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1
LUDBROOK, Steven B., Simon T. BARRY, Chris J. DELVES, and Carmel M. T. HORGAN. "The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3." Biochemical Journal 369, no. 2 (January 15, 2003): 311–18. http://dx.doi.org/10.1042/bj20020809.
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The integrins αvβ1, αvβ5, αvβ6 and αvβ8 have all recently been shown to interact with the RGD motif of the latency-associated peptide (LAPβ1) of transforming growth factor β1 (TGFβ1), with binding to αvβ6 and αvβ8 leading to TGFβ1 activation. Previously it has been suggested that the remaining αv integrin, αvβ3, does not interact with LAPβ1. However, here we show clearly that αvβ3 does indeed interact with the LAPβ1 RGD motif. This interaction is similar to other αvβ3 ligands in terms of the cations required for adhesion, the concentrations of LAPβ1 required for binding and the ability of a small-molecule inhibitor of αvβ3, SB223245, to block the interaction. Using glutathione S-transferase fusion proteins we have mapped a minimal integrin-binding loop in LAPβ1 and then used this approach to probe the integrin-binding properties of the equivalent loops in LAPβ2 and LAPβ3. We show that the RGD motif of LAPβ3 also interacts with αvβ3, in addition to αvβ6, αvβ1 and αvβ5, whereas the corresponding loop in LAPβ2 does not interact with these integrins. These observations therefore correct a previously reported inaccuracy in the literature. Furthermore, they are important as they link αvβ3 and TGFβ, which may have implications in cancer and a number of inflammatory and fibrotic diseases where expression of both proteins has been documented.
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Duque, Hernando, and Barry Baxt. "Foot-and-Mouth Disease Virus Receptors: Comparison of Bovine αV Integrin Utilization by Type A and O Viruses." Journal of Virology 77, no. 4 (February 15, 2003): 2500–2511. http://dx.doi.org/10.1128/jvi.77.4.2500-2511.2003.
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ABSTRACT Three members of the αV integrin family of cellular receptors, αVβ1, αVβ3, and αVβ6, have been identified as receptors for foot-and-mouth disease virus (FMDV) in vitro. The virus interacts with these receptors via a highly conserved arginine-glycine-aspartic acid (RGD) amino acid sequence motif located within the βG-βH (G-H) loop of VP1. Other αV integrins, as well as several other integrins, recognize and bind to RGD motifs on their natural ligands and also may be candidate receptors for FMDV. To analyze the roles of the αV integrins from a susceptible species as viral receptors, we molecularly cloned the bovine β1, β5, and β6 integrin subunits. Using these subunits, along with previously cloned bovine αV and β3 subunits, in a transient expression assay system, we compared the efficiencies of infection mediated by αVβ1, αVβ3, αVβ5, and αVβ6 among three strains of FMDV serotype A and two strains of serotype O. While all the viruses could infect cells expressing these integrins, they exhibited different efficiencies of integrin utilization. All the type A viruses used αVβ3 and αVβ6 with relatively high efficiency, while only one virus utilized αVβ1 with moderate efficiency. In contrast, both type O viruses utilized αVβ6 and αVβ1 with higher efficiency than αVβ3. Only low levels of viral replication were detected in αVβ5-expressing cells infected with either serotype. Experiments in which the ligand-binding domains among the β subunits were exchanged indicated that this region of the integrin subunit appears to contribute to the differences in integrin utilizations among strains. In contrast, the G-H loops of the different viruses do not appear to be involved in this phenomenon. Thus, the ability of the virus to utilize multiple integrins in vitro may be a reflection of the use of multiple receptors during the course of infection within the susceptible host.
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Rowedder, James E., Steve B. Ludbrook, and Robert J. Slack. "Determining the True Selectivity Profile of αv Integrin Ligands Using Radioligand Binding: Applying an Old Solution to a New Problem." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 8 (April 17, 2017): 962–73. http://dx.doi.org/10.1177/2472555217703908.
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The arginyl-glycinyl-aspartic acid (RGD) integrin subfamily contains five members that partner with the αv subunit: αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8. Within the αv integrins, the epithelially restricted αvβ6 has been identified as playing a key role in the activation of transforming growth factor β that is hypothesized to be pivotal in the development of idiopathic pulmonary fibrosis (IPF). As part of a drug discovery program to identify a selective αvβ6 RGD mimetic for IPF, cell adhesion and radioligand binding assays were investigated to screen compounds to determine affinity and αv integrin selectivity. In this study, a pan-αv radioligand was characterized against all the αv integrins and used to determine accurate selectivity profiles for literature and novel RGD ligands, as well as enable an early readout on αvβ6 dissociation kinetics. It has been shown that while cell adhesion offers a high throughput and reliable format for ranking compounds, there are downsides to this format when comparing selectivity across αv integrins. By accurately defining the relationship between these assay formats, a medicinal chemistry effort has identified novel, high-affinity, and selective αvβ6 RGD mimetics with slow dissociation kinetics, with the potential to be developed into clinical candidates for IPF.
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Jackson, Terry, Stuart Clark, Stephen Berryman, Alison Burman, Stephanie Cambier, Dezhi Mu, Stephen Nishimura, and Andrew M. Q. King. "Integrin αvβ8 Functions as a Receptor for Foot-and-Mouth Disease Virus: Role of the β-Chain Cytodomain in Integrin-Mediated Infection." Journal of Virology 78, no. 9 (May 1, 2004): 4533–40. http://dx.doi.org/10.1128/jvi.78.9.4533-4540.2004.
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ABSTRACT Field isolates of foot-and-mouth disease virus (FMDV) have been shown to use three αv integrins, αvβ1, αvβ3, and αvβ6, as cellular receptors. Binding to the integrin is mediated by a highly conserved RGD motif located on a surface-exposed loop of VP1. The RGD tripeptide is recognized by several other members of the integrin family, which therefore have the potential to act as receptors for FMDV. Here we show that SW480 cells are made susceptible to FMDV following transfection with human β8 cDNA and expression of αvβ8 at the cell surface. The involvement of αvβ8 in infection was confirmed by showing that virus binding and infection of the transfected cells are inhibited by RGD-containing peptides and by function-blocking monoclonal antibodies specific for either the αvβ8 heterodimer or the αv chain. Similar results were obtained with a chimeric αvβ8 including the β6 cytodomain (αvβ8/6), showing that the β6 cytodomain can substitute efficiently for the corresponding region of β8. In contrast, virus binding to αvβ6 including the β8 cytodomain (αvβ6/8) was lower than that of the wild-type integrin, and this binding did not lead to infection. Further, the αvβ6 chimera was recognized poorly by antibodies specific for the ectodomain of αvβ6 and displayed a relaxed sequence-binding specificity relative to that of wild-type integrin. These data suggest that the β6 cytodomain is important for maintaining αvβ6 in a conformation required for productive infection by FMDV.
5
Duque, Hernando, Michael LaRocco, William T. Golde, and Barry Baxt. "Interactions of Foot-and-Mouth Disease Virus with Soluble Bovine αVβ3 and αVβ6 Integrins." Journal of Virology 78, no. 18 (September 15, 2004): 9773–81. http://dx.doi.org/10.1128/jvi.78.18.9773-9781.2004.
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ABSTRACT At least four members of the integrin family of receptors, αVβ1, αVβ3, αVβ6, and αVβ8, have been identified as receptors for foot-and-mouth disease virus (FMDV) in vitro. Our investigators have recently shown that the efficiency of receptor usage appears to be related to the viral serotype and may be influenced by structural differences on the viral surface (H. Duque and B. Baxt, J. Virol. 77:2500-2511, 2003). To further examine these differences, we generated soluble αVβ3 and αVβ6 integrins. cDNA plasmids encoding the individual complete integrin αV, β3, and β6 subunits were used to amplify sequences encoding the subunits' signal peptide and ectodomain, resulting in subunits lacking transmembrane and cytoplasmic domains. COS-1 cells were transfected with plasmids encoding the soluble αV subunit and either the soluble β3 or β6 subunit and labeled with [35S]methionine-cysteine. Complete subunit heterodimeric integrins were secreted into the medium, as determined by radioimmunoprecipitation with specific monoclonal and polyclonal antibodies. For the examination of the integrins' biological activities, stable cell lines producing the soluble integrins were generated in HEK 293A cells. In the presence of divalent cations, soluble αVβ6 bound to representatives of type A or O viruses, immobilized on plastic dishes, and significantly inhibited viral replication, as determined by plaque reduction assays. In contrast, soluble αVβ3 was unable to bind to immobilized virus of either serotype; however, virus bound to the immobilized integrin, suggesting that FMDV binding to αVβ3 is a low-affinity interaction. In addition, soluble αVβ3 did not neutralize virus infectivity. Incubation of soluble αVβ6 with labeled type A12 or O1 resulted in a significant inhibition of virus adsorption to BHK cells, while soluble αVβ3 caused a low (20 to 30%), but consistent, inhibition of virus adsorption. Virus incubated with soluble αVβ6 had a lower sedimentation rate than native virus on sucrose density gradients, but the particles retained all of their structural proteins and still contained bound integrin and, therefore, were not exhibiting characteristics of a picornavirus A particle.
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Kossatz, Susanne, Ambros Johannes Beer, and Johannes Notni. "It’s Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals." Cancers 13, no. 23 (November 26, 2021): 5958. http://dx.doi.org/10.3390/cancers13235958.
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For almost the entire period of the last two decades, translational research in the area of integrin-targeting radiopharmaceuticals was strongly focused on the subtype αvβ3, owing to its expression on endothelial cells and its well-established role as a biomarker for, and promoter of, angiogenesis. Despite a large number of translated tracers and clinical studies, a clinical value of αvβ3-integrin imaging could not be defined yet. The focus of research has, thus, been moving slowly but steadily towards other integrin subtypes which are involved in a large variety of tumorigenic pathways. Peptidic and non-peptidic radioligands for the integrins α5β1, αvβ6, αvβ8, α6β1, α6β4, α3β1, α4β1, and αMβ2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvβ6, αvβ8, and α6β1/β4, were subsequently translated into humans during the last few years. αvβ6-Integrin has arguably attracted most attention because it is expressed by some of the cancers with the worst prognosis (above all, pancreatic ductal adenocarcinoma), which substantiates a clinical need for the respective theranostic agents. The receptor furthermore represents a biomarker for malignancy and invasiveness of carcinomas, as well as for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and probably even for Sars-CoV-2 (COVID-19) related syndromes. Accordingly, the largest number of recent first-in-human applications has been reported for radiolabeled compounds targeting αvβ6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvβ3 by αvβ6 as the most popular integrin in theranostics.
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Samanen, James, Zdenka Jonak, David Rieman, and Tian-Li Yue. "Vascular Indications for Integrin αv Antagonists." Current Pharmaceutical Design 3, no. 6 (December 1997): 545–84. http://dx.doi.org/10.2174/138161280306221010111710.
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Abstract: During early investigations into the biology associated with the platelet integrin αlIbβ3, monoclonal antibodies to αllbβ3 indicated that an αllbβ3-like integrin was expressed on endothelial cells, smooth muscle cells and on a variety of cancer cell lines. That integrin became known as the vitronectin receptor. It was shown to contain the same β3 subunit as αllbβ3, but it contained a different alpha subunit, named αv. Instead of a large family of β3 integrins, a large family of av integrins was discovered. To date, the family includes αvβI, αvβ3, αvβ5, αvβ6 and αvβ8. Two members of the family, αvβ3 and αvβ5, have received the most attention, showing potential in therapeutic targets as diverse as osteoporosis, restenosis and angiogenesis. This paper focuses on the potential vascular indications for av antagonists. It reviews the role of αvβ3 and αvβ5 as smooth muscle cell and endothelial cell adhesion receptors, as well as their capacity to mediate cell spreading and migration as signaling receptors. The current evidence for the role of αvβ3 and αvβ5 in restenosis and angiogenesis is reviewed. Endothelial cells, smooth muscle cells, and macrophages (mΦ) express either integrin, depending upon the cytokine that drives the migratory phenotype. Accessory membrane-bound molecules and matrix-degrading proteinases, as well as subcellular second messengers are reviewed. A model for the involvement of Integrin Associated Protein (IAP), and its ligation by thrombospondin is also proposed. A number of αv antagonists that inhibit cell adhesion to αvβ3 and αvβ5 have succeeded in proof of concept experiments in animal disease models. Nonpeptide av antagonists with high selectivity and adequate oral bioavailability have also been discovered. Thus, the field of av antagonists is poised to move into clinical development in the areas of restenosis, cancer, and ocular angiogenesis. Other areas that could blossom with potential for av antagonists include rheumatoid arthritis and atherosclerosis.
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Burman, Alison, Stuart Clark, Nicola G. A. Abrescia, Elizabeth E. Fry, David I. Stuart, and Terry Jackson. "Specificity of the VP1 GH Loop of Foot-and-Mouth Disease Virus for αv Integrins." Journal of Virology 80, no. 19 (October 1, 2006): 9798–810. http://dx.doi.org/10.1128/jvi.00577-06.
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ABSTRACT Foot-and-mouth disease virus (FMDV) can use a number of integrins as receptors to initiate infection. Attachment to the integrin is mediated by a highly conserved arginine-glycine-aspartic acid (RGD) tripeptide located on the GH loop of VP1. Other residues of this loop are also conserved and may contribute to integrin binding. In this study we have used a 17-mer peptide, whose sequence corresponds to the GH loop of VP1 of type O FMDV, as a competitor of integrin-mediated virus binding and infection. Alanine substitution through this peptide identified the leucines at the first and fourth positions following RGD (RGD+1 and RGD+4 sites) as key for inhibition of virus binding and infection mediated by αvβ6 or αvβ8 but not for inhibition of virus binding to αvβ3. We also show that FMDV peptides containing either methionine or arginine at the RGD+1 site, which reflects the natural sequence variation seen across the FMDV serotypes, are effective inhibitors for αvβ6. In contrast, although RGDM-containing peptides were effective for αvβ8, RGDR-containing peptides were not. These observations were confirmed by showing that a virus containing an RGDR motif uses αvβ8 less efficiently than αvβ6 as a receptor for infection. Finally, evidence is presented that shows αvβ3 to be a poor receptor for infection by type O FMDV. Taken together, our data suggest that the integrin binding loop of FMDV has most likely evolved for binding to αvβ6 with a higher affinity than to αvβ3 and αvβ8.
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Bodero, Lizeth, Paula López Rivas, Barbara Korsak, Torsten Hechler, Andreas Pahl, Christoph Müller, Daniela Arosio, Luca Pignataro, Cesare Gennari, and Umberto Piarulli. "Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting." Beilstein Journal of Organic Chemistry 14 (February 14, 2018): 407–15. http://dx.doi.org/10.3762/bjoc.14.29.
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RGD-α-amanitin and isoDGR-α-amanitin conjugates were synthesized by joining integrin ligands to α-amanitin via various linkers and spacers. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the purified αVβ3 receptor, retaining good binding affinity, in the same nanomolar range as the free ligands. The antiproliferative activity of the conjugates was evaluated in three cell lines possessing different levels of αVβ3 integrin expression: human glioblastoma U87 (αVβ3+), human lung carcinoma A549 (αVβ3−) and breast adenocarcinoma MDA-MB-468 (αVβ3−). In the U87, in the MDA-MB-468, and partly in the A549 cancer cell lines, the cyclo[DKP-isoDGR]-α-amanitin conjugates bearing the lysosomally cleavable Val-Ala linker were found to be slightly more potent than α-amanitin. Apparently, for all these α-amanitin conjugates there is no correlation between the cytotoxicity and the expression of αVβ3 integrin. To determine whether the increased cytotoxicity of the cyclo[DKP-isoDGR]-α-amanitin conjugates is governed by an integrin-mediated binding and internalization process, competition experiments were carried out in which the conjugates were tested with U87 (αVβ3+, αVβ5+, αVβ6−, α5β1+) and MDA-MB-468 (αVβ3−, αVβ5+, αVβ6+, α5β1−) cells in the presence of excess cilengitide, with the aim of blocking integrins on the cell surface. Using the MDA-MB-468 cell line, a fivefold increase of the IC50 was observed for the conjugates in the presence of excess cilengitide, which is known to strongly bind not only αVβ3, but also αVβ5, αVβ6, and α5β1. These data indicate that in this case the cyclo[DKP-isoDGR]-α-amanitin conjugates are possibly internalized by a process mediated by integrins different from αVβ3 (e.g., αVβ5).
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Kossatz, Susanne, and Johannes Notni. "Frischer Wind für Integrine." Der Nuklearmediziner 44, no. 02 (June 2021): 152–59. http://dx.doi.org/10.1055/a-1395-0735.
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ZusammenfassungSelektive PET- oder SPECT- Radiopharmaka sind inzwischen nicht nur für αvβ3, sondern auch weitere der 24 verschiedenen Integrine verfügbar, zum Beispiel α5β1, αvβ6, αvβ8 und α6. Da diese unter anderem auch von verschiedenen Karzinomen und im Zuge von Fibrose exprimiert werden, ist die Vorstellung, dass Integrine nur als Zielstrukturen für die Bildgebung von Angiogenese in Betracht kommen, endgültig überholt. Die derzeit besten Aussichten auf eine breite klinische Anwendung, sowohl diagnostisch als auch therapeutisch, haben derzeit αvβ6-Integrin-Radiopharmaka, da αvβ6 von vielen malignen Krebsarten (v. a. Pankreas-, Plattenepithel-, Basalzell-, Lungen- und Colonkarzinom) überexprimiert wird.
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Berghoff, Anna Sophie, Orsolya Rajky, Frank Winkler, Michael Weller, Christoph Zielinski, Jens Schittenhelm, and Matthias Preusser. "Evaluation of invasion patterns and their correlation with integrin alphavbeta expression in brain metastases of solid cancers." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2059. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2059.
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2059 Background: Understanding the pathobiology of brain metastases (BM) could guide the establishment of new targeted therapies. Methods: We collected 57 autopsy specimens of BM (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 1 kidney cancer, 2 colorectal cancer, 13 other) and histologically evaluated the patterns of invasion into the surrounding brain parenchyma. Expression of the following integrins was evaluated using immunohistochemistry: with novel antibodies for αv subunit, αvβ3, αvβ5, αvβ6 and αvβ8 integrin. Results: We observed three main invasion patterns: well-demarcated (29/57, 51%), vascular co-option (10/57, 18%) and diffuse infiltration (18/57, 32%). There was no association of invasion pattern with primary tumor type, although vascular co-option was most common in melanomas (4/10, 40%). αv subunit expression was lowest in the vascular co-option group (p = 0.05, t-test). αvβ6 levels were higher in the well-demarcated group than in the vascular co-option group (p = 0.025; t-test) and were higher in lung cancer BM than in melanoma BM (0.01, t-test). αvβ3 and αvβ5 were frequently expressed in tumoral (αvβ3: 30/57, 53%; αvβ5: 55/57, 97%) and peritumoral (αvβ3: 29/57, 51%, αvβ5: 54/57 (95%) vascular structures and 27/57 (47%) specimens showed avb5 and 6/57 (11%) αvβ3 expression on tumor cells. Prior radio- or chemotherapy did not correlate with invasion pattern or integrin expression. Conclusions: We delineate three distinct invasion patterns of BM into the brain parenchyma: well-demarcated growth, vascular co-option and diffuse infiltration. Integrin expression is frequent on tumor and vascular cells in BM and associated with distinct invasion patterns. Anti-integrin therapy could be a valid treatment option in patients with BM.
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Casiraghi, Costanza, Tatiana Gianni, and Gabriella Campadelli-Fiume. "αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors." Journal of Virology 90, no. 8 (February 3, 2016): 4243–48. http://dx.doi.org/10.1128/jvi.03175-15.
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We report that αvβ3 integrin strongly affects the innate immune response in epithelial cells. αvβ3 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by αvβ3 integrin. The boosting was exerted specifically by αvβ3 integrin but not by αvβ6 or αvβ8 integrin. Current and previous work indicates that integrin-TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response.
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Jackson, Terry, A. Paul Mould, Dean Sheppard, and Andrew M. Q. King. "Integrin αvβ1 Is a Receptor for Foot-and-Mouth Disease Virus." Journal of Virology 76, no. 3 (February 1, 2002): 935–41. http://dx.doi.org/10.1128/jvi.76.3.935-941.2002.
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ABSTRACT Infection by field strains of Foot-and-mouth disease virus (FMDV) is initiated by binding to certain species of arginine-glycine-aspartic acid (RGD)-dependent integrin including αvβ3 and the epithelial integrin αvβ6. In this report we show that the integrin αvβ1, when expressed as a human/hamster heterodimer on transfected CHOB2 cells, is a receptor for FMDV. Virus binding and infection mediated by αvβ1 was inefficient in the presence of physiological concentrations of calcium and magnesium but were significantly enhanced by reagents that activate the integrin and promote ligand binding. The ability of chimeric α5/αv integrin subunits, in association with the β1 chain, to bind FMDV and mediate infection matched the ligand binding specificity of αvβ1, not α5β1, thus providing further evidence for the receptor role of αvβ1. In addition, data are presented suggesting that amino acid residues near the RGD motif may be important for differentiating between the binding specificities of αvβ1 and αvβ6.
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Wang, Jianchuan, Xianchi Dong, Bo Zhao, Jing Li, Chafen Lu, and Timothy A. Springer. "Atypical interactions of integrin αVβ8 with pro-TGF-β1." Proceedings of the National Academy of Sciences 114, no. 21 (May 8, 2017): E4168—E4174. http://dx.doi.org/10.1073/pnas.1705129114.
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Integrins αVβ6 and αVβ8 are specialized for recognizing pro-TGF-β and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin αVβ8 is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine αVβ8 for atypical binding to pro-TGF-β1. In contrast to αVβ6, αVβ8 has a constitutive extended-closed conformation, and binding to pro-TGF-β1 does not stabilize the open conformation of its headpiece. Although Mn2+ potently activates other integrins and increases affinity of αVβ6 for pro-TGF-β1 25- to 55-fold, it increases αVβ8 affinity only 2- to 3-fold. This minimal effect correlates with the inability of Mn2+ and pro-TGF-β1 to stabilize the open conformation of the αVβ8 headpiece. Moreover, αVβ8 was inhibited by high concentrations of Mn2+ and was stimulated and inhibited at markedly different Ca2+ concentrations than αVβ6. These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate αVβ8 binding to and activation of pro-TGF-β.
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Quaglia, Fabio, Shiv Ram Krishn, Yanqing Wang, David W. Goodrich, Peter McCue, Andrew V. Kossenkov, Amy C. Mandigo, et al. "Differential expression of αVβ3 and αVβ6 integrins in prostate cancer progression." PLOS ONE 16, no. 1 (January 22, 2021): e0244985. http://dx.doi.org/10.1371/journal.pone.0244985.
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Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer.
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Janes, Sam M., and Fiona M. Watt. "Switch from αvβ5 to αvβ6 integrin expression protects squamous cell carcinomas from anoikis." Journal of Cell Biology 166, no. 3 (August 2, 2004): 419–31. http://dx.doi.org/10.1083/jcb.200312074.
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Stratified squamous epithelia express the αvβ5 integrin, but in squamous cell carcinomas (SCCs) there is down-regulation of αvβ5 and up-regulation of αvβ6. To investigate the significance of this finding, we transduced an αv-negative human SCC line with retroviral vectors encoding αv integrins. αvβ5-expressing cells underwent suspension-induced apoptosis (anoikis), whereas αv-negative cells and cells expressing αvβ6 did not. Resistance to anoikis correlated with PKB/Akt activation in suspension, but not with changes in PTEN or p110α PI3 kinase levels. Anoikis was induced in parental and αvβ6-expressing cells by inhibiting PI3 kinase. Conversely, activation of Akt or inhibition of caspases in αvβ5-expressing cells suppressed anoikis. Caspase inhibition resulted in increased phosphoAkt, placing caspase activation upstream of decreased Akt activation. Anoikis required the cytoplasmic domain of β5 and was independent of the death receptor pathway. These results suggest that down-regulation of αvβ5 through up-regulation of αvβ6 may protect SCCs from anoikis by activating an Akt survival signal.
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Jackson, Terry, Dean Sheppard, Michael Denyer, Wendy Blakemore, and Andrew M. Q. King. "The Epithelial Integrin αvβ6 Is a Receptor for Foot-and-Mouth Disease Virus." Journal of Virology 74, no. 11 (June 1, 2000): 4949–56. http://dx.doi.org/10.1128/jvi.74.11.4949-4956.2000.
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ABSTRACT Field isolates of foot-and-mouth disease virus (FMDV) have been shown to use the RGD-dependent integrin αvβ3 as a cellular receptor on cultured cells. However, several other RGD-dependent integrins may have the potential to act as receptors for FMDV in vivo. Of these, αvβ6 is a likely candidate for use as a receptor by FMDV as it is expressed on epithelial cells, which correlates with the tissue tropism of the virus. In this report, we show that human colon carcinoma cells (SW480) that are normally nonpermissive for FMDV become susceptible to infection as a result of transfection with the integrin β6 subunit and expression of αvβ6 at the cell surface. Integrin αvβ6 is the major site for virus attachment on the β6-transfected cells, and binding to αvβ6 serves to increase the rate of virus entry into these cells. In addition, we show that virus binding and infection of the β6-transfected cells is mediated through an RGD-dependent interaction that is specifically inhibited by a monoclonal antibody (10D5) that recognizes αvβ6. These studies establish a role for αvβ6 as a cellular receptor for FMDV.
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Rieder, Elizabeth, Tina Henry, Hernando Duque, and Barry Baxt. "Analysis of a Foot-and-Mouth Disease Virus Type A24 Isolate Containing an SGD Receptor Recognition Site In Vitro and Its Pathogenesis in Cattle." Journal of Virology 79, no. 20 (October 15, 2005): 12989–98. http://dx.doi.org/10.1128/jvi.79.20.12989-12998.2005.
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ABSTRACT Foot-and-mouth disease virus (FMDV) initiates infection by binding to integrin receptors via an Arg-Gly-Asp (RGD) sequence found in the G-H loop of the structural protein VP1. Following serial passages of a type A24 Cruzeiro virus (A24Cru) in bovine, via tongue inoculation, a virus was generated which contained an SGD sequence in the cell receptor-binding site and expressed a turbid plaque phenotype in BHK-21 cells. Propagation of this virus in these cells resulted in the rapid selection of viruses that grew to higher titers, produced clear plaques, and now contained an RGD sequence in place of the original SGD. To study the role of the SGD sequence in FMDV receptor recognition and bovine virulence, we assembled an infectious cDNA clone of an RGD-containing A24Cru and derived mutant clones containing either SGD with a single nucleotide substitution in the R144 codon or double substitutions at this position to prevent mutation of the S to an R. The SGD viruses grew poorly in BHK-21 cells and stably maintained the sequence during propagation in BHK-21 cells expressing the bovine αVβ6 integrin (BHK3-αVβ6), as well as in experimentally infected and contact steers. While all the SGD-containing viruses used only the bovine αVβ6 integrin as a cellular receptor with relatively high efficiency, the revertant RGD viruses utilized either the αVβ1 or αVβ3 bovine integrins with higher efficiency than αVβ6 and grew well in BHK-21 cells. Replacing the R at the −1 SGD position with either K or E showed that this residue did not contribute to integrin utilization in vitro. These results illustrate the rapid evolution of FMDV with alteration in receptor specificity and suggest that viruses with sequences other than RGD, but closely related to it, can still infect via integrin receptors and induce and transmit the disease to susceptible animals.
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Monaghan, Paul, Sarah Gold, Jennifer Simpson, Zhidong Zhang, Paul H. Weinreb, Shelia M. Violette, Soren Alexandersen, and Terry Jackson. "The αvβ6 integrin receptor for Foot-and-mouth disease virus is expressed constitutively on the epithelial cells targeted in cattle." Journal of General Virology 86, no. 10 (October 1, 2005): 2769–80. http://dx.doi.org/10.1099/vir.0.81172-0.
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Field strains of Foot-and-mouth disease virus (FMDV) use a number of αv-integrins as receptors to initiate infection on cultured cells, and integrins are believed to be the receptors used to target epithelial cells in animals. In this study, immunofluorescence confocal microscopy and real-time RT-PCR were used to investigate expression of two of the integrin receptors of FMDV, αvβ6 and αvβ3, within various epithelia targeted by this virus in cattle. These studies show that αvβ6 is expressed constitutively on the surfaces of epithelial cells at sites where infectious lesions occur during a natural infection, but not at sites where lesions are not normally formed. Expression of αvβ6 protein at these sites showed a good correlation with the relative abundance of β6 mRNA. In contrast, αvβ3 protein was only detected at low levels on the vasculature and not on the epithelial cells of any of the tissues investigated. Together, these data suggest that in cattle, αvβ6, rather than αvβ3, serves as the major receptor that determines the tropism of FMDV for the epithelia normally targeted by this virus.
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Dutta, Anindita, Jing Li, Carmine Fedele, Aejaz Sayeed, Amrita Singh, Shelia M. Violette, Thomas D. Manes, and Lucia R. Languino. "αvβ6 integrin is required for TGFβ1-mediated matrix metalloproteinase2 expression." Biochemical Journal 466, no. 3 (March 6, 2015): 525–36. http://dx.doi.org/10.1042/bj20140698.
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Transforming growth factor (TGF) β1 activity depends on a complex signalling cascade that controls expression of several genes. Among others, TGFβ1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. In the present study, we demonstrate for the first time that the αvβ6 integrin interacts with TGFβ receptor II (TβRII) through the β6 cytoplasmic domain and promotes Smad3 activation in prostate cancer (PrCa) cells. Another related αv integrin, αvβ5, as well as the αvβ6/3 integrin, which contains a chimeric form of β6 with a β3 cytoplasmic domain, do not associate with TβRII and fail to show similar responses. We provide evidence that αvβ6 is required for up-regulation of MMP2 by TGFβ1 through a Smad3-mediated transcriptional programme in PrCa cells. The functional relevance of these results is underscored by the finding that αvβ6 modulates cell migration in an MMP2-dependent manner on an αvβ6-specific ligand, latency-associated peptide (LAP)–TGFβ. Overall, these mechanistic studies establish that expression of a single integrin, αvβ6, is sufficient to promote activation of Smad3, regulation of MMP2 levels and consequent catalytic activity, as well as cell migration. Our study describes a new TGFβ1–αvβ6–MMP2 signalling pathway that, given TGFβ1 pro-metastatic activity, may have profound implications for PrCa therapy.
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Urquiza, Mauricio, Valentina Guevara, Erika Diaz-Sana, and Felipe Mora. "The Role of αvβ6 Integrin Binding Molecules in the Diagnosis and Treatment of Cancer." Current Organic Chemistry 24, no. 21 (December 7, 2020): 2393–411. http://dx.doi.org/10.2174/1385272824999200528124936.
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Peptidic and non-peptidic αvβ6 integrin-binding molecules have been used in the clinic for detection and treatment of tumors expressing αvβ6 integrin, because this protein is expressed in malignant epithelial cells of the oral cavity, pancreas, breast, ovary, colon and stomach carcinomas but it is not expressed in healthy adult tissue except during wound healing and inflammation. This review focuses on the landscape of αvβ6 integrinbinding molecules and their use in cancer treatment and detection, and discusses recent designs for tumor detection, treatment, and immunotherapy. In the last ten years, several reviews about the αvβ6 integrin have been published but no one assessed the landscape of the αvβ6 integrin-binding molecules and their role in cancer detection and treatment. Firstly, this review describes the role of the αvβ6 integrin in normal tissues, how the expression of this protein is correlated with cancer severity and its role in cancer development. Taking into account the potential of αvβ6 integrin-binding molecules in detection and treatment of specific tumors, special attention is given to several high-affinity αvβ6 integrin-binding peptides used for tumor imaging; particularly, the αvβ6-binding peptide NAVPNLRGDLQVLAQKVART [A20FMDV2], derived from the foot and mouth disease virus. This peptide labeled with either 18F, 111In or with 68Ga has been used for PET imaging of αvβ6 integrin-positive tumors. Moreover, αvβ6 integrin-binding peptides have been used for photoacoustic and fluorescence imaging and could potentially be used in clinical application in cancer diagnosis and intraoperative imaging of αvβ6-integrin positive tumors. Additionally, non-peptidic αvβ6-binding molecules have been designed and used in the clinic for the detection and treatment of αvβ6-expressing tumors. Anti-αvβ6 integrin antibodies are another useful tool for selective identification and treatment of αvβ6 (+) tumors. The utility of these αvβ6 integrin-binding molecules as a tool for tumor detection and treatment is discussed, considering specificity, sensitivity and serum stability. Another use of the αvβ6 integrin-binding peptides is to modify the Ad5 cell tropism for inducing oncolytic activity of αvβ6-integrin positive tumor cells by expressing A20FMDV2 peptide within the fiber knob protein (Ad5NULL-A20). The newly designed oncolytic Ad5NULL-A20 virotherapy is promising for local and systemic targeting of αvβ6-overexpressing cancers. Finally, new evidence has emerged, indicating that chimeric antigen receptor (CAR) containing the αvβ6 integrin- binding peptide on top of CD28+CD3 endodomain displays a potent therapeutic activity in a diverse repertoire of solid tumor models.
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Bieri, Manuela, Rodinde Hendrickx, Michael Bauer, Bin Yu, Tania Jetzer, Birgit Dreier, Peer R. E. Mittl, et al. "The RGD-binding integrins αvβ6 and αvβ8 are receptors for mouse adenovirus-1 and -3 infection." PLOS Pathogens 17, no. 12 (December 15, 2021): e1010083. http://dx.doi.org/10.1371/journal.ppat.1010083.
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Mammalian adenoviruses (AdVs) comprise more than ~350 types including over 100 human (HAdVs) and just three mouse AdVs (MAdVs). While most HAdVs initiate infection by high affinity/avidity binding of their fiber knob (FK) protein to either coxsackievirus AdV receptor (CAR), CD46 or desmoglein (DSG)-2, MAdV-1 (M1) infection requires arginine-glycine-aspartate (RGD) binding integrins. To identify the receptors mediating MAdV infection we generated five novel reporter viruses for MAdV-1/-2/-3 (M1, M2, M3) transducing permissive murine (m) CMT-93 cells, but not B16 mouse melanoma cells expressing mCAR, human (h) CD46 or hDSG-2. Recombinant M1 or M3 FKs cross-blocked M1 and M3 but not M2 infections. Profiling of murine and human cells expressing RGD-binding integrins suggested that αvβ6 and αvβ8 heterodimers are associated with M1 and M3 infections. Ectopic expression of mβ6 in B16 cells strongly enhanced M1 and M3 binding, infection, and progeny production comparable with mαvβ6-positive CMT-93 cells, whereas mβ8 expressing cells were more permissive to M1 than M3. Anti-integrin antibodies potently blocked M1 and M3 binding and infection of CMT-93 cells and hαvβ8-positive M000216 cells. Soluble integrin αvβ6, and synthetic peptides containing the RGDLXXL sequence derived from FK-M1, FK-M3 and foot and mouth disease virus coat protein strongly interfered with M1/M3 infections, in agreement with high affinity interactions of FK-M1/FK-M3 with αvβ6/αvβ8, determined by surface plasmon resonance measurements. Molecular docking simulations of ternary complexes revealed a bent conformation of RGDLXXL-containing FK-M3 peptides on the subunit interface of αvβ6/β8, where the distal leucine residue dips into a hydrophobic pocket of β6/8, the arginine residue ionically engages αv aspartate215, and the aspartate residue coordinates a divalent cation in αvβ6/β8. Together, the RGDLXXL-bearing FKs are part of an essential mechanism for M1/M3 infection engaging murine and human αvβ6/8 integrins. These integrins are highly conserved in other mammals, and may favour cross-species virus transmission.
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Notni, Johannes. "RGD Forever!—Past, Present, and Future of a 3-Letter-Code in Radiopharmacy and Life Sciences." Pharmaceuticals 16, no. 1 (December 30, 2022): 56. http://dx.doi.org/10.3390/ph16010056.
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“RGD” is frequently pictured as a ligand for αvβ3-integrin and useful for molecular targeting of angiogenesis—which is about as simplistic as the idea that laser beams are green or red and particularly useful for arming spaceships. There is, however, much more to RGD. In particular, targeting angiogenesis is likely not the most significant stronghold of RGD-comprising constructs. RGD is the one-letter code of a very short peptide sequence, arginine-lysine-aspartate, which is recognized by eight different integrins, namely, α(IIb)β3, α5β1, α8β1, and the five dimers that αv forms with β1, β3, β5, β6, and β8. These 8 RGD receptors form an own subset among the entire class of 24 known integrins, which furthermore comprises another three distinct groups (4 collagen receptors, 4 laminin receptors, and 8 leukocyte receptors). However, the 8 RGD-recognizing integrins are far from being alike. They do not even share the same tissue prevalences and functions, but are expressed on fundamentally different cell types and fulfill the most diverse biological tasks. For example, α(IIb)β3 is found on platelets and mediates thrombus formation, whereas αvβ6- and αvβ8-integrin are expressed on epithelial cells, activate TFG-β, and thus may promote cancer progression and invasion as well as fibrosis. Recent non-clinical experiments and clinical findings suggest that the highly specific expression of αvβ6-integrin by some carcinoma types, in combination with the availability of the corresponding small-molecule ligands, may open a multitude of new and promising avenues for improved cancer diagnosis and therapy, including, but not limited to, radiopharmaceutical approaches.
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Williams, Çiğdem H., Tommi Kajander, Timo Hyypiä, Terry Jackson, Dean Sheppard, and Glyn Stanway. "Integrin αvβ6 Is an RGD-Dependent Receptor for Coxsackievirus A9." Journal of Virology 78, no. 13 (July 1, 2004): 6967–73. http://dx.doi.org/10.1128/jvi.78.13.6967-6973.2004.
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ABSTRACT Coxsackievirus A9 (CAV9), a member of the Enterovirus genus of Picornaviridae, is a common human pathogen and is one of a significant number of viruses containing a functional arginine-glycine-aspartic acid (RGD) motif in one of their capsid proteins. Previous studies identified the RGD-recognizing integrin αvβ3 as its cellular receptor. However, integrin αvβ6 has been shown to be an efficient receptor for another RGD-containing picornavirus, foot-and-mouth disease virus (FMDV). In view of the similarity in sequence context of the RGD motifs in CAV9 and FMDV, we investigated whether αvβ6 can also serve as a receptor for CAV9. We found that CAV9 can bind to purified αvβ6 and also to SW480 cells transfected with β6 cDNA, allowing expression of αvβ6 on their surface, but it cannot bind to mock-transfected cells. In addition, a higher yield of CAV9 was obtained in β6-expressing cells than in mock-transfected cells. There was no similar enhancement in infection with an RGD-less CAV9 mutant. We also found β6 on the surface of GMK cells, a cell line which CAV9 infects efficiently by an RGD-dependent mechanism. Significantly, this infection is blocked by an antibody to αvβ6, while this antibody did not block the low level of infection by the RGD-less mutant. Thus, integrin αvβ6 is an RGD-dependent receptor for CAV9 and may be important in natural CAV9 infections.
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Jovanović, Jelena, Sarah Iqbal, Sacha Jensen, Helen Mardon, and Penny Handford. "Fibrillin–integrin interactions in health and disease." Biochemical Society Transactions 36, no. 2 (March 20, 2008): 257–62. http://dx.doi.org/10.1042/bst0360257.
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Human fibrillin-1 is the major structural protein of extracellular matrix 10–12 nm microfibrils. It has a disulfide-rich modular organization which consists primarily of cbEGF (Ca2+-binding epidermal growth factor-like) domains and TB (transforming growth factor β-binding protein-like) domains. TB4 contains an RGD (Arg-Gly-Asp) integrin-binding motif. The atomic structure of this region has been solved by X-ray crystallography and shows the TB4 and flanking cbEGF domains to be arranged as a tetragonal pyramid with N- and C-termini exposed at opposite ends of the fragment. The RGD integrin-binding motif is located within a flexible loop. We have used a variety of biophysical, biochemical and cell biology methods to investigate the molecular properties of integrin–fibrillin-1 interactions and have demonstrated that recombinant fibrillin-1 domain fragments mediate binding to integrins αVβ3, α5β1 and αVβ6. Integrin αVβ3 is a high-affinity fibrillin-1 receptor (Kd ∼40 nM), whereas integrins αVβ6 and α5β1 show moderate-affinity (Kd ∼450 nM) and low-affinity (Kd >1 μM) binding respectively. Different patterns of α5β1 distribution are seen when human keratinocytes and fibroblasts are plated on to fibrillin domain fragments compared with those seen for fibronectin, suggesting that fibrillin may cause a lesser degree or different type of intracellular signalling. A number of disease-causing mutations which affect the TB4 domain have been identified. These are being investigated for their effects on integrin binding and/or changes in intramolecular structure.
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Seitsonen, Jani, Petri Susi, Outi Heikkilä, Robert S. Sinkovits, Pasi Laurinmäki, Timo Hyypiä, and Sarah J. Butcher. "Interaction of αVβ3 and αVβ6 Integrins with Human Parechovirus 1." Journal of Virology 84, no. 17 (June 16, 2010): 8509–19. http://dx.doi.org/10.1128/jvi.02176-09.
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ABSTRACT Human parechovirus (HPEV) infections are very common in early childhood and can be severe in neonates. It has been shown that integrins are important for cellular infectivity of HPEV1 through experiments using peptide blocking assays and function-blocking antibodies to αV integrins. The interaction of HPEV1 with αV integrins is presumably mediated by a C-terminal RGD motif in the capsid protein VP1. We characterized the binding of integrins αVβ3 and αVβ6 to HPEV1 by biochemical and structural studies. We showed that although HPEV1 bound efficiently to immobilized integrins, αVβ6 bound more efficiently than αVβ3 to immobilized HPEV1. Moreover, soluble αVβ6, but not αVβ3, blocked HPEV1 cellular infectivity, indicating that it is a high-affinity receptor for HPEV1. We also showed that HPEV1 binding to integrins in vitro could be partially blocked by RGD peptides. Using electron cryo-microscopy and image reconstruction, we showed that HPEV1 has the typical T=1 (pseudo T=3) organization of a picornavirus. Complexes of HPEV1 and integrins indicated that both integrin footprints reside between the 5-fold and 3-fold symmetry axes. This result does not match the RGD position predicted from the coxsackievirus A9 X-ray structure but is consistent with the predicted location of this motif in the shorter C terminus found in HPEV1. This first structural characterization of a parechovirus indicates that the differences in receptor binding are due to the amino acid differences in the integrins rather than to significantly different viral footprints.
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Dong, Xianchi, Bo Zhao, Fu-Yang Lin, Chafen Lu, Bruce N. Rogers, and Timothy A. Springer. "High integrin αVβ6 affinity reached by hybrid domain deletion slows ligand-binding on-rate." Proceedings of the National Academy of Sciences 115, no. 7 (January 29, 2018): E1429—E1436. http://dx.doi.org/10.1073/pnas.1718662115.
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The role of the hybrid domain in integrin affinity regulation is unknown, as is whether the kinetics of ligand binding is modulated by integrin affinity state. Here, we compare cell surface and soluble integrin αVβ6 truncation mutants for ligand-binding affinity, kinetics, and thermodynamics. Removal of the integrin transmembrane/cytoplasmic domains or lower legs has little effect on αVβ6 affinity, in contrast to β1 integrins. In integrin opening, rearrangement at the interface between the βI and hybrid domains is linked to remodeling at the ligand-binding site at the opposite end of the βI domain, which greatly increases in affinity in the open conformation. The larger size of the βI-hybrid interface in the closed state suggests that the hybrid domain stabilizes closing. In agreement, deletion of the hybrid domain raised affinity by 50-fold. Surface plasmon resonance and isothermal titration calorimetry gave similar results and the latter revealed tradeoffs between enthalpy and entropy not apparent from affinity. At extremely high affinity reached in Mn2+ with hybrid domain truncation, αVβ6 on-rate for both pro-TGF-β1 and fibronectin declined. The results suggest that the open conformation of αVβ6 has lower on-rate than the closed conformation, correlate with constriction of the ligand-binding pocket in open αVβ6 structures, and suggest that the extended-closed conformation is kinetically selected for ligand binding. Subsequent transition to the extended-open conformation is stabilized by its much higher affinity for ligand and would also be stabilized by force exerted across ligand-bound integrins by the actin cytoskeleton.
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MacDonald, William J., Praveen R. Srinivasan, Vida Tajiknia, Maximilian Pinho-Schwermann, Connor Purcell, Brooke Verschleiser, and Wafik S. El-Deiry. "Abstract B022: A gradient expression of integrin αvβ6 expression in human cancer cells associates with TGFβ mediated immune evasion." Cancer Research 84, no. 3_Supplement_2 (February 1, 2024): B022. http://dx.doi.org/10.1158/1538-7445.canevol23-b022.
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Abstract Our previous results demonstrate an integrin-mediated mechanism of immune evasion in colorectal cancer. Increased levels of latent TGFβ in the experimental tumor environment led to the upregulation of the immune checkpoint marker PD-L1 in HCT116WT cells, facilitating escape from T-cell killing. This effect was rescued in immune co-cultures by pretreating cancer cells with the broad-spectrum integrin inhibitor GLPG-0187. To further elucidate this system, we investigated the TGFβ-integrin axis. Integrin αvβ6 is a major activator of the inert latent TGFβ into the active, immunosuppressive form. With its high specificity within malignant tissue, inhibition of αvβ6 poses an attractive therapeutic target for disrupting TGFβ signaling while avoiding the toxicities of systemic blockade. To identify an endogenous in vitro model of integrin αvβ6-expressing cancer, computational analysis of publicly available mRNA expression data was performed to determine cancer types with high αvβ6 upregulation. This investigation revealed a strong presence of αvβ6 in pancreatic, bladder, head and neck, and cervical cancer tissues. Further in-silico work identified the head and neck squamous cell carcinoma cell lines CAL-27 and FaDu, as well as the pancreatic adenocarcinoma line Capan-2, as suitable models for in vitro study. Flow cytometry of these cell lines was performed to determine the surface expression of integrin αvβ6, revealing that protein expression correlated with the mRNA data from the previous computational studies. Capan-2 and CAL-27 exhibited high levels αvβ6 of expression, while FaDu expressed moderate levels, and HCT116WT exhibited low αvβ6 expression. These cell lines were pretreated with latent TGFβ, simulating sequestered latent TGFβ in the extracellular matrix, and subsequently co-cultured with TALL-104 T-cells. Quantitative fluorescence microscopy revealed that resistance to killing by T-cells correlated with αvβ6 expression across cell lines. These findings are consistent with the hypothesis that upregulated expression of integrin αvβ6 functions as an immunosuppressive resistance mechanism by increasing tumor microenvironment levels of active TGFβ. Analysis of mRNA sequencing data from the TCGA Pancreatic Adenocarcinoma Firehose database revealed that integrin αvβ6 is a strong marker of poor prognosis in pancreatic adenocarcinoma. Future co-culture experiments will investigate the dynamics of TGFβ activation in the tumor microenvironment in relation to αvβ6 expression. Further in vivo studies can facilitate translation of our findings to therapeutic clinical trials. Citation Format: William J. MacDonald, Praveen R. Srinivasan, Vida Tajiknia, Maximilian Pinho-Schwermann, Connor Purcell, Brooke Verschleiser, Wafik S. El-Deiry. A gradient expression of integrin αvβ6 expression in human cancer cells associates with TGFβ mediated immune evasion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B022.
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Busenhart, Philipp, Ana Montalban-Arques, Egle Katkeviciute, Yasser Morsy, Chiara Van Passen, Larissa Hering, Kirstin Atrott, et al. "Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer." Journal for ImmunoTherapy of Cancer 10, no. 2 (February 2022): e003465. http://dx.doi.org/10.1136/jitc-2021-003465.
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BackgroundIntegrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer.MethodsUsing orthotopic and heterotopic tumor cell injection, we assessed the effect of ITGB6 on tumor growth and tumor immune response in wild type mice, mice with defective TGF-β signaling, and mice treated with anti-integrin αvβ6 antibodies. To examine the effect of ITGB6 in human colorectal cancer, we analyzed RNAseq data from the colon adenocarcinoma dataset of The Cancer Genome Atlas (TCGA-COAD).ResultsWe demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy.ConclusionsThese findings propose inhibition of integrin αvβ6 as a promising new therapy for colorectal cancer, which blocks tumor-promoting TGF-β activation, prevents tumor exclusion of cytotoxic T-cells and enhances the efficacy of immune checkpoint blockade therapy.
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Chalier, Florence, Laura Mugnier, Marion Tarbe, Soioulata Aboudou, Claude Villard, Hervé Kovacic, Didier Gigmes, et al. "Isolation of an Anti–tumour Disintegrin: Dabmaurin–1, a Peptide Lebein–1–like, from Daboia mauritanica Venom." Toxins 12, no. 2 (February 5, 2020): 102. http://dx.doi.org/10.3390/toxins12020102.
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In the soft treatment of cancer tumours, consequent downregulation of the malignant tissue angiogenesis constitutes an efficient way to stifle tumour development and metastasis spreading. As angiogenesis requires integrin–promoting endothelial cell adhesion, migration, and vessel tube formation, integrins represent potential targets of new therapeutic anti–angiogenic agents. Our work is a contribution to the research of such therapeutic disintegrins in animal venoms. We report isolation of one peptide, named Dabmaurin–1, from the hemotoxic venom of snake Daboia mauritanica, and we evaluate its potential anti–tumour activity through in vitro inhibition of the human vascular endothelial cell HMECs functions involved in tumour angiogenesis. Dabmaurin–1 altered, in a dose–dependent manner, without any significant cytotoxicity, HMEC proliferation, adhesion, and their mesenchymal migration onto various extracellular matrix proteins, as well as formation of capillary–tube mimics on MatrigelTM. Via experiments involving HMEC or specific cancers cells integrins, we demonstrated that the above Dabmaurin–1 effects are possibly due to some anti–integrin properties. Dabmaurin–1 was demonstrated to recognize a broad panel of prooncogenic integrins (αvβ6, αvβ3 or αvβ5) and/or particularly involved in control of angiogenesis (α5β1, α6β4, αvβ3 or αvβ5). Furthermore, mass spectrometry and partial N–terminal sequencing of this peptide revealed, it is close to Lebein–1, a known anti–β1 disintegrin from Macrovipera lebetina venom. Therefore, our results show that if Dabmaurin–1 exhibits in vitro apparent anti–angiogenic effects at concentrations lower than 30 nM, it is likely because it acts as an anti–tumour disintegrin.
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DiCara, Danielle, Alison Burman, Stuart Clark, Stephen Berryman, Mark J. Howard, Ian R. Hart, John F. Marshall, and Terry Jackson. "Foot-and-Mouth Disease Virus Forms a Highly Stable, EDTA-Resistant Complex with Its Principal Receptor, Integrin αvβ6: Implications for Infectiousness." Journal of Virology 82, no. 3 (November 28, 2007): 1537–46. http://dx.doi.org/10.1128/jvi.01480-07.
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ABSTRACT The initial stage of foot-and-mouth disease virus (FMDV) infection is virus binding to cell surface integrins via the RGD motif in the GH loop of the VP1 capsid protein. As for all ligand/integrin interactions, the initial contact between FMDV and its integrin receptors is cation dependent and hence inhibited by EDTA. We have investigated this binding process with RGD-containing peptides derived from the VP1 capsid protein of FMDV and discovered that, upon binding, some of these peptides form highly stable, EDTA-resistant associations with integrin αvβ6. Peptides containing specific substitutions show that this stable binding is dependent on a helical structure immediately C terminal to the RGD and, specifically, two leucine residues at positions RGD +1 and RGD +4. These observations have a biological consequence, as we show further that stable, EDTA-resistant binding to αvβ6 is a property also exhibited by FMDV particles. Thus, the integrin-binding loop of FMDV appears to have evolved to form very stable complexes with the principal receptor of FMDV, integrin αvβ6. An ability to induce such stable complexes with its cellular receptor is likely to contribute significantly to the high infectiousness of FMDV.
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Färber, Stefanie Felicitas, Alexander Wurzer, Florian Reichart, Roswitha Beck, Horst Kessler, Hans-Jürgen Wester, and Johannes Notni. "Therapeutic Radiopharmaceuticals Targeting Integrin αvβ6." ACS Omega 3, no. 2 (February 28, 2018): 2428–36. http://dx.doi.org/10.1021/acsomega.8b00035.
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Brzozowska, Ewa, and Sameer Deshmukh. "Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment." International Journal of Molecular Sciences 23, no. 20 (October 15, 2022): 12346. http://dx.doi.org/10.3390/ijms232012346.
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Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that the up- and down-regulation of the expression of αv and other integrins can be a potent marker of malignant diseases and patient prognosis. This review focuses on an arginine-glycine-aspartic acid (RGD)-dependent integrin αVβ6, its biology, and its role in healthy humans. We examine the implications of αVβ6 in cancer progression and the promotion of epithelial-mesenchymal transition (EMT) by contributing to the activation of transforming growth factor beta TGF-β. Although αvβ6 is crucial for proper function in healthy people, it has also been validated as a target for cancer treatment. This review briefly considers aspects of targeting αVβ6 in the clinic via different therapeutic modalities.
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Ahmed, Nuzhat, Clyde Riley, Gregory E. Rice, Michael A. Quinn, and Mark S. Baker. "αvβ6 Integrin-A Marker for the Malignant Potential of Epithelial Ovarian Cancer." Journal of Histochemistry & Cytochemistry 50, no. 10 (October 2002): 1371–79. http://dx.doi.org/10.1177/002215540205001010.
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The mechanism(s) responsible for the progression of non-metastatic or borderline ovarian cancer to invasive Grade I/III ovarian cancer is still unknown. An epithelium-restricted integrin, αvβ6, is present in malignant epithelia but not in normal epithelia. We studied the relative expression and distribution of αvβ6 integrin in early and late-stage invasive (Grade I and Grade III) and non-invasive (benign and borderline) ovarian tumors of serous, mucinous, endometrioid, and clear-cell carcinoma subtypes, to assess its potential as a marker for epithelial ovarian cancer progression. Sixty-six specimens, including eight normal, 13 benign, 14 borderline, 13 Grade I, and 18 Grade III tumors were evaluated by immunohistochemistry (IHC) using a monoclonal antibody (MAb) against αvβ6 integrin. Normal ovarian surface epithelium was negative for αvβ6 integrin expression. All 45 carcinomas studied were positive, and the staining intensity significantly correlated with the grade of the tumor. The Grade III carcinomas of all types showed strong staining intensity. Only mucinous benign tissues were positive, and no reactivity was observed in benign serous neoplasms. On the basis of these observations, we hypothesize that the expression of αvβ6 integrin is associated with epithelial ovarian cancer and that a gradual increase in the expression of the molecule may be a correlative index of the progression of this disease.
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Okabe, M., S. Yamamoto, H. Kitamoto, T. Kuwada, M. Shiokawa, H. Yamazaki, and H. Seno. "P447 Anti-αvβ6 integrin antibody as a novel serum biomarker for diagnosis of ulcerative colitis; a nation-wide multicenter validation study in Japan." Journal of Crohn's and Colitis 18, Supplement_1 (January 1, 2024): i911. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0577.
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Abstract Background There is no established diagnostic biomarker for ulcerative colitis (UC). Although we recently reported an anti-αvβ6 integrin antibody to diagnose UC, there is no large-scale validation study on this antibody to diagnose UC. This study aimed to validate the diagnostic value of anti-αvβ6 integrin antibody for UC in a nation-wide, multicenter cohort (UCV6-Dx Study). Methods We enrolled 1241 UC patients, 798 Crohn’s disease (CD) patients, and 207 other gastrointestinal disease patients from 28 Japanese high-volume referral centers. Anti-Integrin αvβ6 ELISA Kit (MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Tokyo, Japan) was used to measure the titer of anti-αvβ6 integrin antibody. The cut-off value was 1.64 U/mL (the mean +3SD of 83 serum samples from healthy volunteers determined by the manufacturer). The primary outcome was the diagnostic value of the anti-αvβ6 integrin antibody. Secondary outcomes were factors associated with false negative results in UC patients, factors associated with false positive results in non-UC patients, and the optimal cut-off values using receiver operating characteristic (ROC) analysis. Results The diagnostic sensitivity of the anti-αvβ6 integrin antibody in UC was 87.7% and the specificities were 82.0% in CD and 87.4% in other gastrointestinal diseases. Multivariate logistic regression analysis showed that false negative results in UC patients were associated with age at the time of sample collection [odds ratio (OR) 1.0242, p=0.034, 95% confidence interval (CI) 1.0018-1.0470], smoker (OR 2.5504, p=0.002, 95% CI 1.4216-4.5755), partial Mayo score (OR 0.8623, p=0.038, 95% CI 0.7495-0.9921), and advanced therapies (OR 0.5875, p=0.019, 95% CI 0.3765-0.9167) and false positive results in CD patients with disease location L2 (OR 2.6858, p=0.013, 95% CI 1.2323-5.8533). No factor was associated with false positive results in patients with other intestinal diseases. ROC analysis revealed that the optimal cut-off values estimated by the Youden method were 2.07 U/mL [area under the curve (AUC) 0.9003, sensitivity 85%, specificity 87%], and 1.78 U/mL (AUC 0.9206, sensitivity 87%, specificity 89%) for discriminating UC from CD and other gastrointestinal diseases, respectively. Conclusion The usefulness of anti-αvβ6 integrin antibody for diagnosing UC was validated in the Japanese large-scale, nation-wide multicenter study.
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Miller, Laura C., Wendy Blakemore, Dean Sheppard, Amha Atakilit, Andrew M. Q. King, and Terry Jackson. "Role of the Cytoplasmic Domain of the β-Subunit of Integrin αvβ6 in Infection by Foot-and-Mouth Disease Virus." Journal of Virology 75, no. 9 (May 1, 2001): 4158–64. http://dx.doi.org/10.1128/jvi.75.9.4158-4164.2001.
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ABSTRACT Field isolates of foot-and-mouth disease virus (FMDV) are believed to use RGD-dependent integrins as cellular receptors in vivo. Using SW480 cell transfectants, we have recently established that one such integrin, αvβ6, functions as a receptor for FMDV. This integrin was shown to function as a receptor for virus attachment. However, it was not known if the αvβ6 receptor itself participated in the events that follow virus binding to the host cell. In the present study, we investigated the effects of various deletion mutations in the β6 cytoplasmic domain on infection. Our results show that although loss of the β6 cytoplasmic domain has little effect on virus binding, this domain is essential for infection, indicating a critical role in postattachment events. The importance of endosomal acidification in αvβ6-mediated infection was confirmed by experiments showing that infection could be blocked by concanamycin A, a specific inhibitor of the vacuolar ATPase.
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Davies, James A., Gareth Marlow, Hanni K. Uusi-Kerttula, Gillian Seaton, Luke Piggott, Luned M. Badder, Richard W. E. Clarkson, John D. Chester, and Alan L. Parker. "Efficient Intravenous Tumor Targeting Using the αvβ6 Integrin-Selective Precision Virotherapy Ad5NULL-A20." Viruses 13, no. 5 (May 8, 2021): 864. http://dx.doi.org/10.3390/v13050864.
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We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes.
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Müller, Martin, Annette Altmann, Max Sauter, Thomas Lindner, Dirk Jäger, Hendrik Rathke, Christel Herold-Mende, et al. "Preclinical evaluation of peptide-based radiotracers for integrin αvβ6-positive pancreatic carcinoma." Nuklearmedizin 58, no. 04 (May 10, 2019): 309–18. http://dx.doi.org/10.1055/a-0894-4127.
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Abstract Introduction Integrin αvβ6 shows a high expression rate in several cancer entities. As it is absent in most healthy adult tissues, it represents a promising target for tumor targeting with peptidic radiotracers. This study was performed to pave the way of the recently published αvβ6-binding peptide SFLAP3 for the clinical application in patients with pancreatic cancer. Methods The expression of integrin αvβ6 on several pancreatic cancer cell lines was assessed using flow cytometry and cell binding assays. The affinity was determined in competition binding assays followed by internalization and efflux studies. To increase the affinity, the binding sequence was modified and trimerization of the SFLAP3 peptide was achieved by oxime ligation. PET and biodistribution assays were conducted in Capan-2 tumor bearing mice. Finally, a first pancreatic tumor patient was examined with 68Ga-DOTA-SFLAP3. Results Flow cytometric analysis and in vitro cell binding revealed high expression of integrin αvβ6 on most pancreatic tumor cell lines. Modification of SFLAP3 led to compounds with improved in vitro binding properties. Unfortunately, these superior properties could not be transferred into improved pharmacokinetics. Consequently, the first pancreatic tumor patient was examined with 68Ga-DOTA-SFLAP3. The PET revealed specific accumulation (with SUV(max) values in the metastases ranging from 5 to 10) and a long retention in the tumor. Conclusion SFLAP3 showed high affinity to integrin αvβ6 on pancreatic cancer cell lines. The in vitro performance could be confirmed in tumor bearing mice and by PET imaging. These data suggest that DOTA-SFLAP3 is a promising tracer for targeting αvβ6-expressing pancreatic tumors.
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Ciregia, Federica, Céline Deroyer, Gaël Cobraiville, Zelda Plener, Olivier Malaise, Philippe Gillet, Marianne Fillet, Michel G. Malaise, and Dominique de Seny. "Modulation of αVβ6 integrin in osteoarthritis-related synovitis and the interaction with VTN(381–397 a.a.) competing for TGF-β1 activation." Experimental & Molecular Medicine 53, no. 2 (February 2021): 210–22. http://dx.doi.org/10.1038/s12276-021-00558-2.
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AbstractOsteoarthritis is characterized by structural alteration of joints. Fibrosis of the synovial tissue is often detected and considered one of the main causes of joint stiffness and pain. In our earlier proteomic study, increased levels of vitronectin (VTN) fragment (amino acids 381–397) were observed in the serum of osteoarthritis patients. In this work, the affinity of this fragment for integrins and its putative role in TGF-β1 activation were investigated. A competition study determined the interaction of VTN(381–397 a.a.) with αVβ6 integrin. Subsequently, the presence of αVβ6 integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, β6 was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, β6 expression was increased under TGF-β1 stimulation; hence, a TGF-β bioassay was applied. We observed that αVβ6 could mediate TGF-β1 bioavailability and that VTN(381–397 a.a.) could prevent TGF-β1 activation by interacting with αVβ6 in human FLSs and increased α-SMA. Finally, we analyzed serum samples from healthy controls and patients with osteoarthritis and other rheumatic diseases by nano-LC/Chip MS–MS, confirming the increased expression of VTN(381–397 a.a.) in osteoarthritis as well as in lupus erythematosus and systemic sclerosis. These findings corroborate our previous observations concerning the overexpression of VTN(381–397 a.a.) in osteoarthritis but also in other rheumatic diseases. This fragment interacts with αVβ6 integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-β1 precursor in human FLSs.
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Andreucci, Elena, Kelly Bugatti, Silvia Peppicelli, Jessica Ruzzolini, Matteo Lulli, Lido Calorini, Lucia Battistini, Franca Zanardi, Andrea Sartori, and Francesca Bianchini. "Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGFβ-Induced EMT in Human Non-Small Cell Lung Cancer." International Journal of Molecular Sciences 24, no. 2 (January 12, 2023): 1475. http://dx.doi.org/10.3390/ijms24021475.
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Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGFβ is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.
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Saini, Gauri, Joanne Porte, Paul H. Weinreb, Shelia M. Violette, William A. Wallace, Tricia M. McKeever, and Gisli Jenkins. "αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease." European Respiratory Journal 46, no. 2 (March 5, 2015): 486–94. http://dx.doi.org/10.1183/09031936.00210414.
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Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.43 paraffin-embedded, formalin-fixed lung tissue sections were immunostained for five molecules implicated in the pathogenesis of the fibrosis: α-smooth muscle actin (αSMA), αvβ6 integrin, pro-surfactant protein C (SP-C), hepatocyte growth factor (HGF) and tenascin-C (TenC). Levels of immunostaining and numbers of fibroblastic foci were quantified using operator-dependent and -independent methods. The relationship of all these markers to overall survival was analysed.Staining revealed high levels of αSMA, αvβ6 integrin, pro-SP-C, HGF and TenC, and fibroblastic foci. Immunostaining varied across samples for all molecules but only the extent of αvβ6 integrin immunostaining was associated with increased mortality. There was no association with the other markers measured.Our data suggest high levels of αvβ6 integrin may identify a specific endotype of progressive fibrotic lung disease.
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Heikkilä, Outi, Petri Susi, Tuire Tevaluoto, Heidi Härmä, Varpu Marjomäki, Timo Hyypiä, and Saija Kiljunen. "Internalization of Coxsackievirus A9 Is Mediated by β2-Microglobulin, Dynamin, and Arf6 but Not by Caveolin-1 or Clathrin." Journal of Virology 84, no. 7 (January 20, 2010): 3666–81. http://dx.doi.org/10.1128/jvi.01340-09.
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ABSTRACT Coxsackievirus A9 (CAV9) is a member of the human enterovirus B species within the Enterovirus genus of the family Picornaviridae. It has been shown to utilize αV integrins, particularly αVβ6, as its receptors. The endocytic pathway by which CAV9 enters human cells after the initial attachment to the cell surface has so far been unknown. Here, we present a systematic study concerning the internalization mechanism of CAV9 to A549 human lung carcinoma cells. The small interfering RNA (siRNA) silencing of integrin β6 subunit inhibited virus proliferation, confirming that αVβ6 mediates the CAV9 infection. However, siRNAs against integrin-linked signaling molecules, such as Src, Fyn, RhoA, phosphatidylinositol 3-kinase, and Akt1, did not reduce CAV9 proliferation, suggesting that the internalization of the virus does not involve integrin-linked signaling events. CAV9 endocytosis was independent of clathrin or caveolin-1 but was restrained by dynasore, an inhibitor of dynamin. The RNA interference silencing of β2-microglobulin efficiently inhibited virus infection and caused CAV9 to accumulate on the cell surface. Furthermore, CAV9 infection was found to depend on Arf6 as both silencing of this molecule by siRNA and the expression of a dominant negative construct resulted in decreased virus infection. In conclusion, the internalization of CAV9 to A549 cells follows an endocytic pathway that is dependent on integrin αVβ6, β2-microglobulin, dynamin, and Arf6 but independent of clathrin and caveolin-1.
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Guest, Ellen E., Steven A. Oatley, Simon J. F. Macdonald, and Jonathan D. Hirst. "Molecular Simulation of αvβ6 Integrin Inhibitors." Journal of Chemical Information and Modeling 60, no. 11 (May 18, 2020): 5487–98. http://dx.doi.org/10.1021/acs.jcim.0c00254.
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Blanco-Mezquita, José Tomás, Audrey E. K. Hutcheon, Mary Ann Stepp, and James D. Zieske. "αVβ6 Integrin Promotes Corneal Wound Healing." Investigative Opthalmology & Visual Science 52, no. 11 (October 31, 2011): 8505. http://dx.doi.org/10.1167/iovs.11-8194.
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Bloemen, H., A. Livanos, A. Martins, M. Tankelevich, J. Herb, J. Cho, A. Santos, et al. "OP13 Anti-integrin αvβ6 autoantibodies are increased in PSC-IBD and correlate with liver disease severity." Journal of Crohn's and Colitis 18, Supplement_1 (January 1, 2024): i24—i26. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0013.
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Abstract Background Anti-integrin αvβ6 autoantibodies (anti-αvβ6) are a novel biomarker of ulcerative colitis (UC) that precede disease diagnosis by up to 10 years. Given that integrin αvβ6 is also expressed on the biliary epithelium and that primary sclerosing cholangitis (PSC) co-occurs with inflammatory bowel disease (IBD) in up to 90% of patients, we aimed to determine the prevalence of anti-αvβ6 in patients with PSC and to understand the impact of anti-αvβ6 on PSC disease course. Methods Three cohorts of pre-liver transplant patients with PSC and controls (IBD and non-IBD) were recruited from New York, Lisbon and Miami. Anti-αvβ6 levels were measured using ELISA and normalized for serum IgG concentration. Statistical analyses across groups and clinical parameters were performed using the Kruskal-Wallis and Spearman correlation test. Multivariable linear regression was conducted to assess the association between anti-αvβ6 and liver disease severity, correcting for covariates. A mixed-effects model was applied to assess change in anti-αvβ6 over time. Results In total, 94 patients with PSC (53 (56.4%) PSC-UC, 20 (21.3%) PSC-Crohn’s disease (CD) and 21 (22.3%) PSC alone) and 129 controls (74 (57.4%) IBD and 55 (42.6%) non-IBD) were enrolled; table 1 shows the baseline characteristics of the patients with PSC. Follow-up samples (n=22) were collected from 1 up to 3 years after initial baseline sampling from 17 PSC patients. Median (IQR) age was similar in PSC patients (43, 33-56 years) and controls (47, 32-62 years; p=0.59). Median (IQR) anti-αvβ6 levels were significantly higher in PSC-UC (1.07, 0.48-2.65) and UC (1.83, 1.12-3.03) compared to PSC alone (0.40, 0.23-0.63; p=0.0004 and p<0.0001 respectively) and non-IBD controls (0.39, 0.17-0.65; p<0.0001 and p<0.0001 respectively). Anti-αvβ6 levels were comparable between PSC alone and non-IBD controls (p>0.999) (figure 1A). Anti-αvβ6 levels did not increase over time (p=0.23). A positive correlation between anti-αvβ6 levels and the Mayo PSC risk score (r=0.28, p=0.008) as well as alkaline phosphatase (r=0.29, p=0.007) was observed (figure 1B). These associations remain significant after correcting for covariates including age at diagnosis of PSC, gender, race/ethnicity and IBD type in a multivariable linear regression. Conclusion Anti-αvβ6 autoantibodies are a new biomarker of PSC-IBD and are associated with liver disease severity.
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Livanos, A., D. Y. Ganjian, A. A. Acharya, M. J. Chiramel, A. Dunn, H. Bloemen, J. Ostroff, et al. "OP28 Anti-integrin αvβ6 autoantibodies are detected in preclinical, incident and established colonic Crohn’s disease." Journal of Crohn's and Colitis 19, Supplement_1 (January 2025): i56—i58. https://doi.org/10.1093/ecco-jcc/jjae190.0028.
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Abstract Background Anti-integrin αvβ6 autoantibodies (anti-αvβ6) are present in up to 90% of ulcerative colitis (UC) patients and predate disease development, but there is a paucity of data regarding anti-αvβ6 in Crohn’s disease (CD). We hypothesized that anti-αvβ6 would be present in colonic CD given the shared biological characteristics with UC. Methods We measured anti-αvβ6 IgG in peripheral blood samples from seven distinct cohorts representing diverse ethnic backgrounds, geographical locations and stages of disease including preclinical, incident and established IBD as well as non-IBD controls (HC). Seropositivity was defined as greater than the log10 transformed mean + 2 standard deviations of HC. We determined associations with CD disease location (L1: Ileal, L2: colonic, L3: ileocolonic), disease activity, fecal calprotectin and pANCA. Results We assessed for anti-αvβ6 in adult and pediatric subjects from Mount Sinai Hospital (MSH), NY (MSCCR-adult, n=599 and pediatric, n=75). Anti-αvβ6 levels as well as seropositivity were significantly higher in adult CD (16%) compared to HC (2%) (P=0.0330, P<0.0001), but lower than in UC (64%) (Fig. 1A-B). In the Pediatric cohort, we observed similar results with CD seropositivity (22%) greater than HC (0%) (P=0.0073), but lower than UC (79%) (Fig. 1C-D). Next, we examined anti-αvβ6 by CD location. Patients with L2 disease had higher levels than L1 across all cohorts including 2 incident cohorts (MSCCR P<0.0001; Pediatric P=0.0531; COMPASS n=81, P<0.0001; OSCCAR n=167, P=0.0099), while patients with L3 disease had intermediate levels (Fig. E-H). These findings were validated in an independent cohort (Prometheus n=730) using a commercially available ELISA kit (MBL) (Fig. 1I). A significant positive correlation between anti-αvβ6 and pANCA was observed in L2 CD and L3 CD (Spearman r=0.52, P<0.0001; r=0.46, P=0.0012) but not L1 CD (Fig. 1J). In the Leuven cohort (n=163), anti-αvβ6 levels were significantly higher in those with moderate-severe disease activity (SES-CD≥7) and in those with elevated fecal calprotectin (≥150μg/g) (P=0.0024, P=0.0057) (Fig. 1K-L). Finally, in the PREDICTs cohort, anti-αvβ6 were significantly higher in CD subjects compared to HC at all 4 timepoints (n=824) including up to 10 years before diagnosis (Fig. 2A-B) and when stratifying by location, this was primarily driven by patients who develop L2 disease (Fig. 2C). Conclusion In patients with CD, anti-αvβ6 differentiate colonic from ileal disease and predate clinical disease by up to 10 years, potentially serving as a novel biomarker for clinical and preclinical colonic CD.
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Davis, Ryan A., Sven H. Hausner, Rebecca Harris, and Julie L. Sutcliffe. "A Comparison of Evans Blue and 4-(p-Iodophenyl)butyryl Albumin Binding Moieties on an Integrin αvβ6 Binding Peptide." Pharmaceutics 14, no. 4 (March 30, 2022): 745. http://dx.doi.org/10.3390/pharmaceutics14040745.
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Serum albumin binding moieties (ABMs) such as the Evans blue (EB) dye fragment and the 4-(p-iodophenyl)butyryl (IP) have been used to improve the pharmacokinetic profile of many radiopharmaceuticals. The goal of this work was to directly compare these two ABMs when conjugated to an integrin αvβ6 binding peptide (αvβ6-BP); a peptide that is currently being used for positron emission tomography (PET) imaging in patients with metastatic cancer. The ABM-modified αvβ6-BP peptides were synthesized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) chelator for radiolabeling with copper-64 to yield [64Cu]Cu DOTA-EB-αvβ6-BP ([64Cu]1) and [64Cu]Cu DOTA-IP-αvβ6-BP ([64Cu]2). Both peptides were evaluated in vitro for serum albumin binding, serum stability, and cell binding and internalization in the paired engineered melanoma cells DX3puroβ6 (αvβ6 +) and DX3puro (αvβ6 −), and pancreatic BxPC-3 (αvβ6 +) cells and in vivo in a BxPC-3 xenograft mouse model. Serum albumin binding for [64Cu]1 and [64Cu]2 was 53–63% and 42–44%, respectively, with good human serum stability (24 h: [64Cu]1 76%, [64Cu]2 90%). Selective αvβ6 cell binding was observed for both [64Cu]1 and [64Cu]2 (αvβ6 (+) cells: 30.3–55.8% and 48.5–60.2%, respectively, vs. αvβ6 (−) cells <3.1% for both). In vivo BxPC-3 tumor uptake for both peptides at 4 h was 5.29 ± 0.59 and 7.60 ± 0.43% ID/g ([64Cu]1 and [64Cu]2, respectively), and remained at 3.32 ± 0.46 and 4.91 ± 1.19% ID/g, respectively, at 72 h, representing a >3-fold improvement over the non-ABM parent peptide and thereby providing improved PET images. Comparing [64Cu]1 and [64Cu]2, the IP-ABM-αvβ6-BP [64Cu]2 displayed higher serum stability, higher tumor accumulation, and lower kidney and liver accumulation, resulting in better tumor-to-organ ratios for high contrast visualization of the αvβ6 (+) tumor by PET imaging.
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Aseervatham, Jaya, and Kalu U. E. Ogbureke. "Effects of DSPP and MMP20 Silencing on Adhesion, Metastasis, Angiogenesis, and Epithelial-Mesenchymal Transition Proteins in Oral Squamous Cell Carcinoma Cells." International Journal of Molecular Sciences 21, no. 13 (July 2, 2020): 4734. http://dx.doi.org/10.3390/ijms21134734.
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Recent reports highlight the potential tumorigenic role of Dentin Sialophosphoprotein (DSPP) and its cognate partner Matrix Metalloproteinase 20 (MMP-20) in Oral Squamous Cell Carcinomas (OSCCs). However, the function/mechanism of these roles is yet to be fully established. The present study aimed to investigate the effects of DSPP and MMP20 silencing on specific proteins involved in oral cancer cell adhesion, angiogenesis, metastasis, and epithelial-mesenchymal transition (EMT). Stable lines of DSPP/MMP20 silenced OSCC cell line (OSC2), previously established via lentiviral-mediated shRNA transduction, were analyzed for the effects of DSPP, MMP20, and combined DSPP–MMP20 silencing on MMP2, MMP9, integrins αvβ3 and αvβ6, VEGF, Kallikerin- 4,-5,-8,-10, E-cadherin, N-cadherin, Vimentin, met, src, snail, and Twist by Western blot. Results show a significant decrease (p < 0.05) in the expression of MMP2, MMP9, integrin αvβ3, αvβ6, VEGF, Kallikerins -4, -5, -8, -10, N-cadherin, vimentin met, src, snail and twist following DSPP and MMP20 silencing, individually and in combination. On the other hand, the expression of E-cadherin was found to be significantly increased (p < 0.05). These results suggest that the tumorigenic effect of DSPP and MMP20 on OSC2 cells is mediated via the upregulation of the genes involved in invasion, metastasis, angiogenesis, and epithelial-mesenchymal transition (EMT).
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Allen, Michael D., M. Reza Roozitalab, Stephen Murtough, Eleni Maniati, and J. Louise Jones. "Abstract PR011: DCIS-associated myoepithelial cells drive tumor progressive inflammation through up-regulation of integrin αvβ6." Cancer Prevention Research 15, no. 12_Supplement_1 (December 1, 2022): PR011. http://dx.doi.org/10.1158/1940-6215.dcis22-pr011.
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Abstract Background: Ductal carcinoma in-situ (DCIS) is a pre-invasive stage of breast cancer, however <50% will progress to invasion. A key component in promoting tumor invasion is inflammation, though its role in DCIS progression is unclear. We previously, showed αvβ6 expression on DCIS myoepithelial cells promotes tumor cell invasion. We hypothesized that altered myoepithelial phenotype in DCIS may modulate periductal inflammation to contribute to disease progression. Methods: The inflammatory infiltrate in DCIS cases (20 αvβ6+ and 20 αvβ6-) was characterized by immunohistochemistry (IHC) and immunofluorescence-IHC, focusing on Tumor Associated Macrophages (TAM) and Regulatory T cell markers. A myoepithelial cell line over-expressing αvβ6 (β6-1089) and a control counterpart (N-1089) were analyzed for cytokine and signaling molecule expression with proteome profilers and western blotting. The monocyte cell line (THP-1) was exposed to conditioned media from β6-1089 or N-1089 followed by qPCR for TAM markers (IL4, IL10 and IL8), MTS proliferation assay and western blotting for NFkB and STAT6 activation (involved in macrophage differentiation). 3D models were used to examine if the in vivo changes to macrophages can be modelled in vitro. Results: IHC analysis revealed a significant association between myoepithelial αvβ6 expression and increased T-reg cell infiltrate (p< 0.0001). Similarly, αvβ6 expression associated with increased presence of TAM (p=0.0026), αvβ6 positive DCIS with exhibited a microenvironment comprising 15% TAMs compared to 3% in αvβ6 negative DCIS cases. This shift in macrophage phenotype was recapitulated in 3D organotypic assays incorporating macrophages and myoepithelial cells. Proteome profiler analysis of THP-1 cells grown with conditioned media from αvβ6 positive myoepithelial cells demonstrated increased expression of CCL5 while all other proteins analyzed where generally suppressed. Nuclear and cytoplasmic western blotting of THP-1s demonstrated NfκB and STAT activation were altered by CM from myoepithelial cells +/- avb6. Conclusion: DCIS myoepithelial cells upregulate αvβ6 and exhibit changes in the periductal inflammatory infiltrate indicating a switch to a tumor promoting phenotype. Further investigation is required to determine the prognostic value and underlying mechanisms of this change. Citation Format: Michael D. Allen, M. Reza Roozitalab, Stephen Murtough, Eleni Maniati, J. Louise Jones. DCIS-associated myoepithelial cells drive tumor progressive inflammation through up-regulation of integrin αvβ6 [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR011.
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Triantafilou, Kathy, Martha Triantafilou, Yoshikazu Takada, and Nelson Fernandez. "Human Parechovirus 1 Utilizes Integrins αvβ3 and αvβ1 as Receptors." Journal of Virology 74, no. 13 (July 1, 2000): 5856–62. http://dx.doi.org/10.1128/jvi.74.13.5856-5862.2000.
Full textAbstract:
ABSTRACT Human parechovirus 1 (HPEV1) displays an arginine-glycine-aspartic acid (RGD) motif in the VP1 capsid protein, suggesting integrins as candidate receptors for HPEV1. A panel of monoclonal antibodies (MAbs) specific for integrins αvβ3, αvβ1, and αvβ5, which have the ability to recognize the RGD motif, and also a MAb specific for integrin α2β1, an integrin that does not recognize the RGD motif, were tested on A549 cells. Our results showed that integrin αv-specific MAb reduced infectivity by 85%. To specify which αv integrins the virus utilizes, we tested MAbs specific to integrins αvβ3 and αvβ1 which reduced infectivity significantly, while a MAb specific for integrin αvβ5, as well as the MAb specific for α2β1, showed no reduction. When a combination of MAbs specific for integrins αvβ3 and αvβ1 were used, virus infectivity was almost completely inhibited; this shows that integrins αvβ3 and αvβ1 are utilized by the virus. We therefore proceeded to test whether αv integrins' natural ligands fibronectin and vitronectin had an effect on HPEV1 infectivity. We found that vitronectin reduced significantly HPEV1 infectivity, whereas a combination of vitronectin and fibronectin abolished infection. To verify the use of integrins αvβ3 and αvβ1 as HPEV1 receptors, CHO cells transfected and expressing either integrin αvβ3 or integrin αvβ1 were used. It was shown that the virus could successfully infect these cells. However, in immunoprecipitation experiments using HPEV1 virions and allowing the virus to bind to solubilized A549 cell extract, we isolated and confirmed by Western blotting the αvβ3 heterodimer. In conclusion, we found that HPEV1 utilises both integrin αvβ3 and αvβ1 as receptors; however, in cells that express both integrins, HPEV1 may preferentially bind integrin αvβ3.