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Cancers
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Integrins in Cancer
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Integrins in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2017) | Viewed by 155755

Special Issue Editor

Dr. Helen M. Sheldrake

E-Mail Website
Guest Editor
Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
Interests: integrin-targeted therapeutics; multi-integrin targeting; combination therapies in chemoresistance; cyclobutanes; biologically active natural product synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The integrin family of cell adhesion receptors have been shown to play fundamental roles in cell growth, differentiation, motility, and survival. Changes in the expression and activation of integrins are commonly observed in cancers and promote tumour growth, neoangiogenesis, and metastatic dissemination. More recently, the involvement of integrins has been established in site specific metastasis, cancer stem cells, drug resistance via signalling pathways such as β3-KRAS-RalB-NF-κB, β1-Src-Akt and the osteopontin signalling axis, and contributing to tumour immune evasion through activation of TGF-β.

Antibody and small molecule integrin antagonists have been successfully developed for use in acute coronary syndromes (targeting αIIbβ3), multiple sclerosis and inflammatory bowel disease (targeting α4β1/α4β7), however the development of integrin-targeted anticancer agents has proved more challenging. Drugs such as Cilengitide (targeting αvβ3/αvβ5) showed promising preclinical results but did not deliver survival benefits in the clinic.

Developing understanding of the complexity of integrin function, structural requirements for pure antagonism or agonism, and the contribution of multiple integrin receptors and receptor tyrosine kinases to intracellular signalling pathways will support the development of the next generation of integrin targeted agents and multi-targeting strategies to effectively control tumour progression. Research on less investigated integrins, including αvβ6, αvβ8, and α8β1, should yield new diagnostic and therapeutic modalities in emerging areas such as immuno-oncology, and areas of unmet clinical need. This Special Issue will highlight the current state of the art in integrin biology, integrin targeting, and future prospects for improving therapies.

Dr. Helen M Sheldrake
Guest Editor

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • Tumour-microenvironment interaction
  • metastasis
  • cell adhesion mediated drug resistance
  • targeted therapy
  • TGF-β1
  • αv

Published Papers (19 papers)

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Research

Jump to: Review

15 pages, 2197 KiB  
Article
MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells
by Jean-François Groulx, Salah Boudjadi and Jean-François Beaulieu
Cancers 2018, 10(2), 42; https://doi.org/10.3390/cancers10020042 - 03 Feb 2018
Cited by 22 | Viewed by 4933
Abstract
The α6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and β4 integrin subunit (ITGB4) subunits of the α6β4 integrin are increased. [...] Read more.
The α6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and β4 integrin subunit (ITGB4) subunits of the α6β4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro-proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A variant over ITGA6B in colorectal cancer cells remain poorly understood. Here, we show that the promoter activity of the ITGA6 gene is regulated by MYC. Pharmacological inhibition of MYC activity with the MYC inhibitor (MYCi) 10058-F4 or knockdown of MYC expression by short hairpin RNA (shRNA) both lead to a decrease in ITGA6 and ITGA6A levels in colorectal cancer cells, while overexpression of MYC enhances ITGA6 promoter activity. We also found that MYC inhibition decreases the epithelial splicing regulatory protein 2 (ESRP2) splicing factor at both the mRNA and protein levels. Chromatin immunoprecipitation revealed that the proximal promoter sequences of ITGA6 and ESRP2 were occupied by MYC and actively transcribed in colorectal cancer cells. Furthermore, expression studies in primary colorectal tumors and corresponding resection margins confirmed that the up-regulation of the ITGA6A subunit can be correlated with the increase in MYC and ESRP2. Taken together, our results demonstrate that the proto-oncogene MYC can regulate the promoter activation and splicing of the ITGA6 integrin gene through ESRP2 to favor the production of the pro-proliferative ITGA6A variant in colorectal cancer cells. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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1356 KiB  
Article
Investigating the Interaction of Cyclic RGD Peptidomimetics with αVβ6 Integrin by Biochemical and Molecular Docking Studies
by Monica Civera, Daniela Arosio, Francesca Bonato, Leonardo Manzoni, Luca Pignataro, Simone Zanella, Cesare Gennari, Umberto Piarulli and Laura Belvisi
Cancers 2017, 9(10), 128; https://doi.org/10.3390/cancers9100128 - 21 Sep 2017
Cited by 17 | Viewed by 6507
Abstract
The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with αVβ6 integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the αV [...] Read more.
The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with αVβ6 integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the αVβ6 binding site. To this aim, a rigid receptor-flexible ligand docking protocol has been set up and then applied to predict the binding mode of the cyclic RGD peptidomimetics to αVβ6 integrin. Although the RGD interaction with αVβ6 recapitulates the RGD binding mode observed in αVβ3, differences between the integrin binding pockets can strongly affect the ligand binding ability. In general, the peptidomimetics exhibited IC50 values for integrin αVβ6 (i.e., the concentration of compound required for 50% inhibition of biotinylated fibronectin binding to isolated αVβ6 integrin) in the nanomolar range (77–345 nM), about 10–100 times higher than those for the related αVβ3 receptor, with a single notable ligand displaying a low nanomolar IC50 value (2.3 nM). Insights from the properties of the binding pocket combined with the analysis of the docking poses provided a rationale for ligand recognition and selectivity. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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3688 KiB  
Article
Integrin Activation Contributes to Lower Cisplatin Sensitivity in MV3 Melanoma Cells by Inducing the Wnt Signalling Pathway
by Maria B. R. Piva, Bastian Jakubzig and Gerd Bendas
Cancers 2017, 9(9), 125; https://doi.org/10.3390/cancers9090125 - 16 Sep 2017
Cited by 13 | Viewed by 7007
Abstract
Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we [...] Read more.
Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we detected the loss in cisplatin sensitivity of human MV3 melanoma cells upon integrin activation. Underlying cellular pathways were evaluated by flow cytometry. A crosstalk between integrin activation and the canonical wnt signalling pathway was tested by measuring β-catenin activity. Results: MV3 cells display a higher resistance against cisplatin cytotoxicity when cellular integrins were activated by manganese or collagen. Proteome profiler array showed a deregulation of the integrin expression pattern by cisplatin. Integrin activation by manganese induces the phosphorylation of PI3K/AKT. The inhibition of PI3K using BEZ235 strongly increases cell sensitivity to cisplatin, blocking manganese and collagen effects. PI3K/AKT activates wnt signalling by blocking Gsk3-β, which was confirmed by β-catenin up-regulation and nuclear localization. Integrins did not affect E-cadherin expression levels, thus endothelial to mesenchymal transition (EMT) can be excluded. Conclusion: This is the first report on an integrin/wnt signalling activation axis addressing the consequences for chemotherapy sensitiveness of melanoma cells, which thus offers novel therapeutic targets for approaches to interfere with chemoresistance. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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2399 KiB  
Article
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL
by Etai Adam, Hye Na Kim, Eun Ji Gang, Caitlin Schnair, Solomon Lee, Solah Lee, Sajad Khazal, Osanna Kosoyan, Marina Konopleva, Chintan Parekh, Deepa Bhojwani, Alan S. Wayne, Hisham Abdel-Azim, Nora Heisterkamp and Yong-Mi Kim
Cancers 2017, 9(9), 121; https://doi.org/10.3390/cancers9090121 - 10 Sep 2017
Cited by 13 | Viewed by 5401
Abstract
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an [...] Read more.
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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1005 KiB  
Article
Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients
by Susan Cedra, Susanne Wiegand, Marlen Kolb, Andreas Dietz and Gunnar Wichmann
Cancers 2017, 9(9), 117; https://doi.org/10.3390/cancers9090117 - 05 Sep 2017
Cited by 6 | Viewed by 4322
Abstract
Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial [...] Read more.
Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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4970 KiB  
Article
Involvement of the Integrin α1β1 in the Progression of Colorectal Cancer
by Salah Boudjadi, Gérald Bernatchez, Blanche Sénicourt, Marco Beauséjour, Pierre H. Vachon, Julie C. Carrier and Jean-François Beaulieu
Cancers 2017, 9(8), 96; https://doi.org/10.3390/cancers9080096 - 26 Jul 2017
Cited by 31 | Viewed by 5789
Abstract
Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling that participate in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in RAS/ERK proliferative pathway activation and plays an important role [...] Read more.
Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling that participate in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in RAS/ERK proliferative pathway activation and plays an important role in fibroblast proliferation. In the small intestine, the integrin α1 subunit is present in the crypt proliferative compartment and absent in the villus. We have recently shown that the integrin α1 protein and transcript (ITGA1) are present in a large proportion of colorectal cancers (CRC) and that their expression is controlled by the MYC oncogenic factor. Considering that α1 subunit/ITGA1 expression is correlated with MYC in more than 70% of colon adenocarcinomas, we postulated that the integrin α1β1 has a pro-tumoral contribution to CRC. In HT29, T84 and SW480 CRC cells, α1 subunit/ITGA1 knockdown resulted in a reduction of cell proliferation associated with an impaired resistance to anoikis and an altered cell migration in HT29 and T84 cells. Moreover, tumor development in xenografts was reduced in HT29 and T84 sh-ITGA1 cells, associated with extensive necrosis, a low mitotic index and a reduced number of blood vessels. Our results show that α1β1 is involved in tumor cell proliferation, survival and migration. This finding suggests that α1β1 contributes to CRC progression. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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Review

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11 pages, 429 KiB  
Review
Integrin Inhibitors in Prostate Cancer
by Maylein C. Juan-Rivera and Magaly Martínez-Ferrer
Cancers 2018, 10(2), 44; https://doi.org/10.3390/cancers10020044 - 06 Feb 2018
Cited by 40 | Viewed by 6233
Abstract
Prostate cancer (PCa) is the most frequently diagnosed cancer and the third highest cause of cancer-related deaths in men in the U.S. The development of chemotherapeutic agents that can bind PCa tumor cells with high specificity is critical in order to increase treatment [...] Read more.
Prostate cancer (PCa) is the most frequently diagnosed cancer and the third highest cause of cancer-related deaths in men in the U.S. The development of chemotherapeutic agents that can bind PCa tumor cells with high specificity is critical in order to increase treatment effectiveness. Integrin receptors and their corresponding ligands have different expression patterns in PCa cells. They have been identified as promising targets to inhibit pathways involved in PCa progression. Currently, several compounds have proven to target specific integrins and their subunits in PCa cells. In this article, we review the role of integrins inhibitors in PCa and their potential as therapeutic targets for PCa treatments. We have discussed the following: natural compounds, monoclonal antibodies, statins, campothecins analog, aptamers, d-aminoacid, and snake venom. Recent studies have shown that their mechanisms of action result in decrease cell migration, cell invasion, cell proliferation, and metastasis of PCa cells. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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263 KiB  
Review
Role of LFA-1 and ICAM-1 in Cancer
by Manuel Reina and Enric Espel
Cancers 2017, 9(11), 153; https://doi.org/10.3390/cancers9110153 - 03 Nov 2017
Cited by 92 | Viewed by 8794
Abstract
The lymphocyte function-associated antigen-1 (LFA-1) (also known as CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance is derived from its exclusive presence in leukocytes. In this review, we summarize the studies [...] Read more.
The lymphocyte function-associated antigen-1 (LFA-1) (also known as CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance is derived from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (or CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. We also offer a more detailed examination of the role of LFA-1 within B-cell chronic lymphocytic leukemia. Finally, we discuss the role that exosomes harboring LFA-1 play in tumor growth and metastasis. Full article
(This article belongs to the Special Issue Integrins in Cancer)
849 KiB  
Review
Platelet Integrins in Tumor Metastasis: Do They Represent a Therapeutic Target?
by Marion Lavergne, Emily Janus-Bell, Mathieu Schaff, Christian Gachet and Pierre H. Mangin
Cancers 2017, 9(10), 133; https://doi.org/10.3390/cancers9100133 - 28 Sep 2017
Cited by 61 | Viewed by 7961
Abstract
Platelets are small anucleated cell fragments that ensure the arrest of bleeding after a vessel wall injury. They are also involved in non-hemostatic function such as development, immunity, inflammation, and in the hematogeneous phase of metastasis. While the role of platelets in tumor [...] Read more.
Platelets are small anucleated cell fragments that ensure the arrest of bleeding after a vessel wall injury. They are also involved in non-hemostatic function such as development, immunity, inflammation, and in the hematogeneous phase of metastasis. While the role of platelets in tumor metastasis has been recognized for 60 years, the molecular mechanism underlying this process remains largely unclear. Platelets physically and functionally interact with various tumor cells through surface receptors including integrins. Platelets express five integrins at their surface, namely α2β1, α5β1, α6β1, αvβ3, and αIIbβ3, which bind preferentially to collagen, fibronectin, laminin, vitronectin, and fibrinogen, respectively. The main role of platelet integrins is to ensure platelet adhesion and aggregation at sites of vascular injury. Two of these, α6β1 and αIIbβ3, were proposed to participate in platelet–tumor cell interaction and in tumor metastasis. It has also been reported that pharmacological agents targeting both integrins efficiently reduce experimental metastasis, suggesting that platelet integrins may represent new anti-metastatic targets. This review focuses on the role of platelet integrins in tumor metastasis and discusses whether these receptors may represent new potential targets for novel anti-metastatic approaches. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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2843 KiB  
Review
Exploring the Role of RGD-Recognizing Integrins in Cancer
by Markus Nieberler, Ute Reuning, Florian Reichart, Johannes Notni, Hans-Jürgen Wester, Markus Schwaiger, Michael Weinmüller, Andreas Räder, Katja Steiger and Horst Kessler
Cancers 2017, 9(9), 116; https://doi.org/10.3390/cancers9090116 - 04 Sep 2017
Cited by 304 | Viewed by 23020
Abstract
Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression [...] Read more.
Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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760 KiB  
Review
Integrins as Therapeutic Targets: Successes and Cancers
by Sabine Raab-Westphal, John F. Marshall and Simon L. Goodman
Cancers 2017, 9(9), 110; https://doi.org/10.3390/cancers9090110 - 23 Aug 2017
Cited by 165 | Viewed by 15572
Abstract
Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some [...] Read more.
Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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212 KiB  
Review
Integrins and Exosomes, a Dangerous Liaison in Cancer Progression
by Mayra Paolillo and Sergio Schinelli
Cancers 2017, 9(8), 95; https://doi.org/10.3390/cancers9080095 - 26 Jul 2017
Cited by 87 | Viewed by 7001
Abstract
Integrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis. Interestingly, emerging data continue to uncover new roles [...] Read more.
Integrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis. Interestingly, emerging data continue to uncover new roles for integrins in cancer-relevant pathways, particularly concerning the regulation of immune cell activity in the tumor niche, like myeloid cell differentiation and function and, very recently, the regulation of metastatic processes by exosomes. Exosomes are deeply involved in cell-cell communication processes and several studies have shown that integrins found in tumor-associated exosomes can promote cancer progression by two novel cooperative mechanisms: horizontal transfer of integrin transcripts as vescicle cargo, and selection of target tissues to form new tumor niches during metastatic spread by integrins carried on the exosome’s surface. In this review we will discuss mounting evidence that contribute to the development of a new picture for integrins in cancer, highlighting the role of integrins in the processes that leads to tumor niche formation. In particular, the role of the periostin pathway in the recruitment of tumor-associated macrophages, and the proposed contribution of exosome-derived integrins in the metastatic spread will be discussed. Finally, in light of the above considerations, an evaluation of integrins as possible therapeutic targets will be conducted. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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603 KiB  
Review
Integrin αvβ3 Signaling in Tumor-Induced Bone Disease
by Kristin A. Kwakwa and Julie A. Sterling
Cancers 2017, 9(7), 84; https://doi.org/10.3390/cancers9070084 - 08 Jul 2017
Cited by 44 | Viewed by 8797
Abstract
Tumor-induced bone disease is common among patients with advanced solid cancers, especially those with breast, prostate, and lung malignancies. The tendency of these cancers to metastasize to bone and induce bone destruction is, in part, due to alterations in integrin expression and signaling. [...] Read more.
Tumor-induced bone disease is common among patients with advanced solid cancers, especially those with breast, prostate, and lung malignancies. The tendency of these cancers to metastasize to bone and induce bone destruction is, in part, due to alterations in integrin expression and signaling. Substantial evidence from preclinical studies shows that increased expression of integrin αvβ3 in tumor cells promotes the metastatic and bone-invasive phenotype. Integrin αvβ3 mediates cell adhesion to several extracellular matrix proteins in the bone microenvironment which is necessary for tumor cell colonization as well as the transmission of mechanical signals for tumor progression. This review will discuss the αvβ3 integrin receptor in the context of tumor-induced bone disease. Specifically, the focus will be the role of αvβ3 in modulating cancer metastasis to bone and tumor cell response to the bone microenvironment, including downstream signaling pathways that contribute to tumor-induced osteolysis. A better understanding of integrin dysregulation in cancer is critical to developing new therapeutics for the prevention and treatment of bone metastases. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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897 KiB  
Review
Potential of Integrin Inhibitors for Treating Ovarian Cancer: A Literature Review
by Masaki Kobayashi, Kenjiro Sawada and Tadashi Kimura
Cancers 2017, 9(7), 83; https://doi.org/10.3390/cancers9070083 - 08 Jul 2017
Cited by 39 | Viewed by 7222
Abstract
Epithelial ovarian cancer is a fatal disease, with a cure rate of only 30%. Several recent studies have targeted integrins for cancer treatment. Preclinical studies have shown the effectiveness of several integrin inhibitors for blocking cancer progression, especially by blocking angiogenesis. Because the [...] Read more.
Epithelial ovarian cancer is a fatal disease, with a cure rate of only 30%. Several recent studies have targeted integrins for cancer treatment. Preclinical studies have shown the effectiveness of several integrin inhibitors for blocking cancer progression, especially by blocking angiogenesis. Because the initial critical step in ovarian cancer metastasis is the attachment of cancer cells to the peritoneum or omentum and because clinical trials have provided positive results for anti-angiogenic therapy, therapies targeting integrins may be the most feasible approach for treating cancer. This review summarizes the current understanding of integrin biology in ovarian cancer metastasis and various therapeutic approaches involving integrin inhibitors. However, no integrin inhibitor has shown favorable results thus far. However, conjugates of cytotoxic agents with the triplet sequence arginine-glycine-aspartate (RGD) peptides targeting α5β1-, αvβ3-, and αvβ6-integrins may be promising integrin-targeting therapies for further clinical investigation. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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820 KiB  
Review
Inside the Cell: Integrins as New Governors of Nuclear Alterations?
by Elena Madrazo, Andrea Cordero Conde and Javier Redondo-Muñoz
Cancers 2017, 9(7), 82; https://doi.org/10.3390/cancers9070082 - 06 Jul 2017
Cited by 23 | Viewed by 6589
Abstract
Cancer cell migration is a complex process that requires coordinated structural changes and signals in multiple cellular compartments. The nucleus is the biggest and stiffest organelle of the cell and might alter its physical properties to allow cancer cell movement. Integrins are transmembrane [...] Read more.
Cancer cell migration is a complex process that requires coordinated structural changes and signals in multiple cellular compartments. The nucleus is the biggest and stiffest organelle of the cell and might alter its physical properties to allow cancer cell movement. Integrins are transmembrane receptors that mediate cell-cell and cell-extracellular matrix interactions, which regulate numerous intracellular signals and biological functions under physiological conditions. Moreover, integrins orchestrate changes in tumor cells and their microenvironment that lead to cancer growth, survival and invasiveness. Most of the research efforts have focused on targeting integrin-mediated adhesion and signaling. Recent exciting data suggest the crucial role of integrins in controlling internal cellular structures and nuclear alterations during cancer cell migration. Here we review the emerging role of integrins in nuclear biology. We highlight increasing evidence that integrins are critical for changes in multiple nuclear components, the positioning of the nucleus and its mechanical properties during cancer cell migration. Finally, we discuss how integrins are integral proteins linking the plasma membrane and the nucleus, and how they control cell migration to enable cancer invasion and infiltration. The functional connections between these cell receptors and the nucleus will serve to define new attractive therapeutic targets. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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1296 KiB  
Review
Roles of Integrin α6β4 Glycosylation in Cancer
by Yoshinobu Kariya, Yukiko Kariya and Jianguo Gu
Cancers 2017, 9(7), 79; https://doi.org/10.3390/cancers9070079 - 05 Jul 2017
Cited by 30 | Viewed by 7163
Abstract
Malignant transformation is accompanied with aberrant glycosylation of proteins. Such changes in glycan structure also occur in the integrins, which are a large family of cell surface receptors for the extracellular matrix and play key roles in tumor progression. There is now increasing [...] Read more.
Malignant transformation is accompanied with aberrant glycosylation of proteins. Such changes in glycan structure also occur in the integrins, which are a large family of cell surface receptors for the extracellular matrix and play key roles in tumor progression. There is now increasing evidence that glycosylation of integrins affects cellular signaling and interaction with the extracellular matrix, receptor tyrosine kinases, and galectins, thereby regulating cell adhesion, motility, growth, and survival. Integrin α6β4 is a receptor for laminin-332 and the increased expression level is correlated with malignant progression and poor survival in various types of cancers. Recent studies have revealed that integrin α6β4 plays central roles in tumorigenesis and the metastatic process. In this review, we summarize our current understanding of the molecular mechanisms of tumor progression driven by integrin α6β4 and also discuss the modification of glycans on integrin β4 subunit to address the important roles of glycan in integrin-mediated tumor progression. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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Review
Can Integrin Agonists Have Cards to Play against Cancer? A Literature Survey of Small Molecules Integrin Activators
by Alessandra Tolomelli, Paola Galletti, Monica Baiula and Daria Giacomini
Cancers 2017, 9(7), 78; https://doi.org/10.3390/cancers9070078 - 05 Jul 2017
Cited by 32 | Viewed by 8656
Abstract
The ability of integrins to activate and integrate intracellular communication illustrates the potential of these receptors to serve as functional distribution hubs in a bi-directional signal transfer outside-in and inside-out of the cells. Tight regulation of the integrin signaling is paramount for normal [...] Read more.
The ability of integrins to activate and integrate intracellular communication illustrates the potential of these receptors to serve as functional distribution hubs in a bi-directional signal transfer outside-in and inside-out of the cells. Tight regulation of the integrin signaling is paramount for normal physiological functions such as migration, proliferation, and differentiation, and misregulated integrin activity could be associated with several pathological conditions. Because of the important roles of integrins and their ligands in biological development, immune responses, leukocyte traffic, haemostasis, and cancer, their potential as therapeutic tools is now widely recognized. Nowadays extensive efforts have been made to discover and develop small molecule ligands as integrin antagonists, whereas less attention has been payed to agonists. In recent years, it has been recognized that integrin agonists could open up novel opportunities for therapeutics, which gain benefits to increase rather than decrease integrin-dependent adhesion and transductional events. For instance, a significant factor in chemo-resistance in melanoma is a loss of integrin-mediated adhesion; in this case, stimulation of integrin signaling by agonists significantly improved the response to chemotherapy. In this review, we overview results about small molecules which revealed an activating action on some integrins, especially those involved in cancer, and examine from a medicinal chemistry point of view, their structure and behavior. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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Review
RGD-Binding Integrins in Head and Neck Cancers
by Hanadi Talal Ahmedah, Laurence H. Patterson, Steven D. Shnyder and Helen M. Sheldrake
Cancers 2017, 9(6), 56; https://doi.org/10.3390/cancers9060056 - 26 May 2017
Cited by 27 | Viewed by 6254
Abstract
Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and β1 subunits has been [...] Read more.
Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and β1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors αvβ3 and αvβ5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as αvβ6, αvβ8, and β1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the arginine-glycine-aspartate (RGD)-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour-specific identification and therapy. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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Review
NG2 Proteoglycan Enhances Brain Tumor Progression by Promoting Beta-1 Integrin Activation in both Cis and Trans Orientations
by William B. Stallcup
Cancers 2017, 9(4), 31; https://doi.org/10.3390/cancers9040031 - 31 Mar 2017
Cited by 26 | Viewed by 6433
Abstract
By physically interacting with beta-1 integrins, the NG2 proteoglycan enhances activation of the integrin heterodimers. In glioma cells, co-localization of NG2 and 31 integrin in individual cells (cis interaction) can be demonstrated by immunolabeling, and the NG2-integrin interaction can be confirmed by co-immunoprecipitation. [...] Read more.
By physically interacting with beta-1 integrins, the NG2 proteoglycan enhances activation of the integrin heterodimers. In glioma cells, co-localization of NG2 and 31 integrin in individual cells (cis interaction) can be demonstrated by immunolabeling, and the NG2-integrin interaction can be confirmed by co-immunoprecipitation. NG2-dependent integrin activation is detected via use of conformationally sensitive monoclonal antibodies that reveal the activated state of the beta-1 subunit in NG2-positive versus NG2-negative cells. NG2-dependent activation of beta-1 integrins triggers downstream activation of FAK and PI3K/Akt signaling, resulting in increased glioma cell proliferation, motility, and survival. Similar NG2-dependent cis activation of beta-1 integrins occurs in microvascular pericytes, leading to enhanced proliferation and motility of these vascular cells. Surprisingly, pericyte NG2 is also able to promote beta-1 integrin activation in closely apposed endothelial cells (trans interaction). Enhanced beta-1 signaling in endothelial cells promotes endothelial maturation by inducing the formation of endothelial junctions, resulting in increased barrier function of the endothelium and increased basal lamina assembly. NG2-dependent beta-1 integrin signaling is therefore important for tumor progression by virtue of its affects not only on the tumor cells themselves, but also on the maturation and function of tumor blood vessels. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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