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Nature Reviews. Cancer Jan 2010The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours.... (Review)
Review
The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.
Topics: Animals; Apoptosis; Clinical Trials as Topic; Humans; Integrins; Neoplasms; Signal Transduction
PubMed: 20029421
DOI: 10.1038/nrc2748 -
Journal of Neuroinflammation Apr 2022Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that...
BACKGROUND
Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVβ5/AMPK pathway after ICH.
METHODS
Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVβ5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function.
RESULTS
Endogenous irisin and its receptor, integrin αVβ5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVβ5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVβ5, p-AMPK and Bcl-2, and decreased the expression of IL-1β, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVβ5 inhibitor cilengitide and AMPK inhibitor dorsomorphin.
CONCLUSIONS
This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVβ5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Brain Edema; Cerebral Hemorrhage; Fibronectins; Male; Mice; Mice, Inbred C57BL; Neuroinflammatory Diseases; Neuroprotective Agents; Receptors, Vitronectin; Signal Transduction
PubMed: 35392928
DOI: 10.1186/s12974-022-02438-6 -
Cell Aug 2020Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We...
Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.
Topics: Animals; Cicatrix; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Collagen Type V; Extracellular Matrix; Female; Fibrosis; Gene Expression Regulation; Heart Injuries; Integrins; Isoproterenol; Male; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Atomic Force; Microscopy, Electron, Transmission; Myocardial Contraction; Myofibroblasts; Principal Component Analysis; Proteomics; RNA-Seq; Single-Cell Analysis
PubMed: 32621799
DOI: 10.1016/j.cell.2020.06.030 -
Journal of Experimental & Clinical... Jun 2021Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms.
METHODS
Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-β1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133 cell sorting.
RESULTS
The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133 LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvβ3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFβ1 from the extracellular matrix and initiated POSTN/TGFβ1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model.
CONCLUSIONS
The POSTN/TGFβ1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.
Topics: Adult; Animals; Carcinoma, Hepatocellular; Cell Adhesion Molecules; Cell Proliferation; Disease Models, Animal; Feedback, Physiological; Heterografts; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplastic Stem Cells; Transcription Factor AP-2; Transforming Growth Factor beta1
PubMed: 34193219
DOI: 10.1186/s13046-021-02011-8 -
International Journal of Biological... 2020: Integrin β3 is one of the main integrin heterodimer receptors on the surface of cardiac myocytes. Our previous studies showed that hypoxia induces apoptosis and...
: Integrin β3 is one of the main integrin heterodimer receptors on the surface of cardiac myocytes. Our previous studies showed that hypoxia induces apoptosis and increases integrin β3 expression in cardiomyocytes. However, the exact mechanism by which integrin β3 protects against apoptosis remains unclear. Hence, the present investigation aimed to explore the mechanism of integrin β3 in cardiomyocyte proliferation and hypoxia-induced cardiomyocyte apoptosis. : Stable cells and acute and chronic heart failure rat models were generated to reveal the essential role of integrin β3 in cardiomyocyte proliferation and apoptosis. Western blotting and immunohistochemistry were employed to detect the expression of integrin β3 in the stable cells and rat cardiac tissue. Flow cytometer was used to investigate the role of integrin β3 in hypoxia-induced cardiomyocyte apoptosis. Confocal microscopy was used to detect the localization of integrin β3 and integrin αv in cardiomyocytes. : A cobaltous chloride-induced hypoxic microenvironment stimulated cardiomyocyte apoptosis and increased integrin β3 expression in H9C2 cells, AC16 cells, and cardiac tissue from acute and chronic heart failure rats. The overexpression of integrin β3 promoted cardiomyocyte proliferation, whereas silencing integrin β3 expression resulted in decreased cell proliferation . Furthermore, knocking down integrin β3 expression using shRNA or the integrin β3 inhibitor cilengitide exacerbated cobaltous chloride-induced cardiomyocyte apoptosis, whereas overexpression of integrin β3 weakened cobaltous chloride-induced cardiomyocytes apoptosis. We found that integrin β3 promoted cardiomyocytes proliferation through the regulation of the PTEN/Akt/mTOR and ERK1/2 signaling pathways. In addition, we found that knockdown of integrin αv or integrin β1 weakened the effect of integrin β3 in cardiomyocyte proliferation. : Our findings revealed the molecular mechanism of the role of integrin β3 in cardiomyocyte proliferation and hypoxia-induced cardiomyocyte apoptosis, providing new insights into the mechanisms underlying myocardial protection.
Topics: Animals; Apoptosis; Blotting, Western; Cell Line; Cell Proliferation; Cells, Cultured; Cobalt; Immunohistochemistry; Integrin beta3; MAP Kinase Signaling System; Male; Myocytes, Cardiac; PTEN Phosphohydrolase; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Snake Venoms; TOR Serine-Threonine Kinases
PubMed: 32025212
DOI: 10.7150/ijbs.39414 -
Expert Opinion on Investigational Drugs Sep 2020Integrins are a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix (ECM) to actin cytoskeleton in the cell... (Review)
Review
INTRODUCTION
Integrins are a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix (ECM) to actin cytoskeleton in the cell cortex, thus regulating cellular adhesion, migration, proliferation, invasion, survival, and apoptosis. Consequently, integrins play a role in inflammation, angiogenesis and fibrosis.
AREAS COVERED
This review examines individual anti-integrin agents in terms of their chemical nature, route of administration, and anti-integrin action. It also provides a summary of preclinical and clinical studies. Current clinical candidates include risuteganib, THR-687, and SF-0166, which have shown promise in treating diabetic macular edema (DME) and/or age-related macular degeneration (AMD) in early clinical studies. Preclinical candidates include SB-267268, AXT-107, JNJ-26076713, Cilengitide and Lebecetin, which exhibit a decrease in retinal permeability, angiogenesis and/or choroidal neovascularization (CNV).
EXPERT OPINION
Anti-integrin therapies show potential in treating retinal diseases. Anti-integrin agents tackle the multi-factorial nature of diabetic retinopathy (DR) and AMD and show promise as injectable and topical agents in preclinical and early clinical studies. Integrin inhibition has potential to serve as primary therapy, adjunctive therapy to anti-vascular endothelial growth factor agents, or secondary therapy in refractory cases.
Topics: Animals; Choroidal Neovascularization; Diabetic Retinopathy; Drug Development; Humans; Integrins; Macular Degeneration; Macular Edema; Retinal Diseases
PubMed: 32657172
DOI: 10.1080/13543784.2020.1795639 -
Medecine Sciences : M/S May 2022For the last 20 years, integrins have been a therapeutic target of interest in the treatment of fibrotic diseases, particularly regarding the integrins of the αV... (Review)
Review
For the last 20 years, integrins have been a therapeutic target of interest in the treatment of fibrotic diseases, particularly regarding the integrins of the αV family. Initially developed as anti-cancer drugs but with modest benefits, inhibitors of integrins (such as the anti-αV cilengitide) have shown interesting anti-fibrotic effects in different organs including the heart. Cardiac fibrosis is defined as an accumulation of stiff extracellular matrix in the myocardium, and ultimately leads to heart failure, one of the leading causes of mortality worldwide. Understanding the determinants of cardiac fibrosis and the involvement of integrins is a major matter of public health. This review presents the current knowledge on the different types of cardiac fibrosis and their etiologies, and report on first data supporting specific integrin inhibition therapy as a novel anti-fibrotic strategy, in particular to treat cardiac fibrosis.
Topics: Extracellular Matrix; Fibrosis; Humans; Integrins; Myocardium
PubMed: 35608466
DOI: 10.1051/medsci/2022055 -
Redox Biology Feb 2024Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological...
Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.
Topics: Animals; Mice; Ferroptosis; Signal Transduction; Liver Cirrhosis; Hepatocytes; Benzofurans; Depsides
PubMed: 38184998
DOI: 10.1016/j.redox.2024.103029 -
Neurologia Medico-chirurgica 2012Malignant glioma is the most common primary brain tumor and accounts for the majority of diagnoses. Treatment has involved a combination of surgery, radiation, and... (Review)
Review
Malignant glioma is the most common primary brain tumor and accounts for the majority of diagnoses. Treatment has involved a combination of surgery, radiation, and chemotherapy, yet these modalities rarely extend the life of the patient to more than one year from diagnosis. Integrins are expressed in tumor cells and tumor endothelial cells, and are important in angiogenesis and invasion in glioma. αvβ3 and αvβ5 integrins regulate cell adhesion, and inhibitors of these integrins suppress tumor growth in certain pre-clinical models. Several integrin-targeted drugs are in clinical trials as potential compounds for the treatment of cancer. Among them, cilengitide is a novel integrin antagonist for the treatment of glioblastoma. The multimodal anti-glioma effects are based on its cytotoxic, anti-angiogenic, anti-invasive, and synergetic effects. Preclinical studies showed a promising synergy between cilengitide and radiochemotherapy in order to normalize tumor vasculature and attenuate tumor invasion. Cilengitide is currently being assessed in phase III trials for patients with glioblastoma multiforme and in phase II trials for other types of cancers, demonstrating promising therapeutic outcomes to date. The results of these and other clinical studies are expected with great hope and interest. A more clear understanding of the benefits and pitfalls of each approach can then lead to the design of strategies to derive maximal benefit from these therapies.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Integrins; Neoplasm Invasiveness; Snake Venoms
PubMed: 22976135
DOI: 10.2176/nmc.52.539 -
Cilengitide inhibits osteoclast adhesion through blocking the αβ-mediated FAK/Src signaling pathway.Heliyon Jul 2023The remodeling of actin cytoskeleton of osteoclasts on the bone matrix is essential for osteoclastic resorption activity. A specific regulator of the osteoclast...
The remodeling of actin cytoskeleton of osteoclasts on the bone matrix is essential for osteoclastic resorption activity. A specific regulator of the osteoclast cytoskeleton, integrin αβ, is known to provide a key role in the degradation of mineralized bone matrixes. Cilengitide is a potent inhibitor of integrins and is capable of affecting αβ receptors, and has anti-tumor and anti-angiogenic and apoptosis-inducing effects. However, its function on osteoclasts is not fully understood. Here, the cilengitide role on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts was explored. Cells were cultured with varying concentrations of cilengitide (0,0.002,0.2 and 20 μM) for 7 days, followed by detected Cell Counting Kit-8, staining for tartrate resistant acid phosphatase (TRAP), F-actin ring formation, bone resorption assays, adhesion assays, immunoblotting assays, and real-time fluorescent quantitative PCR. Results demonstrated that cilengitide effectively restrained the functionality and formation of osteoclasts in a concentration-dependent manner, without causing any cytotoxic effects. Mechanistically, cilengitide inhibited osteoclast-relevant genes expression; meanwhile, cilengitide downregulated the expression of key signaling molecules associated with the osteoclast cytoskeleton, including focal adhesion kinase (FAK), integrin αβ and c-Src. Therefore, this results have confirmed that cilengitide regulates osteoclast activity by blocking the integrin αβ signal pathway resulting in diminished adhesion and bone resorption of osteoclasts.
PubMed: 37539209
DOI: 10.1016/j.heliyon.2023.e17841