Surgery (RMH) - Research Publications
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ItemRepurposing FDA-approved drugs as inhibitors of therapy-induced invadopodia activity in glioblastoma cells(SPRINGER, 2023-06-01)Glioblastoma (GBM) is the most prevalent primary central nervous system tumour in adults. The lethality of GBM lies in its highly invasive, infiltrative, and neurologically destructive nature resulting in treatment failure, tumour recurrence and death. Even with current standard of care treatment with surgery, radiotherapy and chemotherapy, surviving tumour cells invade throughout the brain. We have previously shown that this invasive phenotype is facilitated by actin-rich, membrane-based structures known as invadopodia. The formation and matrix degrading activity of invadopodia is enhanced in GBM cells that survive treatment. Drug repurposing provides a means of identifying new therapeutic applications for existing drugs without the need for discovery or development and the associated time for clinical implementation. We investigate several FDA-approved agents for their ability to act as both cytotoxic agents in reducing cell viability and as ‘anti-invadopodia’ agents in GBM cell lines. Based on their cytotoxicity profile, three agents were selected, bortezomib, everolimus and fludarabine, to test their effect on GBM cell invasion. All three drugs reduced radiation/temozolomide-induced invadopodia activity, in addition to reducing GBM cell viability. These drugs demonstrate efficacious properties warranting further investigation with the potential to be implemented as part of the treatment regime for GBM.
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ItemExtracellular Vesicles Secreted by Glioma Stem Cells Are Involved in Radiation Resistance and Glioma Progression(MDPI, 2022-03)Glioblastoma is the most aggressive brain tumour with short survival, partly due to resistance to conventional therapy. Glioma stem cells (GSC) are likely to be involved in treatment resistance, by releasing extracellular vesicles (EVs) containing specific molecular cargoes. Here, we studied the EVs secreted by glioma stem cells (GSC-EVs) and their effects on radiation resistance and glioma progression. EVs were isolated from 3 GSCs by serial centrifugation. NanoSight measurement, cryo-electron microscopy and live imaging were used to study the EVs size, morphology and uptake, respectively. The non-GSC glioma cell lines LN229 and U118 were utilised as a recipient cell model. Wound healing assays were performed to detect cell migration. Colony formation, cell viability and invadopodium assays were conducted to detect cell survival of irradiated recipient cells and cell invasion post GSC-EV treatment. NanoString miRNA global profiling was used to select for the GSC-EVs' specific miRNAs. All three GSC cell lines secreted different amounts of EVs, and all expressed consistent levels of CD9 but different level of Alix, TSG101 and CD81. EVs were taken up by both LN229 and U118 recipient cells. In the presence of GSC-EVs, these recipient cells survived radiation exposure and initiated colony formation. After GSC-EVs exposure, LN229 and U118 cells exhibited an invasive phenotype, as indicated by an increase in cell migration. We also identified 25 highly expressed miRNAs in the GSC-EVs examined, and 8 of these miRNAs can target PTEN. It is likely that GSC-EVs and their specific miRNAs induced the phenotypic changes in the recipient cells due to the activation of the PTEN/Akt pathway. This study demonstrated that GSC-EVs have the potential to induce radiation resistance and modulate the tumour microenvironment to promote glioma progression. Future therapeutic studies should be designed to interfere with these GSC-EVs and their specific miRNAs.
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ItemInhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs(MDPI, 2020-10)Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich cell membrane protrusions known as invadopodia can facilitate the highly invasive properties of GBM cells. Ion channels have been proposed to contribute to a pro-invasive phenotype in cancer cells and may also be involved in the invadopodia activity of GBM cells. GBM cell cytotoxicity screening of several ion channel drugs identified three drugs with potent cell killing efficacy: flunarizine dihydrochloride, econazole nitrate, and quinine hydrochloride dihydrate. These drugs demonstrated a reduction in GBM cell invadopodia activity and matrix metalloproteinase-2 (MMP-2) secretion. Importantly, the treatment of GBM cells with these drugs led to a significant reduction in radiation/temozolomide-induced invadopodia activity. The dual cytotoxic and anti-invasive efficacy of these agents merits further research into targeting ion channels to reduce GBM malignancy, with a potential for future clinical translation in combination with the standard therapy.
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ItemA comprehensive meta-analysis of circulation miRNAs in glioma as potential diagnostic biomarker(PUBLIC LIBRARY SCIENCE, 2018-02-14)Glioma is the most common malignant intracranial tumour. Recently, several publications have suggested that miRNAs can be used as potential diagnostic biomarkers of glioma. Here we performed a meta-analysis to identify the diagnostic accuracy of differentially expressed circulating miRNAs in gliomas. Using PubMed, Medline and Cochrane databases, we searched for studies which evaluated a single or panel of miRNAs from circulating blood as potential biomarkers of glioma. Sixteen publications involving 23 studies of miRNAs from serum or plasma met our criteria and were included in this meta-analysis. The pooled diagnostic parameters were calculated by random effect models and overall diagnostic performance of altered miRNAs was illustrated by the summary receiver operator characteristic (SROC) curves. The pooled sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) from each study were calculated. The pooled PLR, NLR and Diagnostic Odds Ratio were 6.39 (95% CI, 4.61-8.87), 0.15 (95% CI, 0.11-0.21) and 41.91 (95% CI, 23.15-75.88), respectively. The pooled sensitivity, specificity and area under the curve (AUC) were 0.87 (95% CI, 0.82-0.91), 0.86 (95% CI, 0.82-0.90) and 0.93 (95% CI, 0.91-0.95), respectively. This meta-analysis demonstrated that circulating miRNAs are capable of distinguishing glioma from healthy controls. Circulating miRNAs are promising diagnostic biomarkers for glioma and can potentially be used as a non-invasive early detection.
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ItemThe role of interleukin-6-STAT3 signalling in glioblastoma(SPANDIDOS PUBL LTD, 2018-10)Glioblastoma is the most common type of malignant brain tumor among adults and is currently a non-curable disease due primarily to its highly invasive phenotype, and the lack of successful current therapies. Despite surgical resection and post-surgical treatment patients ultimately develop recurrence of the tumour. Several signalling molecules have been implicated in the development, progression and aggressiveness of glioblastoma. The present study reviewed the role of interleukin (IL)-6, a cytokine known to be important in activating several pro-oncogenic signaling pathways in glioblastoma. The current study particularly focused on the contribution of IL-6 in recurrent glioblastoma, with particular focus on glioblastoma stem cells and resistance to therapy.
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ItemInhibition of glioblastoma cell proliferation, migration and invasion by the proteasome antagonist carfilzomib(HUMANA PRESS INC, 2016-05)Glioblastoma multiforme is the most aggressive and lethal tumor of the central nervous system with limited treatment strategies on offer, and as such the identification of effective novel therapeutic agents is paramount. To examine the efficacy of proteasome inhibitors, we tested bortezomib, carfilzomib, nafamostat mesylate, gabexate mesylate and acetylsalicylic acid on glioblastoma cell viability, migration and invasion. Both bortezomib and carfilzomib produced significant reduction of cell viability, while nafamostat mesylate, gabexate mesylate and acetylsalicylic acid did not. Subsequent testing showed that carfilzomib significantly reduced cell viability at nM concentrations. Carfilzomib also reduced cell migration, secretion and activation of MMP2 and also cell invasion of all four glioblastoma cells tested. In summary, carfilzomib represents a novel, yet FDA-approved agent for the treatment of glioblastoma multiforme.
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ItemMicroRNA as potential biomarkers in Glioblastoma(SPRINGER, 2015-11)Glioblastoma is the most aggressive and lethal tumour of the central nervous system and as such the identification of reliable prognostic and predictive biomarkers for patient survival and tumour recurrence is paramount. MicroRNA detection has rapidly emerged as potential biomarkers, in patients with glioblastoma. Over the last decade, analysis of miRNA in laboratory based studies have yielded several candidates as potential biomarkers however, the accepted use of these candidates in the clinic is yet to be validated. Here we will examine the use of miRNA signatures to improve glioblastoma stratification into subgroups and summarise recent advances made in miRNA examination as potential biomarkers for glioblastoma progression and recurrence.
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ItemInhibition of Radiation and Temozolomide-Induced Invadopodia Activity in Glioma Cells Using FDA-Approved Drugs(ELSEVIER SCIENCE INC, 2018-12)The most common primary central nervous system tumor in adults is the glioblastoma multiforme (GBM). The highly invasive nature of GBM cells is a significant factor resulting in the inevitable tumor recurrence and poor patient prognosis. Tumor cells utilize structures known as invadopodia to faciliate their invasive phenotype. In this study, utilizing an array of techniques, including gelatin matrix degradation assays, we show that GBM cell lines can form functional gelatin matrix degrading invadopodia and secrete matrix metalloproteinase 2 (MMP-2), a known invadopodia-associated matrix-degrading enzyme. Furthermore, these cellular activities were augmented in cells that survived radiotherapy and temozolomide treatment, indicating that surviving cells may possess a more invasive phenotype posttherapy. We performed a screen of FDA-approved agents not previously used for treating GBM patients with the aim of investigating their "anti-invadopodia" and cytotoxic effects in GBM cell lines and identified a number that reduced cell viability, as well as agents which also reduced invadopodia activity. Importantly, two of these, pacilitaxel and vinorelbine tartrate, reduced radiation/temozolomide-induced invadopodia activity. Our data demonstrate the value of testing previously approved drugs (repurposing) as potential adjuvant agents for the treatment of GBM patients to reduce invadopodia activity, inhibit GBM cell invasion, and potentially improve patient outcome.
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ItemThe peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells(IMPACT JOURNALS LLC, 2015-08-28)Glioma cells release glutamate through expression of system xc-, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate.