Integrin Genetic Variants and Stage-Specific Tumor Recurrence In

Total Page:16

File Type:pdf, Size:1020Kb

Integrin Genetic Variants and Stage-Specific Tumor Recurrence In The Pharmacogenomics Journal (2015) 15, 226–234 © 2015 Macmillan Publishers Limited All rights reserved 1470-269X/15 www.nature.com/tpj ORIGINAL ARTICLE Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer P Bohanes1, D Yang2, F Loupakis1, MJ LaBonte1, A Gerger1, Y Ning1, C Lenz1, F Lenz1, T Wakatsuki1, W Zhang1, L Benhaim1, A El-Khoueiry1, R El-Khoueiry1 and H-J Lenz1 Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR–restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR) = 4.027, 95% confidence interval (95% CI) 1.556–10.421, P = 0.004). This association was also significant in the combined stage II–III cohort (HR = 1.975, 95% CI 1.194–3.269, P = 0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P = 0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P = 0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments. The Pharmacogenomics Journal (2015) 15, 226–234; doi:10.1038/tpj.2014.66; published online 9 December 2014 INTRODUCTION attachment to the surrounding extracellular matrix and, for some Adjuvant chemotherapy has improved survival in patients with ITGs, also to other cells. ITGs are expressed on both tumor cells colon cancer. However, being active in patients with stage III colon and normal cells (for example, endothelial cells, platelets and cancer (and in a subgroup of stage II patients), adjuvant chemo- leucocytes). Therefore, they promote tumor growth not only by therapy fails to eradicate micro-metastatic disease in 30% of direct interaction of tumor cells with the microenvironment but patients.1,2 In contrast, as many as 30–40% of patients with stage also by regulating endothelial cell’s survival and migration during 6 III colon cancer are given unnecessary post-operative treatment angiogenesis and lymphangiogenesis. Recent evidence showing because their tumor has good intrinsic biologic behavior.3 For that ITGs are critical in cancer dormancy suggests that their stage II patients, there are currently no validated clinical param- differential expression or activity may be responsible for tumor eters or biomarkers that identify patients that should be given recurrence.7 post-operative chemotherapy. Therefore, both prognostic factors ITGs are heterodimeric cell surface receptors. Eighteen α- and and predictive factors for oxaliplatin and 5-fluorourcil efficacies are eight β-subunits associate to form 24 different non-covalently of critical importance. associated heterodimers with specific tissue distribution and Recent evidence indicates that molecular biomarkers may have unique ligand specificity.8 ITGs transmit signals in both direction a stage-specific distribution and influence in colon cancer,4,5 of the cell membrane: ITG binding to extracellular matrix changes which has led some authors to consider stage II and III colon the shape and composition of the cytoskeleton; intracellular signal cancer as distinct entities. This data has lead to active research to mechanisms activate the ITGs (conformational change) and identify key pathways that would be responsible for a different increase their affinity.9 These signals are integrated with those clinical behavior across colon cancer stages. A candidate group of originating from the growth factor receptors enabling a specific molecules is the adhesion cell receptors that interact with the cellular response in various biologic situations.10 Multiple ITG extracellular matrix, having a critical role in cell survival, prolifera- heterodimers have been shown to play a role in cancers, including tion, differentiation and migration. The major group of proteins colon cancer. However, most of the attention has been on αV promoting these interactions is the integrins (ITGs), a superfamily heterodimers, notably αVβ3, as it has been shown to be important of transmembrane-related adhesion receptors that regulate in tumor angiogenesis. Several drugs have thus been developed 1Sharon A. Carpenter Laboratory, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA and 2Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Correspondence: Dr H-J Lenz, Sharon A. Carpenter Laboratory, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. E-mail: [email protected] Received 1 April 2014; revised 18 August 2014; accepted 28 August 2014; published online 9 December 2014 Integrin variants and stage II and III colon cancer P Bohanes et al 227 to target αV heterodimers.11 Another important heterodimer that of about 0.5. Deviation of allelic distribution of each ITG polymorphism has caught attention for drug development is α5β1 heterodimer, from Hardy–Weinberg equilibrium was tested using χ2-test in each ethnic as it has been involved in tumor angiogenesis and more recently group. The distribution of polymorphisms by baseline demographic, in cancer dormancy.12 However, recently, interest is growing on clinical and pathological characteristics was examined using Fisher’s exact other ITG heterodimers as many of them have been linked to test. The true mode of inheritance of all ITG polymorphisms tested is not known and this study assumed a codominant, additive, dominant or cancer prognosis. recessive genetic model wherever appropriate. The association between There is substantial genetic variability within the genes coding polymorphisms and TTR was analyzed using Kaplan–Meier curves and log- for the ITGs that may alter the gene expression and/or activity by rank test. In the multivariable Cox regression analysis, the model was affecting various steps in protein synthesis, including transcription, adjusted for stage and type of adjuvant chemotherapy, and stratified by translation or splicing. This, in turn, may alter the tumor behavior race. Other clinico-pathologic parameters were not entered in the model, and/or sensitivity to chemotherapy drugs, thereby causing inter- as they did not seem to be a significant prognostic impact in this cohort of 16 tumor stage or interindividual differences. Based on the hypoth- patients. Interactions between polymorphisms and stage on TTR were esis that specific germline single-nucleotide polymorphism (SNP) tested by comparing likelihood ratio statistics between the baseline and in ITG genes could have different effect across stage II and III colon nested Cox regression models that include the multiplicative product term. P-values for all polymorphisms were adjusted for multiple testing using a cancer patients, we investigated a comprehensive panel of ITG modified test of Conneely and Boehnke17 that was applied for the SNPs in patients with stage II and III colon cancer and linked them correlated tests due to linkage disequilibrium and the different modes of with outcome. Only ITG genes that have been previously asso- inheritance considered. We considered a pACT of o0.15 as being ciated with colon cancer were selected. potentially important given the candidate pathway approach. Recursive partitioning (RP), incorporating cross-validation, was used to explore and identify polymorphism profiles and interactions associated with TTR using MATERIALS AND METHODS the rPart-function in S-plus. Case-wise deletion for missing polymorphisms Eligible patients was used in univariate and multivariable analyses. In the RP analysis, all patients with at least one polymorphism result available were included. All A total of 234 patients with stage III and high-risk stage II colon cancer analyses were performed using the SAS statistical package version 9.2 (SAS were included in this study cohort. Whole blood was available from 206 Institute, Cary, NC, USA) and S-PLUS 7.0 (TIBCO, Palo Alto, CA, USA). patients. All patients were treated with 5-fluorouracil-based adjuvant chemotherapy at the Norris Comprehensive Cancer Center/University of Southern California or the Los Angeles County/University of Southern RESULTS California. At the completion of post-operative therapy, patients were followed clinically every 3 months for the first 2 years and then
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]
  • Integrins: Roles in Cancer Development and As Treatment Targets
    British Journal of Cancer (2004) 90, 561 – 565 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Minireview Integrins: roles in cancer development and as treatment targets 1 ,1,2 H Jin and J Varner* 1John and Rebecca Moores Comprehensive Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0912, USA; 2Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0912, USA The integrin family of cell adhesion proteins promotes the attachment and migration of cells on the surrounding extracellular matrix (ECM). Through signals transduced upon integrin ligation by ECM proteins or immunoglobulin superfamily molecules, this family of proteins plays key roles in regulating tumour growth and metastasis as well as tumour angiogenesis. Several integrins play key roles in promoting tumour angiogenesis and tumour metastasis. Antagonists of several integrins (a5b1, avb3 and avb5) are now under evaluation in clinical trials to determine their potential as therapeutics for cancer and other diseases. British Journal of Cancer (2004) 90, 561 – 565. doi:10.1038/sj.bjc.6601576 www.bjcancer.com & 2004 Cancer Research UK Keywords: angiogenesis; metastasis; apoptosis; integrin a5b1; integrin avb3 During the last 10 years, novel insights into the mechanisms sequences (e.g., integrin a4b1 recognises EILDV and REDV in that regulate cell survival as well as cell migration and invasion alternatively spliced CS-1 fibronectin). Inhibitors of integrin have led to the development of novel integrin-based therapeutics function include function-blocking monoclonal antibodies, pep- for the treatment of cancer. Several integrins play important tide antagonists and small molecule peptide mimetics matrix roles in promoting cell proliferation, migration and survival (reviewed in Hynes, 1992; Cheresh, 1993).
    [Show full text]
  • Cell Adhesion and Angiogenesis
    Cell adhesion and angiogenesis. J Bischoff J Clin Invest. 1997;99(3):373-376. https://doi.org/10.1172/JCI119168. Perspective Find the latest version: https://jci.me/119168/pdf Perspectives Series: Cell Adhesion in Vascular Biology Cell Adhesion and Angiogenesis Joyce Bischoff Department of Surgery, Children’s Hospital and Harvard Medical School, Children’s Hospital, Boston, Massachusetts 02115 Introduction and postcapillary venules (3). Thus, the formation of a new mi- Angiogenesis is the growth of new capillary blood vessels from crovessel requires a number of interactions that must be coor- preexisting capillaries and postcapillary venules. This process dinated in a spatially and temporally specified manner. These is critical for normal growth and development and in protec- adhesion events are likely mediated by endothelial cell adhe- tive responses such as wound healing and inflammation. In sion molecules and ECM molecules that provide instructions healthy adults, angiogenesis does not normally occur except in to the endothelial cells as they migrate into the perivascular certain phases of the female reproductive cycle. However, ab- space and assemble into new vessels with surrounding peri- errant angiogenesis can occur in a variety of pathologic set- cytes. tings. These include the neovascularization of solid tumors, the Cell adhesion and endothelial cell growth growth of vessels into the retina in diabetic retinopathy, and the unwanted vessel growth in chronic inflammatory diseases. Adhesion of endothelial cells to ECM and attainment of an The hypothesis that angiogenic diseases, in particular tumor appropriate cellular shape has been known for many years to growth and metastases, may be alleviated by inhibiting the an- be crucial for endothelial cell growth, differentiation, and sur- giogenic responses (1) has prompted many to investigate the vival.
    [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]
  • Integrin Activity 7Β , and 3Β , 2 Β Chemoattractant-Stimulated Differential Regulation Of
    Differential Regulation of Chemoattractant-Stimulated β2, β3, and β7 Integrin Activity This information is current as Chanchal Sadhu, Boris Masinovsky and Donald E. Staunton of September 26, 2021. J Immunol 1998; 160:5622-5628; ; http://www.jimmunol.org/content/160/11/5622 Downloaded from References This article cites 24 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/160/11/5622.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. b b Differential Regulation of Chemoattractant-Stimulated 2, 3, b and 7 Integrin Activity Chanchal Sadhu,1 Boris Masinovsky, and Donald E. Staunton Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattrac- tants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation a b a b a b of three integrins, 4 7, L 2, and V 3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor a b a b (FPR) in the lymphoid cell line JY.
    [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]
  • Integrins As Therapeutic Targets: Successes and Cancers
    cancers Review Integrins as Therapeutic Targets: Successes and Cancers Sabine Raab-Westphal 1, John F. Marshall 2 and Simon L. Goodman 3,* 1 Translational In Vivo Pharmacology, Translational Innovation Platform Oncology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany; [email protected] 2 Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; [email protected] 3 Translational and Biomarkers Research, Translational Innovation Platform Oncology, Merck KGaA, 64293 Darmstadt, Germany * Correspondence: [email protected]; Tel.: +49-6155-831931 Academic Editor: Helen M. Sheldrake Received: 22 July 2017; Accepted: 14 August 2017; Published: 23 August 2017 Abstract: Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments. Keywords: integrin; therapy; clinical trial; efficacy; health care economics 1. Introduction Integrins are heterodimeric cell-surface adhesion molecules found on all nucleated cells. They integrate processes in the intracellular compartment with the extracellular environment. The 18 α- and 8 β-subunits form 24 different heterodimers each having functional and tissue specificity (reviewed in [1,2]).
    [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]
  • Detection of Osteopontin on Holstein Bull Spermatozoa, in Cauda Epididymal fluid and Testis Homogenates, and Its Potential Role in Bovine Fertilization
    REPRODUCTIONRESEARCH Detection of osteopontin on Holstein bull spermatozoa, in cauda epididymal fluid and testis homogenates, and its potential role in bovine fertilization David W Erikson, Amy L Way1, David A Chapman and Gary J Killian Department of Dairy & Animal Science, John O Almquist Research Center, The Pennsylvania State University, University Park, Pennsylvania 16802, USA and 1Department of Health Science, Lock Haven University, Clearfield Campus, Clearfield, Pennsylvania 16830, USA Correspondence should be addressed to G J Killian; Email: [email protected] Abstract Osteopontin (OPN) is a secreted extracellular matrix phosphoprotein identified in various tissues and fluids including those of the male and female reproductive tracts. OPN was previously identified as a 55 kDa high fertility marker in Holstein bull seminal plasma, produced by the ampulla and the vesicular gland. The objectives of this study were to characterize OPN on ejaculated and cauda epididymal sperm using immunofluorescence and western blot analysis, and to assess the role of sperm OPN in fertilization. Solubilized sperm membrane proteins from ejaculated and cauda epididymal sperm were separated by 1D SDS- PAGE, transferred to nitrocellulose, and probed with an antibody to bovine milk OPN. A 35 kDa protein was detected by this antibody in both ejaculated and cauda epididymal sperm membranes. Analyses also recognized OPN at 55 and 25 kDa in cauda epididymal fluid and testicular parenchyma homogenates respectively. Immunofluorescent analysis of ejaculated and cauda epididymal sperm showed OPN localization in a well-defined band in the postacrosomal region of the sperm head and also on the midpiece. Results of in vitro fertilization experiments showed that sperm treated with an antibody to OPN fertilized fewer oocytes than sperm treated with control medium while increasing incidence of polyspermy, suggesting a role of sperm-associated OPN in fertilization and a block to polyspermy.
    [Show full text]