaded into the poly-lactic-co-glycolic acid/polycaprolactone (PLGA/PCL, PP) sheath layer of coaxial nanofibers, and deferoxamine (DFO) nanoparticles were loaded into its core layer. The novel scaffold PP-LPA-ZnO/DFO maintained a porous nanofibrous architecture after incorporating three active nanoparticles, showing better physicochemical properties and eximious biocompatibility. In vitro studies showed that the bio-scaffold loaded with LPA nanoparticles had excellent cell adhesion, proliferation, and differentiation for MC3T3-E1 cells and synergistic osteogenesis with the addition of ZnO and DFO nanoparticles. Further, the PP-LPA-ZnO/DFO scaffold promoted tube formation and facilitated the expression of vascular endothelial markers in HUVECs. In vitro antibacterial studies against Escherichia Coli and Staphylococcus aureus demonstrated effective antibacterial activity of the PP-LPA-ZnO/DFO scaffold. In vivo studies showed that the PP-LPA-ZnO/DFO scaffold exhibited excellent biocompatibility after subcutaneous implantation and remarkable osteogenesis at 4 weeks post-implantation in the mouse alveolar bone defects. Importantly, the PP-LPA-ZnO/DFO scaffold showed significant antibacterial activity, prominent neovascularization, and new bone formation in the rat fenestration defect model. Overall, the spatially sustained release of LPA, ZnO, and DFO nanoparticles through the coaxial scaffold synergistically enhanced biocompatibility, osteogenesis, angiogenesis, and effective antibacterial properties, which is ultimately beneficial for bone regeneration. This project provides the optimized design of bone regenerative biomaterials and a new strategy for bone regeneration, especially in the potentially infected microenvironment.
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Affiliation(s)
- Danlei Xing
- Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
- Department of Plastic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
| | - Wei Zuo
- Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
| | - Jiahong Chen
- Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
| | - Buyun Ma
- Nano Science and Technology Institute, University of Science and Technology of China, Hefei 230026, People's Republic of China
| | - Xi Cheng
- Department of Plastic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
| | - Xuefeng Zhou
- State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, People's Republic of China
| | - Yunzhu Qian
- Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
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4
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Valencia FP, Marino AF, Noutsos C, Poon K. Concentration-dependent change in hypothalamic neuronal transcriptome by the dietary fatty acids: oleic and palmitic acids. J Nutr Biochem 2022; 106:109033. [DOI: 10.1016/j.jnutbio.2022.109033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 12/20/2021] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
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5
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Khataee H, Fraser M, Neufeld Z. Modelling the Collective Mechanical Regulation of the Structure and Morphology of Epithelial Cell Layers. Front Cell Dev Biol 2022; 10:767688. [PMID: 35399530 PMCID: PMC8987200 DOI: 10.3389/fcell.2022.767688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
The morphology and function of epithelial sheets play an important role in healthy tissue development and cancer progression. The maintenance of structure of closely packed epithelial layers requires the coordination of various mechanical forces due to intracellular activities and interactions with other cells and tissues. However, a general model for the combination of mechanical properties which determine the cell shape and the overall structure of epithelial layers remains elusive. Here, we propose a computational model, based on the Cellular Potts Model, to analyse the interplay between mechanical properties of cells and dynamical transitions in epithelial cell shapes and structures. We map out phase diagrams as functions of cellular properties and the orientation of cell division. Results show that monolayers of squamous, cuboidal, and columnar cells are formed when the axis of cell proliferation is perpendicular to the substrate or along the major axis of the cells. Monolayer-to-multilayer transition is promoted via cell extrusion, depending on the mechanical properties of cells and the orientation of cell division. The results and model predictions are discussed in the context of experimental observations.
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6
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Harryman WL, Marr KD, Nagle RB, Cress AE. Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers. Front Cell Dev Biol 2022; 10:837585. [PMID: 35300411 PMCID: PMC8921537 DOI: 10.3389/fcell.2022.837585] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/04/2022] [Indexed: 11/18/2022] Open
Abstract
Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.
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Affiliation(s)
- William L Harryman
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States
| | - Kendra D Marr
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States.,Medical Scientist Training Program, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Ray B Nagle
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Department of Pathology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Anne E Cress
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Department of Cellular and Molecular Medicine and Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ, United States
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7
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Roblek M, Bicher J, van Gogh M, György A, Seeböck R, Szulc B, Damme M, Olczak M, Borsig L, Siekhaus DE. The Solute Carrier MFSD1 Decreases the Activation Status of β1 Integrin and Thus Tumor Metastasis. Front Oncol 2022; 12:777634. [PMID: 35211397 PMCID: PMC8861502 DOI: 10.3389/fonc.2022.777634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 01/13/2022] [Indexed: 11/17/2022] Open
Abstract
Solute carriers are increasingly recognized as participating in a plethora of pathologies, including cancer. We describe here the involvement of the orphan solute carrier Major Facilitator Superfamily Domain-containing protein 1 (MFSD1) in the regulation of tumor cell migration. Loss of MFSD1 enabled higher levels of metastasis in experimental and spontaneous metastasis mouse models. We identified an increased migratory potential in MFSD1−/− tumor cells which was mediated by increased focal adhesion turnover, reduced stability of mature inactive β1 integrin, and the resulting increased integrin activation index. We show that MFSD1 promoted recycling to the cell surface of endocytosed inactive β1 integrin and thereby protected β1 integrin from proteolytic degradation; this led to dampening of the integrin activation index. Furthermore, downregulation of MFSD1 expression was observed during the early steps of tumorigenesis, and higher MFSD1 expression levels correlate with a better cancer patient prognosis. In sum, we describe a requirement for endolysosomal MFSD1 in efficient β1 integrin recycling to suppress tumor cell dissemination.
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Affiliation(s)
- Marko Roblek
- Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Julia Bicher
- Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Merel van Gogh
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Attila György
- Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Rita Seeböck
- Institute of Clinical Pathology, University Hospital St. Polten, St. Polten, Austria
| | - Bozena Szulc
- Laboratory of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Markus Damme
- Institute of Biochemistry, University of Kiel, Kiel, Germany
| | - Mariusz Olczak
- Laboratory of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Lubor Borsig
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Daria E Siekhaus
- Institute of Science and Technology Austria, Klosterneuburg, Austria
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8
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Velatooru LR, Abe RJ, Imanishi M, Gi YJ, Ko KA, Heo KS, Fujiwara K, Le NT, Kotla S. Disturbed flow-induced FAK K152 SUMOylation initiates the formation of pro-inflammation positive feedback loop by inducing reactive oxygen species production in endothelial cells. Free Radic Biol Med 2021; 177:404-418. [PMID: 34619327 PMCID: PMC8664087 DOI: 10.1016/j.freeradbiomed.2021.09.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 09/16/2021] [Accepted: 09/18/2021] [Indexed: 10/20/2022]
Abstract
Focal adhesion kinase (FAK) activation plays a crucial role in vascular diseases. In endothelial cells, FAK activation is involved in the activation of pro-inflammatory signaling and the progression of atherosclerosis. Disturbed flow (D-flow) induces endothelial activation and senescence, but the exact role of FAK in D-flow-induced endothelial activation and senescence remains unclear. The objective of this study is to investigate the role of FAK SUMOylation in D-flow-induced endothelial activation and senescence. The results showed that D-flow induced reactive oxygen species (ROS) production via NADPH oxidase activation and activated a redox-sensitive kinase p90RSK, leading to FAK activation by upregulating FAK K152 SUMOylation and the subsequent Vav2 phosphorylation, which in turn formed a positive feedback loop by upregulating ROS production. This feedback loop played a crucial role in regulating endothelial activation and senescence. D-flow-induced endothelial activation and senescence were significantly inhibited by mutating a FAK SUMOylation site lysine152 to arginine. Collectively, we concluded that FAK K152 SUMOylation plays a key role in D-flow-induced endothelial activation and senescence by forming a positive feedback loop through ROS production.
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Affiliation(s)
- Loka Reddy Velatooru
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, 77030, Texas, USA
| | - Rei J Abe
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, 77030, Texas, USA
| | - Masaki Imanishi
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
| | - Young Jin Gi
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
| | - Kyung Ae Ko
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
| | - Kyung-Sun Heo
- Institute of Drug Research and Development, Chungnam National University, Daejeon, Republic of Korea
| | - Keigi Fujiwara
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
| | - Nhat-Tu Le
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, 77030, Texas, USA.
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA.
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9
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Titu S, Grapa CM, Mocan T, Balacescu O, Irimie A. Tetraspanins: Physiology, Colorectal Cancer Development, and Nanomediated Applications. Cancers (Basel) 2021; 13:cancers13225662. [PMID: 34830819 PMCID: PMC8616055 DOI: 10.3390/cancers13225662] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/01/2021] [Accepted: 11/09/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Considering the high incidence of colorectal cancer in adults, as well as the need for identifying novel therapies, we hereby explore the role of tetraspanins in the development of colorectal cancer. We have focused on variate aspects starting from the structure and general physiology and ending with the precise mechanisms involved in the dual reported role of tetraspanins (pro–tumoral and tumor suppressor key player element). Moreover, the present review focuses on the potential of tetraspanins as a target for nanotechnology-mediated therapies, also gathering the limited attempts towards this aim and their reported data. Abstract Tetraspanins are transmembrane proteins expressed in a multitude of cells throughout the organism. They contribute to many processes that surround cell–cell interactions and are associated with the progress of some diseases, including cancer. Their crucial role in cell physiology is often understated. Furthermore, recent studies have shown their great potential in being used as targeting molecules. Data have suggested the potential of tetraspanins as a targeting vector for nanomediated distribution and delivery for colorectal cancer applications. Our aim is to provide a review on the important part that tetraspanins play in the human organism and highlight their potential use for drug delivery systems using nanotechnology.
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Affiliation(s)
- Stefan Titu
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Department of Surgical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, 400015 Cluj-Napoca, Romania
| | - Cristiana Maria Grapa
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Nanomedicine Department, Regional Institute of Gastroenterology and Hepatology, 400126 Cluj-Napoca, Romania
| | - Teodora Mocan
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Nanomedicine Department, Regional Institute of Gastroenterology and Hepatology, 400126 Cluj-Napoca, Romania
- Correspondence:
| | - Ovidiu Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, 400015 Cluj-Napoca, Romania;
| | - Alexandru Irimie
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Department of Surgical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, 400015 Cluj-Napoca, Romania
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Mushtaq U, Bashir M, Nabi S, Khanday FA. Epidermal growth factor receptor and integrins meet redox signaling through P66shc and Rac1. Cytokine 2021; 146:155625. [PMID: 34157521 DOI: 10.1016/j.cyto.2021.155625] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 05/23/2021] [Accepted: 06/08/2021] [Indexed: 12/24/2022]
Abstract
This review examines the concerted role of Epidermal Growth Factor Receptor (EGFR) and integrins in regulating Reactive oxygen species (ROS) production through different signaling pathways. ROS as such are not always deleterious to the cells but they also act as signaling molecules, that regulates numerous indespensible physiological fuctions of life. Many adaptor proteins, particularly Shc and Grb2, are involved in mediating the downstream signaling pathways stimulated by EGFR and integrins. Integrin-induced activation of EGFR and subsequent tyrosine phosphorylation of a class of acceptor sites on EGFR leads to alignment and tyrosine phosphorylation of Shc, PLCγ, the p85 subunit of PI-3 K, and Cbl, followed by activation of the downstream targets Erk and Akt/PKB. Functional interactions between these receptors result in the activation of Rac1 via these adaptor proteins, thereby leading to Reactive Oxygen Species. Both GF and integrin activation can produce oxidants independently, however synergistically there is increased ROS generation, suggesting a mutual cooperation between integrins and GFRs for redox signalling. The ROS produced further promotes feed-forward stimulation of redox signaling events such as MAPK activation and gene expression. This relationship has not been reviewed previously. The literature presented here can have multiple implications, ranging from looking at synergistic effects of integrin and EGFR mediated signaling mechanisms of different proteins to possible therapeutic interventions operated by these two receptors. Furthermore, such mutual redox regulation of crosstalk between EGFR and integrins not only add to the established models of pathological oxidative stress, but also can impart new avenues and opportunities for targeted antioxidant based therapeutics.
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Affiliation(s)
- Umar Mushtaq
- Department of Biotechnology, University of Kashmir, Srinagar, JK 190006, India; Department of Biotechnology, Central University of Kashmir, Ganderbal, JK 191201, India
| | - Muneesa Bashir
- Department of Biotechnology, University of Kashmir, Srinagar, JK 190006, India; Department of Higher Education, Government of Jammu & Kashmir, 190001, India
| | - Sumaiya Nabi
- Department of Biochemistry, University of Kashmir, Srinagar, JK 190006, India
| | - Firdous A Khanday
- Department of Biotechnology, University of Kashmir, Srinagar, JK 190006, India.
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11
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The bile acid TUDCA and neurodegenerative disorders: An overview. Life Sci 2021; 272:119252. [PMID: 33636170 DOI: 10.1016/j.lfs.2021.119252] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 02/07/2023]
Abstract
Bear bile has been used in Traditional Chinese Medicine for thousands of years due to its therapeutic potential and clinical applications. The tauroursodeoxycholic acid (TUDCA), one of the acids found in bear bile, is a hydrophilic bile acid and naturally produced in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA). Several studies have shown that TUDCA has neuroprotective action in several models of neurodegenerative disorders (ND), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, based on its potent ability to inhibit apoptosis, attenuate oxidative stress, and reduce endoplasmic reticulum stress in different experimental models of these illnesses. Our research extends the knowledge of the bile acid TUDCA actions in ND and the mechanisms and pathways involved in its cytoprotective effects on the brain, providing a novel perspective and opportunities for treatment of these diseases.
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12
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Castro CD, Boughter CT, Broughton AE, Ramesh A, Adams EJ. Diversity in recognition and function of human γδ T cells. Immunol Rev 2020; 298:134-152. [PMID: 33136294 DOI: 10.1111/imr.12930] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/17/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022]
Abstract
As interest increases in harnessing the potential power of tissue-resident cells for human health and disease, γδ T cells have been thrust into the limelight due to their prevalence in peripheral tissues, their sentinel-like phenotypes, and their unique antigen recognition capabilities. This review focuses primarily on human γδ T cells, highlighting their distinctive characteristics including antigen recognition, function, and development, with an emphasis on where they differ from their αβ T cell comparators, as well as from γδ T cell populations in the mouse. We review the antigens that have been identified thus far to regulate members of the human Vδ1 population and discuss what players are involved in transducing phosphoantigen-mediated signals to human Vγ9Vδ2 T cells. We also briefly review distinguishing features of these cells in terms of TCR signaling, use of coreceptor and costimulatory molecules and their development. These cells have great potential to be harnessed in a clinical setting, but caution must be taken to understand their unique capabilities and how they differ from the populations to which they are commonly compared.
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Affiliation(s)
- Caitlin D Castro
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - Christopher T Boughter
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
- Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL, USA
| | - Augusta E Broughton
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
- Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Amrita Ramesh
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
- Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL, USA
| | - Erin J Adams
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
- Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL, USA
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL, USA
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13
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Kamarajan P, Ateia I, Shin JM, Fenno JC, Le C, Zhan L, Chang A, Darveau R, Kapila YL. Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin. PLoS Pathog 2020; 16:e1008881. [PMID: 33002094 PMCID: PMC7529280 DOI: 10.1371/journal.ppat.1008881] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 08/12/2020] [Indexed: 12/13/2022] Open
Abstract
Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can modulate these pathogen-mediated effects, and thus has therapeutic potential as an antimicrobial and anti-tumorigenic agent.
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Affiliation(s)
- Pachiyappan Kamarajan
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, United States of America
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, United States of America
| | - Islam Ateia
- Department of Oral Medicine and Periodontology, Mansoura University, Mansoura, Egypt
| | - Jae M. Shin
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, United States of America
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States of America
| | - J. Christopher Fenno
- Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann arbor, MI, United States of America
| | - Charles Le
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, United States of America
| | - Ling Zhan
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, United States of America
| | - Ana Chang
- Department of Periodontics, Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States of America
| | - Richard Darveau
- Department of Periodontics, Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States of America
| | - Yvonne L. Kapila
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, United States of America
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, United States of America
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14
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Jing W, Bi Y, Wang G, Zeng S, Han L, Yang H, Wang N, Zhao Y. Krill Oil Perturbs Proliferation and Migration of Mouse Colon Cancer Cells in vitro by Impeding Extracellular Signal-Regulated Protein Kinase Signaling Pathway. Lipids 2020; 56:141-153. [PMID: 32931040 DOI: 10.1002/lipd.12281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 08/16/2020] [Accepted: 08/17/2020] [Indexed: 12/25/2022]
Abstract
The prevalence of colorectal cancer (CRC) continues to increase. Treatment of CRC remains a significant clinical challenge, and effective therapies for advanced CRC are desperately needed. Increasing attention and ongoing research efforts have focused on krill oil that may provide health benefits to the human body. Here we report that krill oil exerts in vitro anticancer activity through a direct inhibition on proliferation, colony formation, migration, and invasion of mouse colon cancer cells. Krill oil inhibited the proliferation and colony formation of CT-26 colon cancer cells by causing G0/G1 cell cycle arrest and apoptosis. Cell cycle arrest was attributable to reduction of cyclin D1 levels in krill oil-treated cells. Further studies revealed that krill oil induced mitochondrial-dependent apoptosis of CT-26 cells, including loss of mitochondrial membrane potential, increased cytosolic calcium levels, activation of caspase-3, and downregulation of anti-apoptotic proteins MCL-1 and BCL-XL. Krill oil suppressed migration of CT-26 cells by disrupting the microfilaments and microtubules. Extracellular signal-regulated protein kinase (ERK) plays crucial roles in regulating proliferation and migration of cancer cells. We found that krill oil attenuated the activation of ERK signaling pathway to exert the effects on cell cycle, apoptosis, and migration of colon cancer cells. We speculate that polyunsaturated fatty acids of krill oil may dampen ERK activation by decreasing the phospholipid saturation of cell membrane. Although findings from in vitro studies may not necessarily translate in vivo, our study provides insights into the possibility that krill oil or its components could have therapeutic potential in colon cancer.
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Affiliation(s)
- Weiqiang Jing
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China
| | - Yuxuan Bi
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China
| | - Ganyu Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China
| | - Shuyan Zeng
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China
| | - Lihui Han
- Department of Immunology, Shandong Provincial Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China
| | - Hui Yang
- Department of Radiology, Qilu Hospital, Shandong University, Wenhua Xi Road, Jinan, 250012, China
| | - Na Wang
- Jinan Jiyuan Biological Technology Co., Ltd, Longao North Road, Jinan, 250102, China
| | - Yunxue Zhao
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China.,Department of Immunology, Shandong Provincial Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Shandong University, Wenhua Xi Road, Jinan, 250012, China
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15
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Cha B, Kim J, Bello A, Lee G, Kim D, Kim BJ, Arai Y, Choi B, Park H, Lee S. Efficient Isolation and Enrichment of Mesenchymal Stem Cells from Human Embryonic Stem Cells by Utilizing the Interaction between Integrin α5 β1 and Fibronectin. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2001365. [PMID: 32995130 PMCID: PMC7507081 DOI: 10.1002/advs.202001365] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/02/2020] [Indexed: 05/09/2023]
Abstract
Human pluripotent stem cells (hPSCs) are a potent source of clinically relevant mesenchymal stem cells (MSCs) that confer functional and structural benefits in cell therapy and tissue regeneration. Obtaining sufficient numbers of MSCs in a short period of time and enhancing the differentiation potential of MSCs can be offered the potential to improve the regenerative activity of MSCs therapy. In addition, the underlying processes in the isolation and derivation of MSCs from hPSCs are still poorly understood and controlled. To overcome these clinical needs, an efficient and simplified technique on the isolation of MSCs from spontaneously differentiated human embryonic stem cells (hESCs) via integrin α5β1 (fibronectin (FN) receptor)-to-FN interactions (hESC-FN-MSCs) is successfully developed. It is demonstrated that hESC-FN-MSCs exhibit a typical MSC surface phenotype, cellular morphology, with the whole transcriptome similar to conventional adult MSCs; but show higher proliferative capacity, more efficient trilineage differentiation, enhanced cytokine secretion, and attenuated cellular senescence. In addition, the therapeutic potential and regenerative capacity of the isolated hESC-FN-MSCs are confirmed by in vitro and in vivo multilineage differentiation. This novel method will be useful in the generation of abundant amounts of clinically relevant MSCs for stem cell therapeutics and regenerative medicine.
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Affiliation(s)
- Byung‐Hyun Cha
- Division of Cardio‐Thoracic SurgeryDepartment of SurgeryCollege of MedicineUniversity of ArizonaTucsonAZ85724USA
| | - Jin‐Su Kim
- CellenGene R&D CenterOpen Innovation BuildingSeoul02455Republic of Korea
- Department of Biomedical ScienceCHA UniversityCHA BiocomplexSeongnam‐siGyeonggi‐do13488Republic of Korea
| | - Alvin Bello
- Department of Integrative EngineeringChung‐Ang UniversitySeoul06974Republic of Korea
| | - Geun‐Hui Lee
- Department of Biomedical ScienceCHA UniversityCHA BiocomplexSeongnam‐siGyeonggi‐do13488Republic of Korea
| | - Do‐Hyun Kim
- Department of Medical BiotechnologyDongguk University32 Dongguk‐ro, Ilsandong‐guGoyangGyeonggi10326Republic of Korea
| | - Byoung Ju Kim
- Department of Medical BiotechnologyDongguk University32 Dongguk‐ro, Ilsandong‐guGoyangGyeonggi10326Republic of Korea
| | - Yoshie Arai
- Department of Medical BiotechnologyDongguk University32 Dongguk‐ro, Ilsandong‐guGoyangGyeonggi10326Republic of Korea
| | - Bogyu Choi
- Department of Biomedical ScienceCHA UniversityCHA BiocomplexSeongnam‐siGyeonggi‐do13488Republic of Korea
| | - Hansoo Park
- Department of Integrative EngineeringChung‐Ang UniversitySeoul06974Republic of Korea
| | - Soo‐Hong Lee
- Department of Medical BiotechnologyDongguk University32 Dongguk‐ro, Ilsandong‐guGoyangGyeonggi10326Republic of Korea
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16
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Liu M, Zhang Y, Yang J, Cui X, Zhou Z, Zhan H, Ding K, Tian X, Yang Z, Fung KMA, Edil BH, Postier RG, Bronze MS, Fernandez-Zapico ME, Stemmler MP, Brabletz T, Li YP, Houchen CW, Li M. ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells. Gastroenterology 2020; 158:679-692.e1. [PMID: 31711924 PMCID: PMC7837454 DOI: 10.1053/j.gastro.2019.10.038] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 10/22/2019] [Accepted: 10/31/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. METHODS We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1-knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured. RESULTS In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3β1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. CONCLUSIONS In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3β1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.
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Affiliation(s)
- Mingyang Liu
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;,Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yuqing Zhang
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;,Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Jingxuan Yang
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;,Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Xiaobo Cui
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;,Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;,Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Hanxiang Zhan
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;,Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Kai Ding
- Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Xiang Tian
- Department of Chemistry and Biochemistry, The University of Oklahoma, Norman, Oklahoma
| | - Zhibo Yang
- Department of Chemistry and Biochemistry, The University of Oklahoma, Norman, Oklahoma
| | - Kar-Ming A. Fung
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Barish H. Edil
- Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Russell G. Postier
- Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Michael S. Bronze
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Martin E. Fernandez-Zapico
- Department of Oncology, Mayo Clinic, Rochester, Minnesota;,Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Marc P. Stemmler
- Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany
| | - Thomas Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany
| | - Yi-Ping Li
- Department of Integrative Biology & Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas
| | - Courtney W. Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Min Li
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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17
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Koo MA, Lee MH, Park JC. Recent Advances in ROS-Responsive Cell Sheet Techniques for Tissue Engineering. Int J Mol Sci 2019; 20:ijms20225656. [PMID: 31726692 PMCID: PMC6888384 DOI: 10.3390/ijms20225656] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Cell sheet engineering has evolved rapidly in recent years as a new approach for cell-based therapy. Cell sheet harvest technology is important for producing viable, transplantable cell sheets and applying them to tissue engineering. To date, most cell sheet studies use thermo-responsive systems to detach cell sheets. However, other approaches have been reported. This review provides the progress in cell sheet detachment techniques, particularly reactive oxygen species (ROS)-responsive strategies. Therefore, we present a comprehensive introduction to ROS, their application in regenerative medicine, and considerations on how to use ROS in cell detachment. The review also discusses current limitations and challenges for clarifying the mechanism of the ROS-responsive cell sheet detachment.
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Affiliation(s)
- Min-Ah Koo
- Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Mi Hee Lee
- Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jong-Chul Park
- Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: ; Tel.: +82-2-2228-1917
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18
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DiPersio CM, Van De Water L. Integrin Regulation of CAF Differentiation and Function. Cancers (Basel) 2019; 11:cancers11050715. [PMID: 31137641 PMCID: PMC6563118 DOI: 10.3390/cancers11050715] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/14/2019] [Accepted: 05/21/2019] [Indexed: 02/07/2023] Open
Abstract
Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed on all tumor and stromal cell types where they regulate both cell adhesion and bidirectional signal transduction across the cell membrane. In this capacity, integrins control pro-tumorigenic cell autonomous functions such as growth and survival, as well as paracrine crosstalk between tumor cells and stromal cells. The myofibroblast-like properties of cancer-associated fibroblasts (CAFs), such as robust contractility and extracellular matrix (ECM) deposition, allow them to generate both chemical and mechanical signals that support invasive tumor growth. In this review, we discuss the roles of integrins in regulating the ability of CAFs to generate and respond to extracellular cues in the tumor microenvironment. Since functions of specific integrins in CAFs are only beginning to emerge, we take advantage of a more extensive literature on how integrins regulate wound myofibroblast differentiation and function, as some of these integrin functions are likely to extrapolate to CAFs within the tumor microenvironment. In addition, we discuss the roles that integrins play in controlling paracrine signals that emanate from epithelial/tumor cells to stimulate fibroblasts/CAFs.
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19
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Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma. Oncotarget 2019; 10:3104-3113. [PMID: 31139323 PMCID: PMC6517103 DOI: 10.18632/oncotarget.5742] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 09/18/2015] [Indexed: 12/31/2022] Open
Abstract
Studies have examined gene expression changes in Sézary syndrome (SS), but disease pathogenesis remains largely unknown, and diagnosis and treatment are difficult. TOX is a transcription factor involved in CD4+ T-cell development with downstream effects on RUNX3, a known tumor suppressor gene. We sought to identify genes involved in SS disease pathogenesis with the potential to enable diagnosis and treatment. We utilized previously reported transcriptome sequencing data to construct a list of candidate genes, which was narrowed using pathway analysis. qRT-PCR confirmed TOX upregulation (>7 fold increase) in SS (n = 5), as well as two established markers, PLS3 and KIRD3DL2. We also evaluated expression of members of the TOX-RUNX3 pathway and confirmed downregulation of RUNX3 (0.59 fold decrease) and upregulation of GATA3 (2 fold increase). Moreover, TOX and RUNX3 expression were significantly inversely proportional. Using siRNA to suppress TOX, we demonstrated that TOX knockdown rescues RUNX3 expression and reduces cell viability. We evaluated TOX protein expression in paraffin-embedded skin biopsies with immunohistochemistry, showing nuclear staining of CTCL infiltrates, suggesting it is a candidate diagnostic biomarker. Further studies validating our findings and evaluating the TOX-RUNX3 pathway and the role of TOX as a disease marker and therapeutic target are warranted.
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20
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Hussain S, Singh A, Nazir SU, Tulsyan S, Khan A, Kumar R, Bashir N, Tanwar P, Mehrotra R. Cancer drug resistance: A fleet to conquer. J Cell Biochem 2019; 120:14213-14225. [PMID: 31037763 DOI: 10.1002/jcb.28782] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/08/2019] [Accepted: 01/14/2019] [Indexed: 12/18/2022]
Abstract
Cancer is a disease that claims millions of lives each year across the world. Despite advancement in technologies and therapeutics for treating the disease, these modes are often found to turn ineffective during the course of treatment. The resistance against drugs in cancer patients stems from multiple factors, which constitute genetic heterogeneity like gene mutations, tumor microenvironment, exosomes, miRNAs, high rate of drug efflux from cells, and so on. This review attempts to collate all such known and reported factors that influence cancer drug resistance and may help researchers with information that might be useful in developing better therapeutics in near future to enable better management of several cancers across the world.
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Affiliation(s)
- Showket Hussain
- Division of Cellular and Molecular Diagnostics, National Institute of Cancer Prevention and Research, Noida, India
| | - Ankita Singh
- Division of Cellular and Molecular Diagnostics, National Institute of Cancer Prevention and Research, Noida, India
| | - Sheeraz Un Nazir
- Division of Cellular and Molecular Diagnostics, National Institute of Cancer Prevention and Research, Noida, India
| | - Sonam Tulsyan
- Division of Preventive Oncology, National Institute of Cancer Prevention and Research, Noida, India
| | - Asiya Khan
- Department of Lab Oncology, AIIMS, New Delhi, India
| | - Ramesh Kumar
- Department of Biochemistry, Bundelkhand University, Jhansi, India
| | - Nasreena Bashir
- College of Applied Medicine, King Khalid University, Abha, Saudi Arabia
| | | | - Ravi Mehrotra
- Division of Preventive Oncology, National Institute of Cancer Prevention and Research, Noida, India
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21
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Souho T, Lamboni L, Xiao L, Yang G. Cancer hallmarks and malignancy features: Gateway for improved targeted drug delivery. Biotechnol Adv 2018; 36:1928-1945. [DOI: 10.1016/j.biotechadv.2018.08.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 07/22/2018] [Accepted: 08/01/2018] [Indexed: 12/13/2022]
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22
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RAC1 GTP-ase signals Wnt-beta-catenin pathway mediated integrin-directed metastasis-associated tumor cell phenotypes in triple negative breast cancers. Oncotarget 2018; 8:3072-3103. [PMID: 27902969 PMCID: PMC5356866 DOI: 10.18632/oncotarget.13618] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 10/27/2016] [Indexed: 12/21/2022] Open
Abstract
The acquisition of integrin-directed metastasis-associated (ID-MA) phenotypes by Triple-Negative Breast Cancer (TNBC) cells is caused by an upregulation of the Wnt-beta-catenin pathway (WP). We reported that WP is one of the salient genetic features of TNBC. RAC-GTPases, small G-proteins which transduce signals from cell surface proteins including integrins, have been implicated in tumorigenesis and metastasis by their role in essential cellular functions like motility. The collective percentage of alteration(s) in RAC1 in ER+ve BC was lower as compared to ER-ve BC (35% vs 57%) (brca/tcga/pub2015). High expression of RAC1 was associated with poor outcome for RFS with HR=1.48 [CI: 1.15-1.9] p=0.0019 in the Hungarian ER-veBC cohort. Here we examined how WP signals are transduced via RAC1 in the context of ID-MA phenotypes in TNBC. Using pharmacological agents (sulindac sulfide), genetic tools (beta-catenin siRNA), WP modulators (Wnt-C59, XAV939), RAC1 inhibitors (NSC23766, W56) and WP stimulations (LWnt3ACM, Wnt3A recombinant) in a panel of 6-7 TNBC cell lines, we studied fibronectin-directed (1) migration, (2) matrigel invasion, (3) RAC1 and Cdc42 activation, (4) actin dynamics (confocal microscopy) and (5) podia-parameters. An attenuation of WP, which (a) decreased cellular levels of beta-catenin, as well as its nuclear active-form, (b) decreased fibronectin-induced migration, (c) decreased invasion, (d) altered actin dynamics and (e) decreased podia-parameters was successful in blocking fibronectin-mediated RAC1/Cdc42 activity. Both Wnt-antagonists and RAC1 inhibitors blocked fibronectin-induced RAC1 activation and inhibited the fibronectin-induced ID-MA phenotypes following specific WP stimulation by LWnt3ACM as well as Wnt3A recombinant protein. To test a direct involvement of RAC1-activation in WP-mediated ID-MA phenotypes, we stimulated brain-metastasis specific MDA-MB231BR cells with LWnt3ACM. LWnt3ACM-stimulated fibronectin-directed migration was blocked by RAC1 inhibition in MDA-MB231BR cells. In the light of our previous report that WP upregulation causes ID-MA phenotypes in TNBC tumor cells, here we provide the first mechanism based evidence to demonstrate that WP upregulation signals ID-MA tumor cell phenotypes in a RAC1-GTPase dependent manner involving exchange-factors like TIAM1 and VAV2. Our study demonstrates for the first time that beta-catenin-RAC1 cascade signals integrin-directed metastasis-associated tumor cell phenotypes in TNBC.
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23
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Bouvier C, Macagno N, Nguyen Q, Loundou A, Jiguet-Jiglaire C, Gentet JC, Jouve JL, Rochwerger A, Mattei JC, Bouvard D, Salas S. Prognostic value of the Hippo pathway transcriptional coactivators YAP/TAZ and β1-integrin in conventional osteosarcoma. Oncotarget 2018; 7:64702-64710. [PMID: 27608849 PMCID: PMC5323109 DOI: 10.18632/oncotarget.11876] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 08/01/2016] [Indexed: 11/25/2022] Open
Abstract
Introduction Currently, very few studies are available concerning the mammalian Hippo pathway in bone sarcomas. YAP/TAZ transcription co-activators are key downstream effectors of this pathway and may also have oncogenic properties. Additionally, recent in-vitro experiments showed that expression of β1-integrin promoted metastasis in osteosarcomas. This study investigated the expression of YAP/TAZ and β1-integrin in human osteosarcomas. Materials and methods We performed automated immunohistochemistry on tissue-microarrays (TMA) in which 69 conventional osteosarcomas biopsies performed prior to chemotherapy were embedded. Cellular localization and semi-quantitative analysis of each immunostain was performed using Immunoreactive Score (IRS) and correlated to clinico-pathological data. Results Cytoplasmic expression of β1-integrin was noted in 54/59 osteosarcomas (92%), with 33/59 cases (56%) displaying membranous staining. YAP/TAZ was expressed in 27/45 osteosarcomas (60%), with 14 cases (31%) showing cytoplasmic expression while 13 other cases (28%) displayed nuclear expression. No link was found between YAP/TAZ or β1-integrin expression and response to chemotherapy. In univariate analysis, YAP/TAZ immunoreactive score was pejoratively correlated with overall survival (p = 0.01). Expression of β1-integrin on cell membrane was also pejorative for OS (p = 0.045). In multivariate analysis, YAP/TAZ nuclear expression was an independent prognostic factor for PFS (p = 0.035). Conclusion this study indicates that β1-integrin and YAP/TAZ proteins are linked to prognosis and therefore could be therapeutic targets in conventional osteosarcomas.
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Affiliation(s)
- Corinne Bouvier
- Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.,Department of Pathology, APHM, Timone Hospital, Marseille, France
| | - Nicolas Macagno
- Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.,Department of Pathology, APHM, Timone Hospital, Marseille, France
| | - Quy Nguyen
- Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France
| | - Anderson Loundou
- Department of Public Health, Aix-Marseille University (AMU), Faculty of Medecine, EA 3270 Research Unit, Marseille, France.,Department of Research and Innovation, APHM, Timone Hospital, Support Unit for Clinical Research and Economic Evaluation, Marseille, France
| | - Carine Jiguet-Jiglaire
- Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France
| | - Jean-Claude Gentet
- Department of Pediatric Oncology, APHM, Timone Hospital, Marseille, France
| | - Jean-Luc Jouve
- Department of Pediatric Orthopaedic Surgery, APHM, Timone Hospital, Marseille, France
| | | | - Jean-Camille Mattei
- Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.,Department of Adult Orthopaedic Surgery, APHM, Nord Hospital, Marseille, France
| | | | - Sébastien Salas
- Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.,Department of Pathology, APHM, Timone Hospital, Marseille, France
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Lappano R, Maggiolini M. GPER is involved in the functional liaison between breast tumor cells and cancer-associated fibroblasts (CAFs). J Steroid Biochem Mol Biol 2018; 176:49-56. [PMID: 28249728 DOI: 10.1016/j.jsbmb.2017.02.019] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 02/02/2017] [Accepted: 02/23/2017] [Indexed: 12/17/2022]
Abstract
The aggressiveness of breast tumors is deeply influenced by the surrounding stroma. In this regard, the functional crosstalk between cancer cells and the tumor microenvironment has received considerable attention in recent years. Cancer-associated fibroblasts (CAFs) are active components of the tumor stroma as they play a main role in the initiation, progression, metastasis and recurrence of breast malignancy. Hence, a better understanding of the mechanisms through which host stroma may contribute to cancer development would lead to novel therapeutic approaches aimed to target both tumor cells and the adjacent microenvironment. The G protein estrogen receptor (GPER/GPR30) has been involved in estrogenic signaling in normal and malignant cells, including breast cancer. It is noteworthy that the potential of GPER to mediate stimulatory effects of estrogens has been also shown in CAFs derived from patients with breast tumors, suggesting that GPER may act at the cross-road between cancer cells and these important components of the tumor microenvironment. This review recapitulates recent findings underlying the breast tumor-promoting action of CAFs, in particular their functional liaison with breast cancer cells via GPER toward the occurrence of malignant features.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
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Xiang X, Wang Y, Zhang H, Piao J, Muthusamy S, Wang L, Deng Y, Zhang W, Kuang R, Billadeau DD, Huang S, Lai J, Urrutia R, Kang N. Vasodilator-stimulated phosphoprotein promotes liver metastasis of gastrointestinal cancer by activating a β1-integrin-FAK-YAP1/TAZ signaling pathway. NPJ Precis Oncol 2018; 2:2. [PMID: 29872721 PMCID: PMC5871906 DOI: 10.1038/s41698-017-0045-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 12/06/2017] [Accepted: 12/28/2017] [Indexed: 12/26/2022] Open
Abstract
Extracellular matrix (ECM)-induced β1-integrin-FAK signaling promotes cell attachment, survival, and migration of cancer cells in a distant organ so as to enable cancer metastasis. However, mechanisms governing activation of the β1-integrin-FAK signaling remain incompletely understood. Here, we report that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, is required for ECM-mediated β1-integrin-FAK-YAP1/TAZ signaling in gastrointestinal (GI) cancer cells and their liver metastasis. In patient-derived samples, VASP is upregulated in 53 of 63 colorectal cancers and 43 of 53 pancreatic ductal adenocarcinomas and high VASP levels correlate with liver metastasis and reduced patient survival. In a Matrigel-based 3-dimensional (3D) culture model, short hairpin RNA (shRNA)-mediated VASP knockdown in colorectal cancer cells (KM12L4, HCT116, and HT29) and pancreatic cancer cells (L3.6 and MIA PaCa-1) suppresses the growth of 3D cancer spheroids. Mechanistic studies reveal that VASP knockdown suppresses FAK phosphorylation and YAP1/TAZ protein levels, but not Akt or Erk-related pathways and that YAP1/TAZ proteins are enhanced by the β1-integrin-FAK signaling. Additionally, VASP regulates the β1-integrin-FAK-YAP1/TAZ signaling by at least two mechanisms: (1) promoting ECM-mediated β1-integrin activation and (2) regulating YAP1/TAZ dephosphorylation at downstream of RhoA to enhance the stability of YAP1/TAZ proteins. In agreement with these, preclinical studies with two experimental liver metastasis mouse models demonstrate that VASP knockdown suppresses GI cancer liver metastasis, β1-integrin activation, and YAP1/TAZ levels of metastatic cancer cells. Together, our data support VASP as a treatment target for liver metastasis of colorectal and pancreatic cancers.
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Affiliation(s)
- Xiaoyu Xiang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Yuanguo Wang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Hongbin Zhang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Jinhua Piao
- Department of Pathology, St. Louis University, School of Medicine, St. Louis, MO 63104 USA
| | - Selvaraj Muthusamy
- Department of Pathology, St. Louis University, School of Medicine, St. Louis, MO 63104 USA
| | - Lei Wang
- Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Yibin Deng
- Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Wei Zhang
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455 USA
| | - Rui Kuang
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455 USA
| | | | | | - Jinping Lai
- Department of Pathology, St. Louis University, School of Medicine, St. Louis, MO 63104 USA
| | - Raul Urrutia
- GI Research Unit, Mayo Clinic, Rochester, MN 55905 USA
| | - Ningling Kang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
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Hou L, Gu W, Zhu H, Yao W, Wang W, Meng Q. Spiroplasma eriocheiris induces mouse 3T6-Swiss albino cell apoptosis that associated with the infection mechanism. Mol Immunol 2017; 91:75-85. [PMID: 28889064 DOI: 10.1016/j.molimm.2017.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/31/2017] [Accepted: 08/07/2017] [Indexed: 11/20/2022]
Abstract
Spiroplasma eriocheiris is a novel pathogen similar to the Spiroplasma mirum and also had an ability to infect the newborn mice and caused cataract. Our study was designed to study how S. eriocheiris infects mouse 3T6-Swiss albino cells and to elucidate the cellular molecular pathogenesis of Spiroplasma. FCM analysis and MTT analysis clearly shown that S. eriocheiris could induce 3T6 cell apoptosis and cause cell viability decreased seriously. Immunofluorescence experiments and TEM analysis shown that S. eriocheiris can invade 3T6 cells and form typical inclusion bodies and exhibit vacuolization in vitro. S. eriocheiris-oxytetracycline protection assay show that the infective bacteria already were detected at 1h post infection, and sharply increased at 12h after the bacteria infection. To further study the infection mechanism of S. eriocheiris, global mRNA and microRNA (miRNA) expression profiling were analyzed after the cells infected with the bacteria. A total of 619 non-redundant annotated transcripts (183 up-regulated and 436 down-regulated) and 22 miRNAs (8 up-regulated and 14 down-regulated) were differential expression after 6h S. eriocheiris infection compared to control group. Integrated analysis shown that homologous genes from differential expression miRNA targets and the differential expression genes of the mRNA microarray were major focused on two important pathways focal adhesion and MAPK signaling pathway. To validate the results of microarray, eight focal adhesion (β-Catenin, Parvin, Grb2 and ERK) and MAPK signaling pathway (FGFR, Grb2, ERK, MKK3, p38 and JNK) genes and the housekeeping gene GAPDH were assayed by qPCR and Western blot to confirm the results. Eight miRNAs (miR-143-3p, miR-214-5p, miR-322-3p, miR-328-5p, miR-351-5p, miR-466h-5p, miR-503-5p and miR-30c-1-3p) and the housekeeping gene U6 miRNA were assayed by qPCR to confirm the results of microarray. All the results help us better understand the infection mechanism of S. eriocheiris.
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Affiliation(s)
- Libo Hou
- Jiangsu Key Laboratory for Microbes & Functional Genomics and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China
| | - Wei Gu
- Jiangsu Key Laboratory for Microbes & Functional Genomics and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China; Co-Innovation Center for Marine Bio-Industry Technology of Jiangsu Province, Lianyungang, Jiangsu 222005, China
| | - Huanxi Zhu
- Jiangsu Key Laboratory for Microbes & Functional Genomics and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China
| | - Wei Yao
- Jiangsu Key Laboratory for Microbes & Functional Genomics and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China
| | - Wen Wang
- Jiangsu Key Laboratory for Microbes & Functional Genomics and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China
| | - Qingguo Meng
- Jiangsu Key Laboratory for Microbes & Functional Genomics and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China; Co-Innovation Center for Marine Bio-Industry Technology of Jiangsu Province, Lianyungang, Jiangsu 222005, China.
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Synthesis, reactivities and anti-cancer properties of ruthenium(II) complexes with a thiaether macrocyclic ligand. Inorganica Chim Acta 2017. [DOI: 10.1016/j.ica.2016.07.050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Cell adhesion phenotyping by quantitative polymerase chain reaction in melanoma: Clarifying misconceptions. J Am Acad Dermatol 2016; 76:e23. [PMID: 27986155 DOI: 10.1016/j.jaad.2016.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/02/2016] [Indexed: 11/20/2022]
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Cho SH, Park SM, Lee HS, Lee HY, Cho KH. Attractor landscape analysis of colorectal tumorigenesis and its reversion. BMC SYSTEMS BIOLOGY 2016; 10:96. [PMID: 27765040 PMCID: PMC5072344 DOI: 10.1186/s12918-016-0341-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 10/10/2016] [Indexed: 02/08/2023]
Abstract
Background Colorectal cancer arises from the accumulation of genetic mutations that induce dysfunction of intracellular signaling. However, the underlying mechanism of colorectal tumorigenesis driven by genetic mutations remains yet to be elucidated. Results To investigate colorectal tumorigenesis at a system-level, we have reconstructed a large-scale Boolean network model of the human signaling network by integrating previous experimental results on canonical signaling pathways related to proliferation, metastasis, and apoptosis. Throughout an extensive simulation analysis of the attractor landscape of the signaling network model, we found that the attractor landscape changes its shape by expanding the basin of attractors for abnormal proliferation and metastasis along with the accumulation of driver mutations. A further hypothetical study shows that restoration of a normal phenotype might be possible by reversely controlling the attractor landscape. Interestingly, the targets of approved anti-cancer drugs were highly enriched in the identified molecular targets for the reverse control. Conclusions Our results show that the dynamical analysis of a signaling network based on attractor landscape is useful in acquiring a system-level understanding of tumorigenesis and developing a new therapeutic strategy. Electronic supplementary material The online version of this article (doi:10.1186/s12918-016-0341-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sung-Hwan Cho
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Sang-Min Park
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Ho-Sung Lee
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Hwang-Yeol Lee
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Kwang-Hyun Cho
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea. .,Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
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Kozlova NI, Morozevich GE, Ushakova NA, Gevorkian NM, Berman AE. Differences between integrin α5β1 and EGRF receptor in signal pathways controlling proliferation and apoptosis of MCF-7/Dox human breast carcinoma cells. BIOCHEMISTRY MOSCOW-SUPPLEMENT SERIES B-BIOMEDICAL CHEMISTRY 2016. [DOI: 10.1134/s1990750816030082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Kozlova N, Morozevich G, Ushakova N, Gevorkian N, Berman A. Implication of integrin alpha5beta1 signal pathways in proliferation and apoptosis of MCF-7/Dox human breast carcinoma cells. ACTA ACUST UNITED AC 2016; 62:272-8. [DOI: 10.18097/pbmc20166203272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In MCF-7/Dox human breast carcinoma cells, down-regulation of integrin alpha5beta1 and inhibition of epidermal growth factor receptor (EGFR) markedly reduced rates of cell proliferation. Mitotic cycle analysis showed that alpha5beta1 down-regulation resulted in cell cycle arrest at the S phase, followed by a significant increase in the population of apoptotic cells (subG1 population). Inhibition of EGFR activity also caused cell cycle arrest at the S-phase but without any increase in the subG1 population. Down-regulation of alpha5beta1 and EGFR inhibition resulted in a significant decrease of cell content of the active (phosphorylated) forms of FAK and Erk protein kinases. The data obtained suggest that alpha5beta1 integrin is implicated in cell growth control via inhibition of apoptotic cell death and through EGFR activation.
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Affiliation(s)
- N.I. Kozlova
- Institute of Biomedical Chemistry, Moscow, Russia
| | | | | | | | - A.E. Berman
- Institute of Biomedical Chemistry, Moscow, Russia
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Ulusoy M, Lavrentieva A, Walter JG, Sambale F, Green M, Stahl F, Scheper T. Evaluation of CdTe/CdS/ZnS core/shell/shell quantum dot toxicity on three-dimensional spheroid cultures. Toxicol Res (Camb) 2016; 5:126-135. [PMID: 30090332 PMCID: PMC6060716 DOI: 10.1039/c5tx00236b] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 07/30/2015] [Indexed: 11/21/2022] Open
Abstract
In this work, three-dimensional (3D) spheroid cultures of human adipose-derived mesenchymal stem cells (hAD-MSCs), with tissue-mimetic morphology through well developed cell-cell and cell-matrix interactions and distinct diffusion/transport characteristics, were assessed for dose-dependent toxic effects of red-emitting CdTe/CdS/ZnS quantum dots (Qdots). Morphological investigations and time-resolved microscopy analysis in addition to cell metabolic activity studies revealed that 3D spheroid cultures are more resistant to Qdot-induced cytotoxicity in comparison to conventional 2D cultures. The obtained results suggest the presence of two distinct cell populations in 2D cultures with different sensitivity to Qdots, however that effect wasn't observed in 3D spheroids. Our investigations were aimed to improve the prediction of nanotoxicity of Qdot on tissue-level and provide the essential screening steps prior to any in vivo application. Moreover, penetration ability of highly fluorescent Qdots to densely-packed spheroids will fortify the biological application of developed Qdots in tissue-like structures.
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Affiliation(s)
- Mehriban Ulusoy
- Gottfried Wilhelm Leibniz University of Hannover , Institute of Technical Chemistry , 30167 Hanover , Germany . ; Tel: +49 (0)511 762-2968
| | - Antonina Lavrentieva
- Gottfried Wilhelm Leibniz University of Hannover , Institute of Technical Chemistry , 30167 Hanover , Germany . ; Tel: +49 (0)511 762-2968
| | - Johanna-Gabriela Walter
- Gottfried Wilhelm Leibniz University of Hannover , Institute of Technical Chemistry , 30167 Hanover , Germany . ; Tel: +49 (0)511 762-2968
| | - Franziska Sambale
- Gottfried Wilhelm Leibniz University of Hannover , Institute of Technical Chemistry , 30167 Hanover , Germany . ; Tel: +49 (0)511 762-2968
| | - Mark Green
- King's College London , Department of Physics , The Strand , WC2R LS London , UK . ; Tel: +44 (0)2078 48212
| | - Frank Stahl
- Gottfried Wilhelm Leibniz University of Hannover , Institute of Technical Chemistry , 30167 Hanover , Germany . ; Tel: +49 (0)511 762-2968
| | - Thomas Scheper
- Gottfried Wilhelm Leibniz University of Hannover , Institute of Technical Chemistry , 30167 Hanover , Germany . ; Tel: +49 (0)511 762-2968
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Detchokul S, Williams ED, Parker MW, Frauman AG. Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies. Br J Pharmacol 2015; 171:5462-90. [PMID: 23731188 DOI: 10.1111/bph.12260] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 05/16/2013] [Accepted: 05/16/2013] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED One of the hallmarks of cancer is the ability to activate invasion and metastasis. Cancer morbidity and mortality are largely related to the spread of the primary, localized tumour to adjacent and distant sites. Appropriate management and treatment decisions based on predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are components of metastasis that are common to all primary tumours: dissociation from the primary tumour mass, reorganization/remodelling of extracellular matrix, cell migration, recognition and movement through endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma. One of the key and initial events is the increased ability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanin family of proteins play important roles in regulation of cancer cell migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, the tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis. LINKED ARTICLES This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24.
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Affiliation(s)
- S Detchokul
- Clinical Pharmacology and Therapeutics Unit, Department of Medicine (Austin Health/Northern Health), The University of Melbourne, Heidelberg, Vic., Australia
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Meves A, Nikolova E, Heim JB, Squirewell EJ, Cappel MA, Pittelkow MR, Otley CC, Behrendt N, Saunte DM, Lock-Andersen J, Schenck LA, Weaver AL, Suman VJ. Tumor Cell Adhesion As a Risk Factor for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma. J Clin Oncol 2015; 33:2509-15. [PMID: 26150443 DOI: 10.1200/jco.2014.60.7002] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. PATIENTS AND METHODS Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. RESULTS ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). CONCLUSION The addition of cell adhesion-linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.
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Affiliation(s)
- Alexander Meves
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Ekaterina Nikolova
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Joel B Heim
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Edwin J Squirewell
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mark A Cappel
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mark R Pittelkow
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Clark C Otley
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nille Behrendt
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ditte M Saunte
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jorgen Lock-Andersen
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Louis A Schenck
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Amy L Weaver
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Vera J Suman
- Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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McGarry T, Veale DJ, Gao W, Orr C, Fearon U, Connolly M. Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis. Arthritis Res Ther 2015; 17:153. [PMID: 26055925 PMCID: PMC4495696 DOI: 10.1186/s13075-015-0664-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 05/27/2015] [Indexed: 01/09/2023] Open
Abstract
Introduction This study investigates the role of Toll-like receptor 2 (TLR2) in the regulation of migratory and invasive mechanisms in rheumatoid arthritis (RA). Methods Invasion, migration, matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) expression, β-integrin binding, cytoskeletal rearrangement and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation in response to a TLR2-ligand, Pam3CSK4 (1 μg/ml), in ex vivo RA synovial tissue explants, primary RA synovial fibroblasts (RASFC) and microvascular endothelial cells (HMVEC) were assessed by Transwell Matrigel™ invasion chambers, enzyme-linked immunosorbent assay (ELISA), multiplex adhesion binding assay, reverse transcription polymerase chain reaction (RT-PCR), F-actin immunofluorescent staining, matrigel synovial outgrowths, Rac1 pull-down assays/Western blot and zymography. β1-integrin expression in RA/control synovial tissue was assessed by immunohistology. The effect of Pam3CSK4 on cell migration, invasion, MMP-3 and Rac1 activation was examined in the presence or absence of anti-β1-integrin (10 μg/ml) or anti-IgG control (10 μg/ml). The effect of an anti-TLR-2 mAb (OPN301)(1 μg/ml) or immunoglobulin G (IgG) control (1 μg/ml) on RASFC migration and RA synovial tissue MMP activity was assessed by wound assays, ELISA and zymography. Results Pam3CSK4 significantly induced cell migration, invasion, MMP-1, MMP-3, MMP-2 and MMP-9 expression and induced the MMP-1/TIMP-3 and MMP-3/TIMP-3 ratio in RASFC and explants (p <0.05). β1-integrin expression was significantly higher in RA synovial tissue compared to controls (p <0.05). Pam3CSK4 specifically induced β1-integrin binding in RASFC (p <0.05), with no effect observed for β2-4, β6, αvβ5 or α5β1. Pam3CSK4 increased β1-integrin mRNA expression, Rac1 activation, RASFC outgrowths and altered cytoskeletal dynamic through induction of filopodia formation. Pam3CSK4-regulated cell migration and invasion processes, but not MMP-3, were inhibited in the presence of anti-β1-integrin (p <0.05), with no effect observed for anti-IgG control. Furthermore, anti-β1-integrin inhibited Pam3CSK4-induced Rac1 activation. Finally, blockade of TLR2 with OPN301 significantly decreased spontaneous release of MMP-3, MMP-2 and MMP-9 and increased TIMP-3 secretion from RA synovial explant cultures (p <0.05). Incubation of RASFC with OPN301 RA ex vivo conditioned media inhibited migration and invasion compared to IgG control. Conclusions TLR2 activation induces migrational and invasive mechanisms, which are critically involved in the pathogenesis of RA, suggesting TLR2 as a potential therapeutic target for the treatment of RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0664-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Trudy McGarry
- Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin Academic Health Care and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Douglas J Veale
- Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin Academic Health Care and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Wei Gao
- Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin Academic Health Care and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Carl Orr
- Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin Academic Health Care and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Ursula Fearon
- Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin Academic Health Care and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
| | - Mary Connolly
- Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin Academic Health Care and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
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Guo J, Cheng C, Chen CS, Xing X, Xu G, Feng J, Qin X. Overexpression of Fibulin-5 Attenuates Ischemia/Reperfusion Injury After Middle Cerebral Artery Occlusion in Rats. Mol Neurobiol 2015; 53:3154-3167. [DOI: 10.1007/s12035-015-9222-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 05/21/2015] [Indexed: 02/07/2023]
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Zhang LQ, Zhao GZ, Xu XY, Fang J, Chen JM, Li JW, Gao XJ, Hao LJ, Chen YZ. Integrin-β1 regulates chondrocyte proliferation and apoptosis through the upregulation of GIT1 expression. Int J Mol Med 2015; 35:1074-80. [PMID: 25715677 DOI: 10.3892/ijmm.2015.2114] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 02/05/2015] [Indexed: 01/25/2023] Open
Abstract
Chondrocytes play a critical role in the repair process of osteoarthritis, which is also known as degenerative arthritis. Integrins, as the key family of cell surface receptors, are responsible for the regulation of chondrocyte proliferation, differentiation, survival and apoptosis through the recruitment and activation of downstream adaptor proteins. Moreover, G-protein-coupled receptor kinase interacting protein-1 (GIT1) exerts its effects on cell proliferation and migration through interaction with various cytokines. It has been previously suggested that GIT1 acts as a vital protein downstream of the integrin-mediated pathway. In the present study, we investigated the effects of integrin-β1 on cell proliferation and apoptosis, as well as the underlying mechanisms in chondrocytes in vitro. Following transfection with a vector expressing integrin-β1, our results revealed that the overexpression of integrin-β1 enhanced GIT1 expression, whereas the knockdown of integrin-β1 by siRNA suppressed GIT1 expression. However, no significant effect was observed on integrin-β1 expression following the enforced overexpression of GIT1, which suggests that GIT1 is localized downstream of integrin-β1. In other words, integrin-β1 regulates the expression of GIT1. Furthermore, this study demonstrated that integrin-β1 and GIT1 increased the expression levels of aggrecan and type II collagen, thus promoting chondrocyte proliferation; however, they inhibited chondrocyte apoptosis. Taken together, our data demonstrate that integrin-β1 plays a vital role in chondrocyte proliferation, differentiation and apoptosis. GIT1 exerts effects similar to those of integrin-β1 and is a downstream target of integrin-β1.
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Affiliation(s)
- Long-Qiang Zhang
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Guang-Zong Zhao
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Xiao-Yan Xu
- Department of Oncology, Qingzhou Hospital of Traditional Chinese Medicine, Qingzhou, Shandong 262500, P.R. China
| | - Jun Fang
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Jing-Ming Chen
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Ji-Wen Li
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Xue-Jian Gao
- Department of Orthopedics, The 89th Hospital of PLA, Weifang, Shandong 261021, P.R. China
| | - Li-Juan Hao
- Department of Urologic Surgery, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Yun-Zhen Chen
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Vay C, Hosch SB, Stoecklein NH, Klein CA, Vallböhmer D, Link BC, Yekebas EF, Izbicki JR, Knoefel WT, Scheunemann P. Integrin expression in esophageal squamous cell carcinoma: loss of the physiological integrin expression pattern correlates with disease progression. PLoS One 2014; 9:e109026. [PMID: 25398092 PMCID: PMC4232252 DOI: 10.1371/journal.pone.0109026] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 08/28/2014] [Indexed: 12/17/2022] Open
Abstract
The integrins are a family of heterodimeric transmembrane signaling receptors that mediate the adhesive properties of epithelial cells affecting cell growth and differentiation. In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis. However, only few studies have investigated the role of integrin expression in esophageal squamous cell carcinoma (ESCC). Using a novel quantifying immunofluorescence-staining assay, we investigated the expression of the integrins α2β1, α3β1, α6β1, and α6β4 in primary ESCC of 36 patients who underwent surgical resection. Magnitude and distribution of expression were analyzed in primary tumor samples and autologous esophageal squamous epithelium. The persistence of the physiologically polarized expression of the subunits α6, β1, and β4 in the tumor tissue was significantly associated with prolonged relapse-free survival (p = 0.028, p = 0.034, p = 0.006). In contrast, patients with reduced focal α6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong α6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (p = 0.001). Multivariate regression analysis identified the maintenance of strong α6 immunoreactivity at the invasion front as an independent prognostic factor for increased relapse-free and disease-specific survival (p = 0.003; p = 0.003). Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients. Particularly, the distinct expression of the integrins α6β4 and α6β1 at the invasion front as well as the maintenance of a polarized integrin expression pattern in the tumor tissue may serve as valuable new markers to assess the aggressiveness of ESCC.
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Affiliation(s)
- Christian Vay
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail:
| | - Stefan B. Hosch
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Vascular, and Visceral Surgery, Ingolstadt Medical Center, Ingolstadt, Germany
| | - Nikolas H. Stoecklein
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph A. Klein
- Division of Oncogenomics, Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Daniel Vallböhmer
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
| | - Björn-Christian Link
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Emre F. Yekebas
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wolfram T. Knoefel
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter Scheunemann
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pediatric Surgery, University Hospital Rostock, Rostock, Germany
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Fu S, Fan L, Pan X, Sun Y, Zhao H. Integrin αv promotes proliferation by activating ERK 1/2 in the human lung cancer cell line A549. Mol Med Rep 2014; 11:1266-71. [PMID: 25370835 DOI: 10.3892/mmr.2014.2860] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 07/09/2014] [Indexed: 11/06/2022] Open
Abstract
Lung cancer is a leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) constitutes ~85% of lung cancers. However, the mechanisms underlying the progression of NSCLC remain unclear. In this study, we found the mRNA and protein expression levels of integrin αv are both increased in NSCLC tissues compared to healthy ones, which indicates that integrin αv may play an important role in NSCLC progression. To further investigate the roles of integrin αv in NSCLC, we overexpressed the integrin αv gene in the NSCLC cell line A549, and found that the cell proliferative ability increased. The apoptosis of A549 cells was inhibited with overexpression of integrin αv. To elucidate the molecular mechanism underlying the role of integrin αv in promoting NSCLC progression, we studied the expression of proteins from a number of important pathways associated with tumorigenesis, and found that the extracellular signal regulated protein kinase (ERK)1/2 signaling pathway may be involved in the mediation of the observed integrin αv effects. component of an important pathway for tumorigenesis, the ERK 1/2. Following inhibition of ERK 1/2 signaling, the proliferation of A549 cells induced by integrin αv was reduced, while the inhibition of apoptosis was attenuated. Our findings demonstrate that integrin αv promotes the proliferation of the human lung cancer cell line A549 by activating the ERK 1/2 signaling pathway, which suggests that this pathway may be a promising target for the treatment of human lung cancer.
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Affiliation(s)
- Shijie Fu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Limin Fan
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Xufeng Pan
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Yifeng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Heng Zhao
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, P.R. China
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Tian J, Zhang FJ, Lei GH. Role of integrins and their ligands in osteoarthritic cartilage. Rheumatol Int 2014; 35:787-98. [PMID: 25261047 DOI: 10.1007/s00296-014-3137-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 09/17/2014] [Indexed: 12/31/2022]
Abstract
Osteoarthritis (OA) is a degenerative disease, which is characterized by articular cartilage destruction, and mainly affects the older people. The extracellular matrix (ECM) provides a vital cellular environment, and interactions between the cell and ECM are important in regulating many biological processes, including cell growth, differentiation, and survival. However, the pathogenesis of this disease is not fully elucidated, and it cannot be cured totally. Integrins are one of the major receptors in chondrocytes. A number of studies confirmed that the chondrocytes express several integrins including α5β1, αVβ3, αVβ5, α6β1, α1β1, α2β1, α10β1, and α3β1, and some integrins ligands might act as the OA progression biomarkers. This review focuses on the functional role of integrins and their extracellular ligands in OA progression, especially OA cartilage. Clear understanding of the role of integrins and their ligands in OA cartilage may have impact on future development of successful therapeutic approaches to OA.
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Affiliation(s)
- Jian Tian
- Department of Orthopaedics, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, China
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Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy. Cancer Lett 2014; 325:99-107. [PMID: 25016063 DOI: 10.1016/j.canlet.2012.06.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 05/31/2012] [Accepted: 06/24/2012] [Indexed: 12/14/2022]
Abstract
With prostate cancer (PCa), circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) portend a poor clinical prognosis. Their unknown biology precludes rational therapeutic design. We demonstrate that CTC and DTC cell lines, established from mice bearing human PCa orthotopic implants, exhibit increased cellular invasion in vitro, increased metastasis in mice, and express increased epithelial to mesenchymal transition biomarkers. Further, they are selectively resistant to growth inhibition by mitoxantrone-like agents. These findings demonstrate that CTC formation is accompanied by phenotypic progression without obligate reversion. Their increased metastatic potential, selective therapeutic resistance, and differential expression of potential therapeutic targets provide a rational basis to test further interventions.
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Yang XN, Lu YP, Liu JJ, Huang JK, Liu YP, Xiao CX, Jazag A, Ren JL, Guleng B. Piezo1 is as a novel trefoil factor family 1 binding protein that promotes gastric cancer cell mobility in vitro. Dig Dis Sci 2014; 59:1428-35. [PMID: 24798994 DOI: 10.1007/s10620-014-3044-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 01/20/2014] [Indexed: 12/09/2022]
Abstract
BACKGROUND Trefoil factor family 1 (TFF1) is a member of the TFF-domain peptide family involved in epithelial restitution and cell motility. Recently, we screened Piezo1 as a candidate TFF1-binding protein. AIM We aimed to confirm Piezo1 as a novel TFF1 binding protein and to assess the role of this interaction in mediating gastric cancer cell mobility. METHODS This interaction was confirmed by co-immunoprecipitation and co-localisation of TFF1 and Piezo1 in GES-1 cells. We used stable RNA interference to knockdown Piezo1 protein expression and restored the expression of TFF1 in the gastric cancer cell lines SGC-7901 and BGC-823. Cell motility was evaluated using invasion assay and migration assay in vitro. The expression levels of the integrin subunits β1, β5, α1 as well as the expression of β-catenin and E-cadherin were detected by Western blot. RESULTS We demonstrate that TFF1, but not TFF2 or TFF3, bind to and co-localize with Piezo1 in the cytoplasm in vitro. TFF1 interacts with the C-terminal portion of the Piezo1 protein. Wound healing and trans-well assays demonstrated that the restored expression of TFF1 promoted cell mobility in gastric cancer cells, and this effect was attenuated by the knockdown of Piezo1. Western blots demonstrated the decreased expression of integrin β1 in Piezo1-knockdown cells. CONCLUSIONS Our data demonstrate that Piezo1 is a novel TFF1 binding protein that is important for TFF1-mediated cell migration and suggest that this interaction may be a therapeutic target in the invasion and metastasis of gastric cancer.
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Affiliation(s)
- Xiao-Ning Yang
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, China
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Aggarwal A, Al-Rohil RN, Batra A, Feustel PJ, Jones DM, DiPersio CM. Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer. BMC Cancer 2014; 14:459. [PMID: 24950714 PMCID: PMC4069347 DOI: 10.1186/1471-2407-14-459] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 06/13/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Expression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3β1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3β1 and COX2 by testing for their correlated expression among various forms of human breast cancer. METHODS Immunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman's rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria. RESULTS Although expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (r(s) = 0.49, p < 0.001, n = 59) and archived samples (r(s) = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage. CONCLUSIONS COX2 and α3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin α3β1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of α3β1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target α3β1, and that α3 expression might serve as an independent prognostic biomarker.
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Affiliation(s)
- Anshu Aggarwal
- Center for Cell Biology & Cancer Research, Albany Medical College, Mail Code 165, Room MS-420, 47 New Scotland Avenue, Albany, NY 12208-3479, USA
| | - Rami N Al-Rohil
- Department of Pathology, Albany Medical Center, Albany, NY 12208, USA
| | - Anupam Batra
- Department of Internal Medicine, Albany Medical Center, Albany, NY 12208, USA
| | - Paul J Feustel
- Center for Neuropharmacology and Neurosciences, Albany Medical College, Albany, NY 12208, USA
| | - David M Jones
- Department of Pathology, Albany Medical Center, Albany, NY 12208, USA
| | - C Michael DiPersio
- Center for Cell Biology & Cancer Research, Albany Medical College, Mail Code 165, Room MS-420, 47 New Scotland Avenue, Albany, NY 12208-3479, USA
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Skaik Y, Vahlsing S, Goudeva L, Eiz-Vesper B, Battermann A, Blasczyk R, Figueiredo C. Secreted β3-integrin enhances natural killer cell activity against acute myeloid leukemia cells. PLoS One 2014; 9:e98936. [PMID: 24919191 PMCID: PMC4053493 DOI: 10.1371/journal.pone.0098936] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 05/09/2014] [Indexed: 01/27/2023] Open
Abstract
Integrins are a large family of heterodimeric proteins that are involved in cell adhesion, migration, and proliferation. Integrin diversity and function is regulated by alternative splicing. Membrane-bound and truncated β3-integrins were shown to be key players in cancer metastasis. However, the immunomodulatory functions of the soluble (s) β3-integrin have not been investigated yet. In this study, we described a novel form of sβ3-integrin in acute myeloid leukaemia (AML) patients. Furthermore, we assessed the role of the sβ3-integrin in the modulation of natural killer (NK)-cell activity. Levels of sβ3-integrin were analysed in plasma samples of 23 AML patients and 26 healthy donors by ELISA. The capacity of sβ3-integrin to regulate NK cell activity was investigated using proliferation, cytokine secretion, and cytotoxicity assays. Circulating sβ3-integrin was detected in the plasma of 8 AML patients. NK cells showed significantly higher proliferation rates after stimulation with sβ3-integrin and IL-2, IL-15 (73%). Significant increases in the NK cells’ secreted levels of TNF-α, IFN-γ were measured in presence of sβ3-integrin. In addition, sβ3-integrin caused the upregulation of Granzyme B transcripts levels as well as FasL expression levels in NK cells. Most importantly, significantly higher K562 or AML blast target cell lysis rates were observed when NK cells were exposed to sβ3-integrin. This study reports the identification of a novel sβ3-integrin in AML patients and provides novel insights into its role in the immunomodulation of NK cell activity.
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Affiliation(s)
- Younis Skaik
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Stefanie Vahlsing
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Lilia Goudeva
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Britta Eiz-Vesper
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Anja Battermann
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Constança Figueiredo
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
- * E-mail:
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Winograd-Katz SE, Fässler R, Geiger B, Legate KR. The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol 2014; 15:273-88. [PMID: 24651544 DOI: 10.1038/nrm3769] [Citation(s) in RCA: 462] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The adhesive interactions of cells with their environment through the integrin family of transmembrane receptors have key roles in regulating multiple aspects of cellular physiology, including cell proliferation, viability, differentiation and migration. Consequently, failure to establish functional cell adhesions, and thus the assembly of associated cytoplasmic scaffolding and signalling networks, can have severe pathological effects. The roles of specific constituents of integrin-mediated adhesions, which are collectively known as the 'integrin adhesome', in diverse pathological states are becoming clear. Indeed, the prominence of mutations in specific adhesome molecules in various human diseases is now appreciated, and experimental as well as in silico approaches provide insights into the molecular mechanisms underlying these pathological conditions.
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Affiliation(s)
- Sabina E Winograd-Katz
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Reinhard Fässler
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
| | - Benjamin Geiger
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Kyle R Legate
- 1] Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. [2] Center for Nanosciences, Department of Applied Physics, Ludwig-Maximilians University, 80799 Munich, Germany
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Schwankhaus N, Gathmann C, Wicklein D, Riecken K, Schumacher U, Valentiner U. Cell adhesion molecules in metastatic neuroblastoma models. Clin Exp Metastasis 2014; 31:483-96. [PMID: 24549749 DOI: 10.1007/s10585-014-9643-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 02/03/2014] [Indexed: 12/11/2022]
Abstract
Several cell adhesion molecules (CAMs) including selectins, integrins, cadherins and immunoglobulin-like CAMs are involved in leukocyte adhesion especially at sites of inflammation. In cancer cells, these CAMs have been associated with the growth and metastatic behavior in several malignant entities. In this study adhesion of LAN 1 and SK-N-SH neuroblastoma cells to selectins, hyaluronan and endothelial cells were determined under flow conditions. Furthermore cells were injected subcutaneously into wildtype and selectin deficient scid mice and their growth and metastatic behavior were analyzed. Under shear stress SK-N-SH cells firmly adhered to E-selectin-Fc-fusion protein, hyaluronan and endothelial cells, while LAN 1 cells showed less or hardly any adhesive events by comparison. In the SK-N-SH xenograft model metastasis formation was slightly dependent on the expression of selectins, while LAN 1 cells developed metastases completely independent of selectin expression. The different adhesive and metastatic properties of LAN 1 and SK-N-SH cells are reflected by a different expression profile of several CAMs. The results indicate that endothelial selectins are not essential for metastasis formation of human LAN 1 and SK-N-SH cells. However, other CAMs namely CD44, N-cadherin, NCAM and integrins were upregulated or downregulated, respectively, in SK-N-SH and LAN 1 cells and are potential adhesion molecules involved in the metastatic cascade of these cells.
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Affiliation(s)
- Nina Schwankhaus
- Center for Experimental Medicine, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Christina Gathmann
- Center for Experimental Medicine, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Daniel Wicklein
- Center for Experimental Medicine, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, Center for Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Udo Schumacher
- Center for Experimental Medicine, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Ursula Valentiner
- Center for Experimental Medicine, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
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Lo ST, Kumar A, Hsieh JT, Sun X. Dendrimer nanoscaffolds for potential theranostics of prostate cancer with a focus on radiochemistry. Mol Pharm 2013; 10:793-812. [PMID: 23294202 DOI: 10.1021/mp3005325] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dendrimers are a class of structurally defined macromolecules featured with a central core, a low-density interior formed by repetitive branching units, and a high-density exterior terminated with surface functional groups. In contrast to their polymeric counterparts, dendrimers are nanosized and symmetrically shaped, which can be reproducibly synthesized on a large scale with monodispersity. These unique features have made dendrimers of increasing interest for drug delivery and other biomedical applications as nanoscaffold systems. Intended to address the potential use of dendrimers for the development of theranostic agents, which combines therapeutics and diagnostics in a single entity for personalized medicine, this review focuses on the reported methodologies of using dendrimer nanoscaffolds for targeted imaging and therapy of prostate cancer. Of particular interest, relevant chemistry strategies are discussed due to their important roles in the design and synthesis of diagnostic and therapeutic dendrimer-based nanoconjugates and potential theranostic agents, targeted or nontargeted. Given the developing status of nanoscaffolded theranostics, major challenges and potential hurdles are discussed along with the examples representing current advances.
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Affiliation(s)
- Su-Tang Lo
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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Abstract
Shc (Src homology and collagen homology) proteins are considered prototypical signalling adaptors in mammalian cells. Consisting of four unique members, ShcA, B, C and D, and multiple splice isoforms, the family is represented in nearly every cell type in the body, where it engages in an array of fundamental processes to transduce environmental stimuli. Two decades of investigation have begun to illuminate the mechanisms of the flagship ShcA protein, whereas much remains to be learned about the newest discovery, ShcD. It is clear, however, that the distinctive modular architecture of Shc proteins, their promiscuous phosphotyrosine-based interactions with a multitude of membrane receptors, involvement in central cascades including MAPK (mitogen-activated protein kinase) and Akt, and unconventional contributions to oxidative stress and apoptosis all require intricate regulation, and underlie diverse physiological function. From early cardiovascular development and neuronal differentiation to lifespan determination and tumorigenesis, Shc adaptors have proven to be more ubiquitous, versatile and dynamic than their structures alone suggest.
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Xu JK, Chen HJ, Li XD, Huang ZL, Xu H, Yang HL, Hu J. Optimal intensity shock wave promotes the adhesion and migration of rat osteoblasts via integrin β1-mediated expression of phosphorylated focal adhesion kinase. J Biol Chem 2012; 287:26200-12. [PMID: 22654119 PMCID: PMC3406705 DOI: 10.1074/jbc.m112.349811] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2012] [Revised: 05/15/2012] [Indexed: 02/05/2023] Open
Abstract
To search for factors promoting bone fracture repair, we investigated the effects of extracorporeal shock wave (ESW) on the adhesion, spreading, and migration of osteoblasts and its specific underlying cellular mechanisms. After a single period of stimulation by 10 kV (500 impulses) of shock wave (SW), the adhesion rate was increased as compared with the vehicle control. The data from both wound healing and transwell tests confirmed an acceleration in the migration of osteoblasts by SW treatment. RT-PCR, flow cytometry, and Western blotting showed that SW rapidly increased the surface expression of α5 and β1 subunit integrins, indicating that integrin β1 acted as an early signal for ESW-induced osteoblast adhesion and migration. It has also been found that a significant elevation occurred in the expression of phosphorylated β-catenin and focal adhesion kinase (FAK) at the site of tyrosine 397 in response to SW stimulation after the increasing expression of the integrin β1 molecule. When siRNAs of integrin α5 and β1 subunit were added, the level of FAK phosphorylation elevated by SW declined. Interestingly, the adhesion and migration of osteoblasts were decreased when these siRNA reagents as well as the ERK1/2 signaling pathway inhibitors, U0126 and PD98059, were present. Further studies demonstrated that U0126 could inhibit the downstream integrin-dependent signaling pathways, such as the FAK signaling pathway, whereas it had no influence on the synthesis of integrin β1 molecule. In conclusion, these data suggest that ESW promotes the adhesion and migration of osteoblasts via integrin β1-mediated expression of phosphorylated FAK at the Tyr-397 site; in addition, ERK1/2 are also important for osteoblast adhesion, spreading, migration, and integrin expression.
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Affiliation(s)
- Jian-kun Xu
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
| | - Hong-jiang Chen
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
| | - Xue-dong Li
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
| | - Zhong-lian Huang
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
| | - Huan Xu
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
| | - Hai-long Yang
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
| | - Jun Hu
- From the Department of Orthopedics, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China
- To whom correspondence should be addressed. Tel.: 86-754-88905206; Fax: 86-754-88259850; E-mail:
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Vickerman V, Kamm RD. Mechanism of a flow-gated angiogenesis switch: early signaling events at cell-matrix and cell-cell junctions. Integr Biol (Camb) 2012; 4:863-74. [PMID: 22673733 DOI: 10.1039/c2ib00184e] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A bias towards angiogenesis from the venous circulation has long been known, but its cause remains unclear. Here we explore the possibility that high interstitial pressure in tumors and the resultant net filtration pressure gradient that would induce flow from the interstitium into the venous circulation or lymphatics could also be an important mechanical regulator of angiogenesis. The objective of this study was to test the hypothesis that basal-to-apical (B-A) transendothelial flow promotes angiogenesis and to investigate potential mechanisms. Macro- and microvascular endothelial monolayers were cultured on type I collagen gels in a microfluidic cell culture device and subjected to apical-to-basal (A-B) and B-A transendothelial flows. Samples were perfusion fixed and analyzed for morphological responses, localization and degree of phosphorylation of certain signaling proteins. Application of B-A, but not A-B flow, to cultured endothelial monolayers was found to promote capillary morphogenesis and resulted in distinct localization patterns of VE-cadherin and increased FAK phosphorylation. These results suggest that B-A flow triggers the transition of vascular endothelial cells from a quiescent to invasive phenotype and that the flow-mediated response involves signaling at cell-cell and cell-matrix interfaces. These results support the hypothesis that transendothelial pressure gradients resulting in B-A flow promotes sprouting angiogenesis and are consistent with early observations that tumor angiogenesis occurs from the venous side of the circulation.
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Affiliation(s)
- Vernella Vickerman
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, USA
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