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Integrins and Human Pathologies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 34125

Special Issue Editors


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Guest Editor
Research Team: Tumor Radioresistance, from Signalling Pathways to Therapy Department of Experimental Therapeutics Inserm U1037 Toulouse Cancer Research Center (CRCT) & IUCT 2 av. Hubert Curien, 31100 Toulouse, France
Interests: cell death; apoptosis; cellular differentiation; cellular and mitochondrial metabolism; cellular and mitochondrial homoeostasis; oxidative stress; cancer; cancer stem cells; glioma; radiotherapy & radioresistance
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Guest Editor
Centre de Recherches en Cancérologie de Toulouse - CRCT UMR1037 Inserm/Université Toulouse III-Paul Sabatier-ERL5294, CNRS 2 avenue Hubert Curien Oncopole entrée C CS 53717, 31037 Toulouse, France
Interests: invasion; RhoGTPases; integrins; stem cells, cancer; resistance to chemotherapy and radiotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Integrins are adhesion molecules that connect cells to ligands in the extracellular matrix, or to ligands expressed by blood cells. Upon binding to their ligands, integrin activate signaling pathways involved in key cellular processes like migration/invasion, cytoskeleton organization, survival and angiogenesis. Deregulation of integrins leads to various human pathologies: Inflammatory diseases like atherosclerosis or inflammatory bowel disease; cancers; cardiovascular pathology and respiratory diseases. This Special Issue of the International Journal of Molecular Sciences, “Integrins and Human Pathologies”, will focus on the role of integrins in human pathologies. Authors are invited to submit manuscripts that study or review the role of these adhesion molecules in one of these human pathologies and that underline which integrins can be targeted in order to improve treatment of these diseases.

Prof. Dr. Anthony Lemarié
Dr. Sylvie Monferran
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • integrin
  • Glanzmann thrombasthenia
  • angiogenesis
  • cardiovascular disease
  • cancer
  • Crohn’s disease
  • ulcerative disease
  • multiple sclerosis
  • inflammatory bowel disease
  • respiratory diseases
  • eosinophilic esophagitis
  • age-related macular degeneration
  • epidermolysis bullosa

Published Papers (6 papers)

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Research

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14 pages, 43146 KiB  
Article
β4 and β6 Integrin Expression Is Associated with the Subclassification and Clinicopathological Features of Intrahepatic Cholangiocarcinoma
by Yurie Soejima, Miho Takeuchi, Takumi Akashi, Motoji Sawabe and Toshio Fukusato
Int. J. Mol. Sci. 2018, 19(4), 1004; https://doi.org/10.3390/ijms19041004 - 27 Mar 2018
Cited by 11 | Viewed by 4189
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous group of cancers of the intrahepatic biliary tract. However, few studies have evaluated integrin expression according to an ICC subgroup. We immunohistochemically investigated α6β4 (β4) and αvβ6 (β6) integrin expressions in 48 ICCs, and evaluated their relationship [...] Read more.
Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous group of cancers of the intrahepatic biliary tract. However, few studies have evaluated integrin expression according to an ICC subgroup. We immunohistochemically investigated α6β4 (β4) and αvβ6 (β6) integrin expressions in 48 ICCs, and evaluated their relationship with clinical and pathological parameters and ligand expression, as well as transforming growth factor (TGF)-β1. β4 and β6 expressions were detected in 46 (96%) and 35 (73%) ICC cases, respectively. We classified ICC into negative, low (β4, 29 cases; β6, 36 cases), or high (β4, 19 cases; β6, 12 cases) integrin expression groups. β4 and β6 integrin levels were higher in the non-peripheral central localization type ICC than in the peripheral localization type; they were also higher in the periductal-infiltrating or intraductal-growth types than in the mass-forming type ICC; lastly, they were higher in the well-differentiated type than in the poorly-differentiated type ICC. High expression was related to bile duct invasion. In addition, β4 and β6 expressions were associated with mucin production and the expression of cytoplasmic epithelial membrane antigen, laminin-5, and tenascin-C. TGF-β1 was correlated with β6 expression and poor overall survival. These results suggest that integrin expression is associated with subclassification and clinicopathological features of ICC through the coincident expression of their ligands and TGF-β1. Full article
(This article belongs to the Special Issue Integrins and Human Pathologies)
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15 pages, 2324 KiB  
Article
Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo
by Mohan Nair, Juan Romero, Aria Mahtabfar, Ahmed M. Meleis, Ramsey A. Foty and Siobhan A. Corbett
Int. J. Mol. Sci. 2018, 19(2), 572; https://doi.org/10.3390/ijms19020572 - 14 Feb 2018
Cited by 6 | Viewed by 3538
Abstract
Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor–related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. [...] Read more.
Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor–related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. It does so by triggering α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV). How Dex specifically activates α5 integrin in these GBM lines is unknown. Several chaperone proteins are known to activate integrins, including calreticulin (CALR). We explore the role of CALR as a potential mediator of Dex-dependent induction of α5 integrin activity in primary human GBM cells. We use CALR knock-down and knock-in strategies to explore the effects on FNMA, aggregate compaction, and dispersal velocity in vitro, as well as dispersal ex vivo on extirpated mouse retina and brain slices. We show that Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated FNMA. Overexpression of CALR in GBM cells activates FNMA, increases compaction, and decreases DV in vitro and on explants of mouse retina and brain slices. Our results define a novel interaction between Dex, CALR, and FNMA as inhibitors of GBM dispersal. Full article
(This article belongs to the Special Issue Integrins and Human Pathologies)
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5371 KiB  
Article
Combination Therapy of PEG-HM-3 and Methotrexate Retards Adjuvant-Induced Arthritis
by Jingchao Hao, Xiaodong Wu, Sarra Setrerrahmane, Kun Qian, Yueying Hou, Liting Yu, Chenyu Lin, Qianqian Wu and Hanmei Xu
Int. J. Mol. Sci. 2017, 18(7), 1538; https://doi.org/10.3390/ijms18071538 - 21 Jul 2017
Cited by 9 | Viewed by 5721
Abstract
At present, the early phenomenon of inflammatory angiogenesis is rarely studied in Rheumatoid arthritis (RA). Previous research found that PEG-HM-3, an integrin inhibitor, possessed anti-angiogenesis and anti-rheumatic activity. In this study, the advantages of inhibiting angiogenesis and immune cell adhesion and migration, as [...] Read more.
At present, the early phenomenon of inflammatory angiogenesis is rarely studied in Rheumatoid arthritis (RA). Previous research found that PEG-HM-3, an integrin inhibitor, possessed anti-angiogenesis and anti-rheumatic activity. In this study, the advantages of inhibiting angiogenesis and immune cell adhesion and migration, as well as the benefits of anti-arthritis effects, were evaluated using a combination of PEG-HM-3 and methotrexate (MTX). In vitro, spleen cell proliferation and the levels of tumor necrosis factor α (TNF-α) in macrophage supernatant were assessed. Hind paw edema, arthritis index, clinical score, body weight and immunohistochemistry (IHC) of the spleen, thymus, and joint cavity were evaluated in vivo in adjuvant-induced arthritis rats. Joints of the left hind paws were imaged by X-ray. The expression of the toll-like receptor 4 (TLR-4) protein was assessed in lipopolysaccharide (LPS)-induced synoviocytes. PEG-HM-3 combined with MTX significantly reduced primary and secondary swelling of the hind paws, the arthritis index, the clinical score and bone erosion. The results of IHC showed that the levels of interleukin-6 (IL-6) in spleens and the levels of TNF-α, CD31 (cluster of differentiation 31), and CD105 in the joint cavity were decreased. The body weight of rats was maintained during combination therapy. Ankle cavity integrity, and bone erosion and deformity were improved in combination treatment. The expression of TLR-4 was significantly reduced with combination treatment in rat synoviocytes. Co-suppression of both inflammation and angiogenesis in arthritis was achieved in this design with combination therapy. The activity of nuclear transcription factor (NF-κB) and the expression of inflammatory factors were down regulated via integrin αvβ3 and TLR-4 signaling pathways. In the future, the application of this combination can be a candidate in early and mid-term RA therapy. Full article
(This article belongs to the Special Issue Integrins and Human Pathologies)
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Review

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24 pages, 10960 KiB  
Review
Multifaced Roles of the αvβ3 Integrin in Ehlers–Danlos and Arterial Tortuosity Syndromes’ Dermal Fibroblasts
by Nicoletta Zoppi, Nicola Chiarelli, Marco Ritelli and Marina Colombi
Int. J. Mol. Sci. 2018, 19(4), 982; https://doi.org/10.3390/ijms19040982 - 26 Mar 2018
Cited by 26 | Viewed by 7419
Abstract
The αvβ3 integrin, an endothelial cells’ receptor-binding fibronectin (FN) in the extracellular matrix (ECM) of blood vessels, regulates ECM remodeling during migration, invasion, angiogenesis, wound healing and inflammation, and is also involved in the epithelial mesenchymal transition. In vitro-grown human control fibroblasts organize [...] Read more.
The αvβ3 integrin, an endothelial cells’ receptor-binding fibronectin (FN) in the extracellular matrix (ECM) of blood vessels, regulates ECM remodeling during migration, invasion, angiogenesis, wound healing and inflammation, and is also involved in the epithelial mesenchymal transition. In vitro-grown human control fibroblasts organize a fibrillar network of FN, which is preferentially bound on the entire cell surface to its canonical α5β1 integrin receptor, whereas the αvβ3 integrin is present only in rare patches in focal contacts. We report on the preferential recruitment of the αvβ3 integrin, due to the lack of FN–ECM and its canonical integrin receptor, in dermal fibroblasts from Ehlers–Danlos syndromes (EDS) and arterial tortuosity syndrome (ATS), which are rare multisystem connective tissue disorders. We review our previous findings that unraveled different biological mechanisms elicited by the αvβ3 integrin in fibroblasts derived from patients affected with classical (cEDS), vascular (vEDS), hypermobile EDS (hEDS), hypermobility spectrum disorders (HSD), and ATS. In cEDS and vEDS, respectively, due to defective type V and type III collagens, αvβ3 rescues patients’ fibroblasts from anoikis through a paxillin-p60Src-mediated cross-talk with the EGF receptor. In hEDS and HSD, without a defined molecular basis, the αvβ3 integrin transduces to the ILK-Snail1-axis inducing a fibroblast-to-myofibroblast-transition. In ATS cells, the deficiency of the dehydroascorbic acid transporter GLUT10 leads to redox imbalance, ECM disarray together with the activation of a non-canonical αvβ3 integrin-TGFBRII signaling, involving p125FAK/p60Src/p38MAPK. The characterization of these different biological functions triggered by αvβ3 provides insights into the multifaced nature of this integrin, at least in cultured dermal fibroblasts, offering future perspectives for research in this field. Full article
(This article belongs to the Special Issue Integrins and Human Pathologies)
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17 pages, 2421 KiB  
Review
Integrins in T Cell Physiology
by Alessandra Bertoni, Oscar Alabiso, Alessandra Silvia Galetto and Gianluca Baldanzi
Int. J. Mol. Sci. 2018, 19(2), 485; https://doi.org/10.3390/ijms19020485 - 06 Feb 2018
Cited by 53 | Viewed by 6706
Abstract
From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (αLβ2 integrin) and VLA-4 (α4β1 integrin) play a key role throughout the T [...] Read more.
From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (αLβ2 integrin) and VLA-4 (α4β1 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of α4β7 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research. Full article
(This article belongs to the Special Issue Integrins and Human Pathologies)
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17 pages, 645 KiB  
Review
The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia
by Silje Johansen, Annette K. Brenner, Sushma Bartaula-Brevik, Håkon Reikvam and Øystein Bruserud
Int. J. Mol. Sci. 2018, 19(1), 251; https://doi.org/10.3390/ijms19010251 - 15 Jan 2018
Cited by 35 | Viewed by 5633
Abstract
Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α [...] Read more.
Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two β3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and β3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, β3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The β3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased β3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of β2 integrins. Finally, high integrin αV/β3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of β3 integrins for leukemogenesis and chemosensitivity in AML. Full article
(This article belongs to the Special Issue Integrins and Human Pathologies)
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