Integrin α10-Antibodies Reduce Glioblastoma Tumor Growth and Cell Migration.
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ABSTRACT:
SUBMITTER: Masoumi KC
PROVIDER: S-EPMC7980568 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the immune system's potential against tumor cells. Our previous data showed a B-cell-based vaccine, BVax, can provide a promising therapeutic potential for GBM. In this study, we aim to characterize the antigenic reactivity of BVax-derived antibodies and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and human GBM patient samples.
2024-09-10 | PXD046712 | Pride
Project description:Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored. Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo. Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvβ5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection. Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvβ5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.
| S-EPMC9169371 | biostudies-literature
Project description:Glioblastoma is diagnosed by biopsy or, if clinically feasible, tumor resection. However, emerging evidence suggests that this surgical intervention may increase the risk of tumor cell spread. It has been hypothesized that the damage to the tumor leads to infiltration of immune cells that consequently form an environment that favors tumor cell motility. In mouse glioma models, it was previously found that biopsy induced migration of tumor cells in vivo and that recruitment of monocytes from the blood was involved in this effect. However, the role of neutrophils in this process is still unclear. Here, we study the contribution of neutrophils on the pro-migratory effect of surgical interventions in glioma. Using repetitive intravital microscopy, in vivo migration of glioma tumor cells before and after biopsy was compared in mice systemically depleted of neutrophils. Interestingly, macrophages/microglia were almost completely absent from neutrophil-depleted tumors, indicating that neutrophils may be indirectly involved in biopsy-induced migration of glioma tumor cells through the recruitment of macrophages to the tumor. To further investigate whether neutrophils have the potential to also directly promote glioblastoma tumor cell migration, we performed in vitro migration assays using human neutrophils. Indeed, wound-healing of human primary glioblastoma tumor cell lines was promoted by human neutrophils. The pro-migratory effects of human neutrophils on glioblastoma tumor cells could also be recapitulated in transwell migration assays, indicating that soluble factor(s) are involved. We therefore provide evidence for both an indirect and direct involvement of neutrophils in tumor spread following biopsy of glioblastoma tumors.
| S-EPMC9324761 | biostudies-literature
Project description:Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers. Nanoparticles hold tremendous promise to overcome the pharmacokinetic challenges and off-target adverse effects. However, an inhibitory effect of nanoparticles by themselves on metastasis has not been explored. In this study, we developed transferrin-conjugated porous silicon nanoparticles (Tf@pSiNP) and studied their effect on inhibiting GBM migration by means of a microfluidic-based migration chip. This platform, designed to mimic the tight extracellular migration tracts in brain parenchyma, allowed high-content time-resolved imaging of cell migration. Tf@pSiNP were colloidally stable, biocompatible, and their uptake into GBM cells was enhanced by receptor-mediated internalisation. The migration of Tf@pSiNP-exposed cells across the confined microchannels was suppressed, but unconfined migration was unaffected. The pSiNP-induced destabilisation of focal adhesions at the leading front may partially explain the migration inhibition. More corroborating evidence suggests that pSiNP uptake reduced the plasticity of GBM cells in reducing cell volume, an effect that proved crucial in facilitating migration across the tight confined tracts. We believe that the inhibitory effect of Tf@pSiNP on cell migration, together with the drug-delivery capability of pSiNP, could potentially offer a disruptive strategy to treat GBM.
| S-EPMC7012928 | biostudies-literature
Project description: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 ?10?1 as a therapeutic target in GBMs. Expression levels and the role of integrin ?10?1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin ?10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin ?10?1 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 ?3, ?6, and ?7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin ?10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin ?10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin ?10?1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
| S-EPMC6521287 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is a highly invasive brain tumor that develops florid microvascular proliferation and hemorrhage. However, mechanisms that favor invasion versus angiogenesis in this setting remain largely uncharacterized. Here, we show that integrin β8 is an essential regulator of both GBM-induced angiogenesis and tumor cell invasiveness. Highly angiogenic and poorly invasive tumors expressed low levels of β8 integrin, whereas highly invasive tumors with limited neovascularization expressed high levels of β8 integrin. Manipulating β8 integrin protein levels altered the angiogenic and invasive growth properties of GBMs, in part, reflected by a diminished activation of latent TGFβs, which are extracellular matrix protein ligands for β8 integrin. Taken together, these results establish a role for β8 integrin in differential control of angiogenesis versus tumor cell invasion in GBM. Our findings suggest that inhibiting β8 integrin or TGFβ signaling may diminish tumor cell invasiveness during malignant progression and following antivascular therapies.
| S-EPMC3193578 | biostudies-literature
Project description:The ?9?1 integrin accelerates cell migration through binding of the ?9 cytoplasmic domain to SSAT, which catalyzes the catabolism of higher order polyamines, spermidine and spermine, to the lower order polyamine, putrescine. SSAT levels were downregulated at both the mRNA and protein levels by shRNA-mediated simultaneous knockdown of MMP-9 and uPAR/cathepsin B. In addition, we noted a prominent reduction in the expression of SSAT with MMP-9 and uPAR/cathepsin B knockdown in the tumor regions of 5310 injected nude mice brains. Further, SSAT knockdown in glioma xenograft cells significantly reduced their migration potential. Interestingly, MMP-9, uPAR and cathepsin B overexpression in these xenograft cells significantly elevated SSAT mRNA and protein levels. The migratory potential of MMP-9/uPAR/cathepsin B-overexpressed 4910 and 5310 cells was not affected by either glybenclamide (Kir 6.x inhibitor) or tertiapin-Q (Kir 1.1 and 3.x inhibitor) but instead was significantly inhibited by either barium or Kir4.2 siRNA treatments. Co-localization of ?9 integrin with Kir4.2 was observed in both 4910 and 5310 xenograft cells. However, MMP-9 and uPAR/cathepsin B knockdown in these cells prominently reduced the co-localization of ?9 with Kir4.2. Taken together, our results clearly demonstrate that ?9?1 integrin-mediated cell migration utilizes SSAT and the Kir4.2 potassium channel pathway, and inhibition of the migratory potential of these glioma xenograft cells by simultaneous knockdown of MMP-9 and uPAR/cathepsin B could be attributed to the reduced SSAT levels and co-localization of ?9 integrin with Kir4.2 inward rectifier potassium channels.
| S-EPMC3205329 | biostudies-literature
Project description:In cancer cells integrins modulate important cellular events that regulate the metastasic cascade which involves detachment from the tumor mass, dissemination and attachment to the oncogenic niche. The α5β1, αvβ3 and αvβ5 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. In human glioblastoma, αvβ3 integrin expression correlates with tumor grade, suggesting that this integrin may play a crucial role in the highly infiltrative behavior of high grade gliomas. However, few selective RGD-like antagonists have been developed and few studies have investigated their effects in in vitro models of human glioblastoma. In this study, we investigated several cellular effects and the underlying molecular mechanisms exerted by a new small-molecule RGD antagonist, 1a-RGD, in the U251 and U373 human glioblastoma cell lines. Treatment with 1a-RGD (20 µM) demonstrated a weak effect on cell viability and cell proliferation but strongly inhibited cell attachment and cell migration together with actin cytoskeleton disassembly. Prolonged 1a-RGD treatment (72 h) induced anoikis, assessed by Annexin staining and nucleosome assay, particularly in the detached cells. When integrin-linked transduction pathways were investigated, 1aRGD was found to exert a marked reduction in focal adhesion kinase (FAK) phosphorylation without affecting the AKT- and ERK-dependent pathways. Our data indicate that 1a-RGD, probably via modulation of the FAK-dependent pathway, inhibits cell migration and attachment and induces anoikis in glioblastoma cells. This novel finding suggests that the development of an RGD-like molecule may represent a promising tool for the pharmacological approach aimed at reducing the malignancy of glioblastoma cells.
| S-EPMC3583633 | biostudies-literature
Project description:Fibronectin (FN1) is an extracellular matrix protein gaining increasing attention for its multifaceted roles in cancer progression. Using our recently established circulating tumor cell (CTC) lines, we had demonstrated increased FN1 expression and enhanced migration in CTC lines, in comparison to primary tumor cell lines. Whether increased FN1 expression is directly required for CTC migration, and the specific role of FN1's regulation of integrin B1 (ITGB1) and SLUG (SNAI2) in CTC migration remains unclear. Here, for the first time, we report that the knockdown of FN1, ITGB1, or SLUG expression in CTCs leads to a significant decrease in CTC migration. Knocking down two or all three of these proteins simultaneously did not further inhibit migration. We observed a corresponding increase in CTC migration when recombinant FN1 was added to CTCs. This effect was significantly impeded by prior knockdown of ITGB1 or SLUG. Using knock down experiments and western blotting analysis, we confirmed FN1's regulation of ITGB1 and SLUG to occur via two separate, independent pathways. Consequently, we can conclude that FN1-dependent enhanced migration of CTCs requires downstream signaling through either ITGB1 or SLUG and that FN1 regulation of ITGB1 and SLUG may have important implications for cancer progression and metastasis.
| S-EPMC7408126 | biostudies-literature
Project description:BackgroundTissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient-specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures.MethodsWith use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR.ResultsMigration analysis identified significant patient-to-patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors.ConclusionsThese data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion.
| S-EPMC3714155 | biostudies-literature