Inhibiting Integrin β8 to Differentiate and Radiosensitize Glioblastoma-Initiating Cells (original) (raw)
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Cancer stem cells (CSCs) are a subpopulation of tumor cells suggested to be critical for tumor maintenance, metastasis, and therapeutic resistance. Prospective identification and targeting of CSCs are therefore priorities for the development of novel therapeutic paradigms. Although CSC enrichment has been achieved with cell surface proteins including CD133 (Prominin-1), the roles of current CSC markers in tumor maintenance remain unclear. We examined the glioblastoma stem cell (GSC) perivascular microenvironment in patient specimens to identify enrichment markers with a functional significance and identified integrin a6 as a candidate. Integrin a6 is coexpressed with conventional GSC markers and enriches for GSCs. Targeting integrin a6 in GSCs inhibits self-renewal, proliferation, and tumor formation capacity. Our results provide evidence that GSCs express high levels of integrin a6, which can serve not only as an enrichment marker but also as a promising antiglioblastoma therapy.
Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma
Cell stem cell, 2017
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic ...
Expression of Integrin α6β1 Enhances Tumorigenesis in Glioma Cells
The American Journal of Pathology, 2009
The integrin ␣61 and its main ligand laminin-111 are overexpressed in glioblastoma, as compared with normal brain tissue, suggesting they may be involved in glioblastoma malignancy. To address this question, we stably expressed the ␣6 integrin subunit in the U87 cell line via retroviral-mediated gene transfer. We show that cell surface expression of the ␣61 integrin led to dramatic changes in tumor U87 cell behavior, both in vitro and in vivo. Nude mice receiving either subcutaneous or intracerebral inoculation of ␣61expressing cells developed substantially more voluminous tumors than mice injected with control cells. The difference in tumor growth was associated with a marked increase in vascularization in response to ␣61 integrin expression and may also be related to changes in the balance between cell proliferation and survival. Indeed, expression of ␣61 enhanced proliferation and decreased apoptosis of U87 cells both in the tumor and in vitro. Additionally, we demonstrate that ␣61 is implicated in glioblastoma cell migration and invasion and that laminin-111 might mediate dissemination of ␣61-positive cells in vivo. Our results highlight for the first time the considerable role of the integrin ␣61 in glioma progression. (Am J Pathol 2009, 175:844 -855;
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New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and...
Integrin control of the transforming growth factor- pathway in glioblastoma
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Transforming growth factor-b is a central mediator of the malignant phenotype of glioblastoma, the most common and malignant form of intrinsic brain tumours. Transforming growth factor-b promotes invasiveness and angiogenesis, maintains cancer cell stemness and induces profound immunosuppression in the host. Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation, differentiation and motility, and may be involved in the activation of transforming growth factor-b. We report that avb3, avb5 and avb8 integrins are broadly expressed not only in glioblastoma blood vessels but also in tumour cells. Exposure to av, b3 or b5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological integrin inhibition using the cyclic RGD peptide EMD 121974 (cilengitide) results in reduced phosphorylation of Smad2 in most glioma cell lines, including glioma-initiating cell lines and reduced transforming growth factor-b-mediated reporter gene activity, coinciding with reduced transforming growth factor-b protein levels in the supernatant. Time course experiments indicated that the loss of transforming growth factor-b bioactivity due to integrin inhibition likely results from two distinct mechanisms: an early effect on activation of preformed inactive protein, and second, major effect on transforming growth factor-b gene transcription as confirmed by decreased activity of the transforming growth factor-b gene promoter and decreased transforming growth factor-b 1 and transforming growth factor-b 2 messenger RNA expression levels. In vivo, EMD 121974 (cilengitide), which is currently in late clinical development as an antiangiogenic agent in newly diagnosed glioblastoma, was a weak antagonist of pSmad2 phosphorylation. These results validate integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block transforming growth factor-b-controlled features of malignancy including invasiveness, stemness and immunosuppression in human glioblastoma.
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Glioblastoma (GBM) is the most lethal primary brain tumor in adults and is known to be particularly aggressive and resistant to anti-cancer therapies, mainly due to the presence of GBM stem cells (GBMSC). By in vitro approaches supported by analysis from patients’ databases, we determined how α6-integrin and Fibroblast Growth Factor Receptor 1 (FGFR1) work in concert to regulate proliferation and stemness of GBMSC. We showed that α6-integrin regulates the expression of FGFR1 and its target gene Fokhead Box M1 (FOXM1) via the ZEB1/YAP1 transcription complex. These results were in accordance with the positive correlation observed in GBM between α6-integrin expression and its target genes ZEB1/YAP1, FGFR1, and FOXM1 in the databases, TCGA and Rembrandt. In addition, the clinical data demonstrate that GBM patients with high levels of the five genes signature, including α6-integrin, ZEB1/YAP1, FGFR1 and FOXM1, have a significantly shorter overall survival. In vitro, we observed a similar...
Integrin Signaling in Glioma Pathogenesis: From Biology to Therapy
International Journal of Molecular Sciences, 2020
Integrins are a large family of transmembrane adhesion receptors, which play a key role in interactions of a cell with the surrounding stroma. Integrins are comprised of non-covalently linked α and β chains, which form heterodimeric receptor complexes. The signals from integrin receptors are combined with those originating from growth factor receptors and participate in orchestrating morphological changes of cells, organization of the cytoskeleton, stimulation of cell proliferation and rescuing cells from programmed cell death induced by extracellular matrix (ECM) detachment. Upon binding to specific ligands or ECM components, integrin dimers activate downstream signaling pathways, including focal adhesion kinase, phosphoinositide-3-kinase (PI3K) and AKT kinases, which regulate migration, invasion, proliferation and survival. Expression of specific integrins is upregulated in both tumor cells and stromal cells in a tumor microenvironment. Therefore, integrins became an attractive th...
Brain Pathology, 2008
In malignant gliomas, the integrin adhesion receptors seem to play a key role for invasive growth and angiogenesis. However, there is still a controversy about the expression and the distribution of avb3 integrin caused by malignancy. The aim of our study was to assess the extent and pattern of avb3 integrin expression within primary glioblastomas (GBMs) compared with low-grade gliomas (LGGs). Tumor samples were immunostained for the detection of avb3 integrin and quantified by an imaging software. The expression of avb3 was found to be significantly higher in GBMs than in LGGs, whereby focal strong reactivity was restricted to GBMs only. Subsequent analysis revealed that not only endothelial cells but also, to a large extent, glial tumor cells contribute to the overall amount of avb3 integrin in the tumors. To further analyze the integrin subunits, Western blots from histologic sections were performed, which demonstrated a significant difference in the expression of the b3 integrin subunit between GBMs and LGGs. The presented data lead to new insights in the pattern of avb3 integrin in gliomas and are of relevance for the inhibition of avb3 integrin with specific RGD peptides and interfering drugs to reduce angiogenesis and tumor growth.
IS20I, a Specific ??v??3 Integrin Inhibitor, Reduces Glioma Growth in Vivo
Neurosurgery, 2003
The biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. ␣v3 integrin is highly expressed in malignant gliomas and plays a role in glioma growth. This article investigates the in vitro and in vivo effects of a synthetic ␣v3 integrin inhibitor called IS20I on human malignant gliomas. METHODS: The in vitro effects of IS20I were studied by performing adhesion assays, competition studies, semi-in vivo angiogenic assays, and migration and proliferation assays. For the in vivo experiments, IS20I was administered systemically in nude mouse intracranial and subcutaneous malignant glioma models. RESULTS: IS20I reacted selectively to ␣v3 integrin in glioma cells and tissues. In vitro, IS20I strongly inhibited angiogenesis and simultaneously exhibited potent antimitotic and antimigratory effects on numerous tumor and endothelial cell lines. In addition, at high concentrations, IS20I induced endothelial and tumor cell apoptosis. In vivo, when IS20I was administered intraperitoneally in subcutaneous and intracranial nude mouse glioma models, it potently reduced malignant glioma growth. Inhibition levels of 76 and 82% were observed at concentrations of 1 and 5 mg/kg, respectively, in the U87 intracranial model. The suppression of tumor growth is associated with a decrease in tumor vascularity, an increase in apoptosis, and a decrease in tumor cell proliferation. CONCLUSION: This work expands the understanding of the effects of anti-␣v3 integrin inhibitors on malignant gliomas. In addition to direct proapoptotic and antiangiogenic effects, IS20I inhibits tumor and endothelial cell proliferation and migration, resulting in a potent inhibition of glioma growth in vivo.