DOCSLIB.ORG

Targeting Integrin Alpha5 Receptor in Pancreatic Stellate Cells to Diminish Tumor-Promoting

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeting Integrin Alpha5 Receptor in Pancreatic Stellate Cells to Diminish Tumor-Promoting bioRxiv preprint doi: https://doi.org/10.1101/350678; this version posted June 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kuninty et al. Targeting ITGA5 in pancreatic cancer Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer Praneeth R. Kuninty1, Ruchi Bansal1†, Sanne W.L. De Geus2†, Jonas Schnittert1, Joop van Baarlen3, Gert Storm1,4, Maarten F. Bijlsma5, 6, Hanneke W. van Laarhoven7, Peter J.K. Kuppen2, Alexander L. Vahrmeijer2, Arne Östman8, Cornelis F.M. Sier2, Jai Prakash1,8,9, * 1Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, The Netherlands. 2Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. 3 Laboratory Pathology Oost Netherlands (LabPON), Hengelo, The Netherlands. 4 Department of Pharmaceutics, Utrecht University, The Netherlands. 5Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center and Cancer Center Amsterdam, Amsterdam, The Netherlands. 6Oncode Institute, Academic Medical Center, Amsterdam. The Netherlands. 7Department of Medical Oncology, Academic Medical Center and Cancer Center Amsterdam, Amsterdam, The Netherlands. 8Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. 9ScarTec Therapeutics BV, Enschede, The Netherlands. † Authors contributed equally 1 bioRxiv preprint doi: https://doi.org/10.1101/350678; this version posted June 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kuninty et al. Targeting ITGA5 in pancreatic cancer * Corresponding author’s email: [email protected] Corresponding address: Section Targeted Therapeutics Department of Biomaterials Science and Technology Faculty of Science and Technology University of Twente Zuidhorst 254 7500 AE Enschede The Netherlands T (+31)-53-489 3096 Keywords: Integrin alpha5, pancreatic stellate cells, pancreatic cancer, stroma. 2 bioRxiv preprint doi: https://doi.org/10.1101/350678; this version posted June 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kuninty et al. Targeting ITGA5 in pancreatic cancer Abstract: Pancreatic stellate cells (PSCs) are the main precursors of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC), known to induce cancer aggressiveness. Integrin alpha5 (ITGA5), a fibronectin receptor, was found to be overexpressed by CAFs in stroma and linked to poor overall survival (log-rank p=0.022, n=137) of patients with PDAC. In vitro, knockdown of ITGA5 in human PSCs (hPSCs) inhibited their adhesion, migration, and proliferation and also inhibited TGF-b-mediated differentiation. In vivo, co-injection of PANC-1 tumor cells and hPSCs (sh-ITGA5) developed tumors with reduced fibrosis and slower growth rate compared to those composed of PANC-1 and hPSC (sh-Ctrl). Furthermore, we developed a ITGA5-antagonizing peptidomimetic (AV3) which inhibited TGFb-mediated hPSC differentiation by blocking ITGA5/FAK pathway. In vivo, treatment with AV3 intraperitoneally attenuated tumor fibrosis and thereby enhanced the efficacy of gemcitabine in patient-derived xenografts in mice. Altogether, this study reports the therapeutic importance of ITGA5 in PDAC and provides novel therapeutic peptidomimetic to enhance the effect of chemotherapy. 3 bioRxiv preprint doi: https://doi.org/10.1101/350678; this version posted June 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kuninty et al. Targeting ITGA5 in pancreatic cancer Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating cancers with a 5-year survival rate of less than 8% 1. Currently available therapies are insufficient to substantially halt the growth of PDAC, indicating an unmet clinical need to develop novel therapeutics. PDAC is characterized by abundant tumor stroma (up to 90% of the total tumor mass), which has been shown to promote tumor growth and metastasis, and confer resistance to chemotherapy, as well as act as a physical barrier by preventing tumor delivery of therapeutics 2, 3, 4. Pancreatic tumor stroma is composed of non-malignant cells such as cancer-associated fibroblasts (CAFs), immune cells, vasculature and a network of extracellular matrix (ECM), which interact with tumor cells in a bi- directional manner 2, 5, 6. CAFs are key effector cells in stroma, which produce ECM molecules such as collagen, fibronectin, laminin and secrete various cytokines and growth factors, which altogether stimulate tumor growth, angiogenesis, invasion, and metastases 7, 8, 9. CAFs mainly originate from pancreatic stellate cells (PSCs), the resident mesenchymal cells in pancreas 10. PSCs are normally present in low numbers in a quiescent form storing vitamin A droplets. However, during malignant transformation PSCs get activated and transform into myofibroblasts identified by α-smooth muscle actin (α-SMA) expression 5. Furthermore, PSCs have been shown to secrete growth factors that induce tumor cell growth, survival and migration 11, 12. In a recent study, we have also shown that TGFb-activated PSCs stimulated tumor cell proliferation and endothelial cell activation, while inhibition of miR-199a/-214 in PSCs inhibited their pro-tumorigenic functions 13. Similarly, other studies have shown reprograming of the activated myofibroblasts in desmoplasia to normal state yields a better therapeutic response 11. By contrast, Özdemir et al. have demonstrated depleting αSMA+ myofibroblasts in PDAC genetic models resulted in aggressive tumors by compromising the immune system 14. In another study, Rhim et al. targeted deletion of 4 bioRxiv preprint doi: https://doi.org/10.1101/350678; this version posted June 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kuninty et al. Targeting ITGA5 in pancreatic cancer sonic hedgehog (Shh) in fibroblasts led to aggressive tumor growth with undifferentiated phenotype 15. Although these studies suggest to take caution when targeting CAFs, new targets are desperately needed to design therapies to re-program CAFs to gain benefit for cancer therapy. Integrins are heterodimeric transmembrane receptors consisting of α and β subunits, which form a large family of about 24 αβ integrins 16, 17. As cell adhesion receptors, integrins mediate cell-cell and cell-ECM interactions, but they also play an active role in signal transduction by regulating cytoskeletal organization, cell migration, proliferation and survival 17, 18, 19. Several integrins, αvβ3, αvβ5, αvβ6¸ α6β4¸ α4β1, α11β1 and α5β1 are reported to be overexpressed in various cancer types, being involved in tumor progression through tumor cell invasion and metastases 20, 21, 22, 23, 24, 25. The integrin α5 chain (ITGA5) forms a heterodimer with β1 and together they act as a receptor for fibronectin 16, 22. However, most studies have investigated integrins solely in relation to malignant tumor cells or vasculature 21, 22 and there is scarce information on the significance of integrins in CAFs 23. However, significance of integrins and in particular ITGA5 in tumor stroma and CAFs is not well studied yet. In this study, we investigated the prognostic and therapeutic role of ITGA5 in stroma of pancreatic tumors. We first evaluated the expression levels of ITGA5 in PDAC samples from patients and correlated them with the overall survival rate. Then, we examined the expression of ITGA5 in activated human PSCs in vitro and studied the impact of ITGA5 knockdown on the activation of PSCs and their phenotype. Next, we investigated the effect of ITGA5 knockdown in PSC-mediated tumor growth in a co-injection (PANC-1 + PSCs) tumor mouse xenograft model in vivo. Furthermore, in view of future clinical application, we designed a novel short peptidomimetic (AV3) against ITGA5 and examined its therapeutic efficacy in vitro and in vivo in the co-injection model and in patient-derived xenograft (PDX) models. Our study reveals ITGA5 as a key 5 bioRxiv preprint doi: https://doi.org/10.1101/350678; this version posted June 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Kuninty et al. Targeting ITGA5 in pancreatic cancer prognostic marker and a therapeutic target in pancreatic tumor. Importantly, our novel AV3 peptidomimetic inhibited the TGFb-mediated ITGA5/FAK pathway in vitro. In vivo, AV3 reduced fibrosis and enhanced the efficacy of gemcitabine in PDX tumor model. Results Expression of ITGA5 in pancreatic tumor tissues and human pancreatic stellate cells The immunohistochemical analyses for ITGA5 expression showed a strong expression in human PDAC samples, while there was no expression in normal pancreatic tissues (Fig. 1A). Within the tumor region, ITGA5 was largely and differentially expressed in the tumor stroma compared with tumor epithelial cells in which
Load more

Recommended publications
  • PAPC Couples the Segmentation Clock to Somite Morphogenesis by Regulating N-Cadherin-Dependent Adhesion
    © 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 664-676 doi:10.1242/dev.143974 RESEARCH ARTICLE PAPC couples the segmentation clock to somite morphogenesis by regulating N-cadherin-dependent adhesion Jérome Chal1,2,3,4,5,*, Charlenè Guillot3,4,* and Olivier Pourquié1,2,3,4,5,6,7,‡ ABSTRACT specific level of the PSM called the determination front. The Vertebrate segmentation is characterized by the periodic formation of determination front is defined as a signaling threshold epithelial somites from the mesenchymal presomitic mesoderm implemented by posterior gradients of Wnt and FGF (Aulehla (PSM). How the rhythmic signaling pulse delivered by the et al., 2003; Diez del Corral and Storey, 2004; Dubrulle et al., segmentation clock is translated into the periodic morphogenesis of 2001; Hubaud and Pourquie, 2014; Sawada et al., 2001). Cells of somites remains poorly understood. Here, we focused on the role of the posterior PSM exhibit mesenchymal characteristics and paraxial protocadherin (PAPC/Pcdh8) in this process. We showed express Snail-related transcription factors (Dale et al., 2006; that in chicken and mouse embryos, PAPC expression is tightly Nieto, 2002). In the anterior PSM, cells downregulate snail/slug regulated by the clock and wavefront system in the posterior PSM. We expression and upregulate epithelialization-promoting factors such observed that PAPC exhibits a striking complementary pattern to N- as paraxis (Barnes et al., 1997; Sosic et al., 1997). This molecular cadherin (CDH2), marking the interface of the future somite boundary transition correlates with the anterior PSM cells progressively in the anterior PSM. Gain and loss of function of PAPC in chicken acquiring epithelial characteristics (Duband et al., 1987; Martins embryos disrupted somite segmentation by altering the CDH2- et al., 2009).
    [Show full text]
  • Kinetic Properties of Collagen Receptors on Human Keratinocytes 2337
    Journal of Cell Science 112, 2335-2345 (1999) 2335 Printed in Great Britain © The Company of Biologists Limited 1999 JCS9937 Integrin α and β subunit contribution to the kinetic properties of α2β1 collagen receptors on human keratinocytes analyzed under hydrodynamic conditions Bénédicte Masson-Gadais, Anne Pierres, Anne-Marie Benoliel, Pierre Bongrand* and Jean-Claude Lissitzky Laboratoire d’Immunologie, INSERM U 387, Hôpital de Sainte-Marguerite, BP 29, 13274 Marseille Cedex 09, France *Author for correspondence (e-mail: [email protected]) Accepted 10 May; published on WWW 24 June 1999 SUMMARY The adhesion of keratinocytes to type I collagen or with ligand recognition and also with the ligand-β1 chain laminin 5 was studied in a laminar flow chamber. These interactions responsible for bond stabilization. The latter experiments provided an insight into the binding kinetics hypothesis was supported by the finding that the partial of integrins in their natural environment and the effects of alteration of α2 chain function by inhibiting antibodies was monoclonal antibodies specific for α and β chains. Cells corrected by anti-β1 chain antibody TS2/16. These results driven by a force too low to alter the natural lifetime of a could not be ascribed to allosteric changes of the functional single bond displayed multiple arrests. Studying the region of β1 integrin subunits regulated by TS2/16 since frequency and duration of these arrests yielded fairly direct there was no competition between the binding of TS2/16 information on the rate of bond formation (on-rate) and and anti-α2 chain antibodies. dissociation (off-rate). Off-rate values obtained on collagen Interpreted within the framework of current concepts of or laminin 5 (0.06 seconds−1) were tenfold lower than values integrin-ligand binding topology, these data suggest that determined on selectins.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • CD Markers Are Routinely Used for the Immunophenotyping of Cells
    ptglab.com 1 CD MARKER ANTIBODIES www.ptglab.com Introduction The cluster of differentiation (abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules. So-called CD markers are routinely used for the immunophenotyping of cells. Despite this use, they are not limited to roles in the immune system and perform a variety of roles in cell differentiation, adhesion, migration, blood clotting, gamete fertilization, amino acid transport and apoptosis, among many others. As such, Proteintech’s mini catalog featuring its antibodies targeting CD markers is applicable to a wide range of research disciplines. PRODUCT FOCUS PECAM1 Platelet endothelial cell adhesion of blood vessels – making up a large portion molecule-1 (PECAM1), also known as cluster of its intracellular junctions. PECAM-1 is also CD Number of differentiation 31 (CD31), is a member of present on the surface of hematopoietic the immunoglobulin gene superfamily of cell cells and immune cells including platelets, CD31 adhesion molecules. It is highly expressed monocytes, neutrophils, natural killer cells, on the surface of the endothelium – the thin megakaryocytes and some types of T-cell. Catalog Number layer of endothelial cells lining the interior 11256-1-AP Type Rabbit Polyclonal Applications ELISA, FC, IF, IHC, IP, WB 16 Publications Immunohistochemical of paraffin-embedded Figure 1: Immunofluorescence staining human hepatocirrhosis using PECAM1, CD31 of PECAM1 (11256-1-AP), Alexa 488 goat antibody (11265-1-AP) at a dilution of 1:50 anti-rabbit (green), and smooth muscle KD/KO Validated (40x objective). alpha-actin (red), courtesy of Nicola Smart. PECAM1: Customer Testimonial Nicola Smart, a cardiovascular researcher “As you can see [the immunostaining] is and a group leader at the University of extremely clean and specific [and] displays Oxford, has said of the PECAM1 antibody strong intercellular junction expression, (11265-1-AP) that it “worked beautifully as expected for a cell adhesion molecule.” on every occasion I’ve tried it.” Proteintech thanks Dr.
    [Show full text]
  • Of VLA-4 and VLA-5 VCAM-1 and Fibronectin Through Clustering Promoting Macrophage Adhesion to Chemerin Contributes to Inflammati
    Chemerin Contributes to Inflammation by Promoting Macrophage Adhesion to VCAM-1 and Fibronectin through Clustering of VLA-4 and VLA-5 This information is current as of October 1, 2021. Rosie Hart and David R. Greaves J Immunol 2010; 185:3728-3739; Prepublished online 18 August 2010; doi: 10.4049/jimmunol.0902154 http://www.jimmunol.org/content/185/6/3728 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/08/18/jimmunol.090215 Material 4.DC1 http://www.jimmunol.org/ References This article cites 60 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/185/6/3728.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Chemerin Contributes to Inflammation by Promoting Macrophage Adhesion to VCAM-1 and Fibronectin through Clustering of VLA-4 and VLA-5 Rosie Hart and David R.
    [Show full text]
  • Cell Adhesion Molecules in Normal Skin and Melanoma
    biomolecules Review Cell Adhesion Molecules in Normal Skin and Melanoma Cian D’Arcy and Christina Kiel * Systems Biology Ireland & UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland; [email protected] * Correspondence: [email protected]; Tel.: +353-1-716-6344 Abstract: Cell adhesion molecules (CAMs) of the cadherin, integrin, immunoglobulin, and selectin protein families are indispensable for the formation and maintenance of multicellular tissues, espe- cially epithelia. In the epidermis, they are involved in cell–cell contacts and in cellular interactions with the extracellular matrix (ECM), thereby contributing to the structural integrity and barrier for- mation of the skin. Bulk and single cell RNA sequencing data show that >170 CAMs are expressed in the healthy human skin, with high expression levels in melanocytes, keratinocytes, endothelial, and smooth muscle cells. Alterations in expression levels of CAMs are involved in melanoma propagation, interaction with the microenvironment, and metastasis. Recent mechanistic analyses together with protein and gene expression data provide a better picture of the role of CAMs in the context of skin physiology and melanoma. Here, we review progress in the field and discuss molecular mechanisms in light of gene expression profiles, including recent single cell RNA expression information. We highlight key adhesion molecules in melanoma, which can guide the identification of pathways and Citation: D’Arcy, C.; Kiel, C. Cell strategies for novel anti-melanoma therapies. Adhesion Molecules in Normal Skin and Melanoma. Biomolecules 2021, 11, Keywords: cadherins; GTEx consortium; Human Protein Atlas; integrins; melanocytes; single cell 1213. https://doi.org/10.3390/ RNA sequencing; selectins; tumour microenvironment biom11081213 Academic Editor: Sang-Han Lee 1.
    [Show full text]
  • Myeloid Innate Immunity Mouse Vapril2018
    Official Symbol Accession Alias / Previous Symbol Official Full Name 2810417H13Rik NM_026515.2 p15(PAF), Pclaf RIKEN cDNA 2810417H13 gene 2900026A02Rik NM_172884.3 Gm449, LOC231620 RIKEN cDNA 2900026A02 gene Abcc8 NM_011510.3 SUR1, Sur, D930031B21Rik ATP-binding cassette, sub-family C (CFTR/MRP), member 8 Acad10 NM_028037.4 2410021P16Rik acyl-Coenzyme A dehydrogenase family, member 10 Acly NM_134037.2 A730098H14Rik ATP citrate lyase Acod1 NM_008392.1 Irg1 aconitate decarboxylase 1 Acot11 NM_025590.4 Thea, 2010309H15Rik, 1110020M10Rik,acyl-CoA Them1, thioesterase BFIT1 11 Acot3 NM_134246.3 PTE-Ia, Pte2a acyl-CoA thioesterase 3 Acox1 NM_015729.2 Acyl-CoA oxidase, AOX, D130055E20Rikacyl-Coenzyme A oxidase 1, palmitoyl Adam19 NM_009616.4 Mltnb a disintegrin and metallopeptidase domain 19 (meltrin beta) Adam8 NM_007403.2 CD156a, MS2, E430039A18Rik, CD156a disintegrin and metallopeptidase domain 8 Adamts1 NM_009621.4 ADAM-TS1, ADAMTS-1, METH-1, METH1a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 1 Adamts12 NM_175501.2 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 12 Adamts14 NM_001081127.1 Adamts-14, TS14 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 14 Adamts17 NM_001033877.4 AU023434 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 17 Adamts2 NM_001277305.1 hPCPNI, ADAM-TS2, a disintegrin and ametalloproteinase disintegrin-like and with metallopeptidase thrombospondin
    [Show full text]
  • Anti-ITGB1 Monoclonal Antibody, Clone 4C7 (DCABH-1896) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-ITGB1 monoclonal antibody, clone 4C7 (DCABH-1896) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview Mouse monoclonal to Integrin beta 1 Antigen Description Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands.
    [Show full text]
  • Comparative Proteomic Analysis Identifies Epha2 As a Specific Cell
    International Journal of Molecular Sciences Article Comparative Proteomic Analysis Identifies EphA2 as a Specific Cell Surface Marker for Wharton’s Jelly-Derived Mesenchymal Stem Cells Ashraf Al Madhoun 1,2,* , Sulaiman K. Marafie 3 , Dania Haddad 2, Motasem Melhem 2, Mohamed Abu-Farha 3 , Hamad Ali 2,4 , Sardar Sindhu 1 , Maher Atari 5 and Fahd Al-Mulla 2 1 Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait; [email protected] 2 Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; [email protected] (D.H.); [email protected] (M.M.); [email protected] (H.A.); [email protected] (F.A.-M.) 3 Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; sulaiman.marafi[email protected] (S.K.M.); [email protected] (M.A.-F.) 4 Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center (HSC), Kuwait University, Jabriya 046302, Kuwait 5 Medical-Surgical Pathology Department, Regenerative Medicine Research Institute, Universitat Internacional de Catalunya, 08195 Barcelona, Spain; [email protected] * Correspondence: [email protected] Received: 28 June 2020; Accepted: 1 September 2020; Published: 3 September 2020 Abstract: Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) are a valuable tool in stem cell research due to their high proliferation rate, multi-lineage differentiation potential, and immunotolerance properties. However, fibroblast impurity during WJ-MSCs isolation is unavoidable because of morphological similarities and shared surface markers. Here, a proteomic approach was employed to identify specific proteins differentially expressed by WJ-MSCs in comparison to those by neonatal foreskin and adult skin fibroblasts (NFFs and ASFs, respectively).
    [Show full text]
  • Integrin Α5β1, the Fibronectin Receptor, As a Pertinent Therapeutic Target in Solid Tumors
    Cancers 2013, 5, 27-47; doi:10.3390/cancers5010027 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors Florence Schaffner, Anne Marie Ray and Monique Dontenwill * UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France; E-Mails: [email protected] (F.S.); [email protected] (A.M.R.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +33-3688-54267; Fax: +33-3688-54313. Received: 5 December 2012; in revised form: 9 January 2013 / Accepted: 11 January 2013 / Published: 15 January 2013 Abstract: Integrins are transmembrane heterodimeric proteins sensing the cell microenvironment and modulating numerous signalling pathways. Changes in integrin expression between normal and tumoral cells support involvement of specific integrins in tumor progression and aggressiveness. This review highlights the current knowledge about α5β1 integrin, also called the fibronectin receptor, in solid tumors. We summarize data showing that α5β1 integrin is a pertinent therapeutic target expressed by tumoral neovessels and tumoral cells. Although mainly evaluated in preclinical models, α5β1 integrin merits interest in particular in colon, breast, ovarian, lung and brain tumors where its overexpression is associated with a poor prognosis for patients. Specific α5β1 integrin antagonists will be listed that may represent new potential therapeutic agents to fight defined subpopulations of particularly aggressive tumors. Keywords: α5β1; integrin; fibronectin receptor; solid tumors; angiogenesis; antagonists 1. Introduction In recent years, integrins have attracted increasing interest for their potential to act as tumor therapeutic targets [1,2].
    [Show full text]
  • Integrin and Gene Network Analysis Reveals That ITGA5 and ITGB1 Are Prognostic in Non-Small-Cell Lung Cancer
    Journal name: OncoTargets and Therapy Article Designation: Original Research Year: 2016 Volume: 9 OncoTargets and Therapy Dovepress Running head verso: Zheng et al Running head recto: ITGA5 and ITGB1 are prognostic in NSCLC open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S91796 Open Access Full Text Article ORIGINAL RESEARCH Integrin and gene network analysis reveals that ITGA5 and ITGB1 are prognostic in non-small-cell lung cancer Weiqi Zheng Background: Integrin expression has been identified as a prognostic factor in non-small-cell Caihui Jiang lung cancer (NSCLC). This study was aimed at determining the predictive ability of integrins Ruifeng Li and associated genes identified within the molecular network. Patients and methods: A total of 959 patients with NSCLC from The Cancer Genome Atlas Department of Radiation Oncology, Guangqian Hospital, Quanzhou, Fujian, cohorts were enrolled in this study. The expression profile of integrins and related genes were People’s Republic of China obtained from The Cancer Genome Atlas RNAseq database. Clinicopathological characteristics, including age, sex, smoking history, stage, histological subtype, neoadjuvant therapy, radiation therapy, and overall survival (OS), were collected. Cox proportional hazards regression models as well as Kaplan–Meier curves were used to assess the relative factors. Results: In the univariate Cox regression model, ITGA1, ITGA5, ITGA6, ITGB1, ITGB4, and ITGA11 were predictive of NSCLC prognosis. After adjusting for clinical factors, ITGA5 (odds ratio =1.17, 95% confidence interval: 1.05–1.31) andITGB1 (odds ratio =1.31, 95% confidence interval: 1.10–1.55) remained statistically significant. In the gene cluster network analysis, PLAUR, ILK, SPP1, PXN, and CD9, all associated with ITGA5 and ITGB1, were identified as independent predictive factors of OS in NSCLC.
    [Show full text]
  • Cardiac Fibrosis: Key Role of Integrins in Cardiac Homeostasis and Remodeling
    cells Review Cardiac Fibrosis: Key Role of Integrins in Cardiac Homeostasis and Remodeling Patrick B. Meagher 1,2, Xavier Alexander Lee 1,2 , Joseph Lee 1,2 , Aylin Visram 1,2, Mark K. Friedberg 2,3,4 and Kim A. Connelly 1,2,3,* 1 Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; [email protected] (P.B.M.); [email protected] (X.A.L.); [email protected] (J.L.); [email protected] (A.V.) 2 Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; [email protected] 3 Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada 4 Labatt Family Heart Center and Department of Paediatrics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada * Correspondence: [email protected]; Tel.: +141-686-45201 Abstract: Cardiac fibrosis is a common finding that is associated with the progression of heart failure (HF) and impacts all chambers of the heart. Despite intense research, the treatment of HF has primarily focused upon strategies to prevent cardiomyocyte remodeling, and there are no targeted antifibrotic strategies available to reverse cardiac fibrosis. Cardiac fibrosis is defined as an accumulation of extracellular matrix (ECM) proteins which stiffen the myocardium resulting in the deterioration cardiac function. This occurs in response to a wide range of mechanical and biochemical signals. Integrins are transmembrane cell adhesion receptors, that integrate signaling Citation: Meagher, P.B.; Lee, X.A.; between cardiac fibroblasts and cardiomyocytes with the ECM by the communication of mechanical Lee, J.; Visram, A.; Friedberg, M.K.; stress signals.
    [Show full text]