Integrin-αVβ3 is a fundamental factor in medulloblastoma tumorigenicity and radioresistance: A new game for an old player (original) (raw)
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Inhibiting Integrin β8 to Differentiate and Radiosensitize Glioblastoma-Initiating Cells
Molecular Cancer Research, 2019
Glioblastomas (GB) are malignant brain tumors with poor prognosis despite treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a subpopulation of GB-initiating cells (GIC), which contribute to tumor aggressiveness, resistance, and recurrence. Some integrins are specifically expressed by GICs and could be actionable targets to improve GB treatment. Here, integrin β8 (ITGB8) was identified as a potential selective target in this highly tumorigenic GIC subpopulation. Using several patient-derived primocultures, it was demonstrated that ITGB8 is overexpressed in GICs compared with their differentiated progeny. Furthermore, ITGB8 is also overexpressed in GB, and its overexpression is correlated with poor prognosis and with the expression of several other classic stem cell markers. Moreover, inhibiting ITGB8 diminished several main GIC characteristics and features, including self-renewal ability, stemness, migra...
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.
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;
Cancers
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...
Activation of tumor cell integrin α v β 3 controls angiogenesis and metastatic growth in the brain
Proceedings of the National Academy of Sciences, 2009
The incidence of brain metastasis is rising and poses a severe clinical problem, as we lack effective therapies and knowledge of mechanisms that control metastatic growth in the brain. Here we demonstrate a crucial role for high-affinity tumor cell integrin α v β 3 in brain metastatic growth and recruitment of blood vessels. Although α v β 3 is frequently up-regulated in primary brain tumors and metastatic lesions of brain homing cancers, we show that it is the α v β 3 activation state that is critical for brain lesion growth. Activated, but not non-activated, tumor cell α v β 3 supports efficient brain metastatic growth through continuous up-regulation of vascular endothelial growth factor (VEGF) protein under normoxic conditions. In metastatic brain lesions carrying activated α v β 3 , VEGF expression is controlled at the post-transcriptional level and involves phosphorylation and inhibition of translational respressor 4E-binding protein (4E-BP1). In contrast, tumor cells with non...
Stage-specific expression of integrin alphaVbeta3 in neuroblastic tumors
The American journal of pathology, 1996
The ligand specificity of the integrin cell adhesion receptors probably determines the ability of specific integrins to promote tumor cell proliferation and metastasis. Therefore, we compared the expression of integrin alphaVbeta3, a promiscuous receptor that binds with high affinity to numerous cell matrix proteins, with the expression of integrin alphaVbeta5 and the integrin beta 1 subunit (which pairs with multiple alpha subunits) in neuroblastic tumors at various stages of differentiation. Undifferentiated neuroblastoma tumors rapidly invade and metastasize, whereas ganglioneuroblastomas rarely metastasize. Differentiating neuroblastomas are associated with an intermediate prognosis. Paraffin sections of neuroblastic tumors at various stages of differentiation obtained at biopsy from 17 patients were hybridized with antisense integrin subunit-specific alphaV, beta3, beta1, and beta5 riboprobes. All neuroblastic tumors and seven adrenal glands obtained at autopsy were analyzed im...
Integrin v 3-Targeted Radioimmunotherapy of Glioblastoma Multiforme
Clinical Cancer Research, 2008
Purpose: Abegrin is a monoclonal antibody to human integrin a V h 3 , a cell adhesion molecule highly expressed on actively angiogenic endothelium and glioblastoma multiforme tumor cells. The purpose of this study was to evaluate the efficacy of a novel 90 Y-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities. Experimental Design: A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of 90 Y-Abegrin. Antitumor efficacy was also characterized in an orthotopic U87MG and in a HT-29 colorectal cancer model, a low integrin-expressing carcinoma. Small-animal positron emission tomography imaging was used to correlate histologic findings of treatment efficacy. Results: MTD and dose response analysis revealed 200 ACi per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. 90 Y-Abegrin^treated U87MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in 90 Y-IgG, Abegrin, and saline groups. 18 F-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas 18 F-FLT reflected decreased DNA synthesis in the 90 Y-Abegrin group. Ki67 analysis showed reduced proliferative index and quantitative terminal deoxynucleotidyl transferase dUTP nick-end labeling^positive analysis revealed increased DNA fragmentation and apoptosis in 90 Y-Abegrin animals. CD31and 4 ¶,6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in 90 Y-Abegrin animals only. Orthotopic U87MG tumors treated with 90 Y-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups. Conclusion: Radioimmunotherapy with 90 Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.
Integrin control of the transforming growth factor- pathway in glioblastoma
Brain, 2013
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.
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 ...