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As microtubule-based structures, primary cilia are typically present on the cells during the G0 or G1-S/G2 phase of the cell cycle and are closely related to the development of the central nervous system. The presence or absence of this special organelle may regulate the central nervous system tumorigenesis (e.g., glioblastoma) and several degenera...
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Gliomas are complex and heterogeneous central nervous system tumors with poor prognosis. Despite the increasing development of aggressive combination therapies, the prognosis of glioma is generally unsatisfactory. Exosomal microRNA (miRNA) has been successfully used in other diseases as a reliable biomarker and even therapeutic target. Recent studi...
Citations
... 42 Primary cilia are abundant on the surface of the glioma cell membrane, forming the structural basis of SHH/GLI1 signal transduction and pathway activation. 43 TTFields can destroy primary cilia, thus affecting SHH pathway activity and interfering with glioma cell invasion and metastasis. 44 Angiogenesis is also closely related to tumor metastasis. ...
Background
Glioblastoma is the most common primary malignant brain tumor in adults. TTFields is a therapy that use intermediate‐frequency and low‐intensity alternating electric fields to treat tumors. For patients with ndGBM, the addition of TTFields after the concurrent chemoradiotherapy phase of the Stupp regimen can improve prognosis. However, TTFields still has the potential to further prolong the survival of ndGBM patients.
Aim
By summarizing the mechanism and application status of TTFields in the treatment of ndGBM, the application prospect of TTFields in ndbm treatment is prospected.
Methods
We review the recent literature and included 76 articles to summarize the mechanism of TTfields in the treatment of ndGBM. The current clinical application status and potential health benefits of TTFields in the treatment of ndGBM are also discussed.
Results
TTFields can interfere with tumor cell mitosis, lead to tumor cell apoptosis and increased autophagy, hinder DNA damage repair, induce ICD, activate tumor immune microenvironment, reduce cancer cell metastasis and invasion, and increase BBB permeability. TTFields combines with chemoradiotherapy has made progress, its optimal application time is being explored and the problems that need to be considered when retaining the electrode patches for radiotherapy are further discussed. TTFields shows potential in combination with immunotherapy, antimitotic agents, and PARP inhibitors, as well as in patients with subtentorial gliomas.
Conclusion
This review summarizes mechanisms of TTFields in the treatment of ndGBM, and describes the current clinical application of TTFields in ndGBM. Through the understanding of its principle and application status, we believe that TTFields still has the potential to further prolong the survival of ndGBM patients. Thus,research is still needed to explore new ways to combine TTFields with other therapies and optimize the use of TTFields to realize its full potential in ndGBM patients.
... While several studies have shown the potential of TEFT in reversing TMZ resistance in GBM, the underlying mechanism is not fully understood and requires further investigation. [4,[13][14][15] ...
To explore the mechanisms behind tumor electric field treatment (TEFT) in reversing temozolomide (TMZ) resistance in glioblastoma (GBM). Transcriptome data of TMZ- resistant GBM cells treated with TEFT were obtained using a novel electric field cell culture device (CL-301A). Key biological processes and genes were identified through differential gene analysis and enrichment analysis. The association between key genes and patient prognosis was examined using a GBM open-source database. The results were validated in two GBM-resistant cell lines(U251R,T98GR)and primary cell lines (GPDC1,GPDC8). The results suggest that TEFT increased the sensitivity of U251R and T98GR to TMZ. Bioinformatics analysis showed the importance of the extracellular matrix structure and identified BCL3 as a key gene. Survival analysis indicated that GBM patients with high BCL3 expression had a poor prognosis. BCL3 was upregulated in U251R and T98GR, increased resistance to TMZ, while BCL3 knockdown resulted in increased sensitivity to TMZ. Western blot assays showed that downregulation of BCL3 decreased AKT phosphorylation and correlated with reduced resistance to TMZ. It was finally concluded that TEFT reversed the drug resistance of GBM to TMZ by reducing AKT phosphorylation and BCL3 expression, enhancing the proapoptotic effect of TMZ on GBM cells. Keywords: tumor electric field therapy; BCL3; drug resistance; glioblastoma; temozolomide.
... Other cilium-related pathways, including the lysophosphatidic acid receptor 1 (LPAR1) and pericentriolar material 1 (PCM1) pathways, inhibit the proliferation and development of GBM cell lines. The EGFR, PDGFRα, MGMT, and isocitrate dehydrogenase 1 (IDH1) pathways promote GBM therapeutic resistance, which is associated with or modulated by the assembly and disassembly of PCs [132]. ...
... GBM is commonly stratified into four subtypes: classical, mesenchymal, proneural, and neural. Since each subtype displays different genomic features that affect the resistance mechanisms associated with or modulated by the PC, it has been proposed that PCs could be used as a diagnostic tool to discriminate the different subtypes or to predict the response to targeted therapies [132]. PCs could also serve as a diagnostic tool in medulloblastoma, where the presence or absence of cilia is associated with specific variants. ...
... In glioblastoma, several therapeutic strategies have been proposed to target factors belonging to HH signaling, including PTCH-SMO [132]. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme and downstream effector of the HH cascade, has been reported to significantly contribute to the development of drug resistance in both glioma and glioblastoma [172]. ...
Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications.
... The use of TTFields inhibits mitosis and the cell cycle, induces cancer cell autophagy, disturbs DNA repair, undermines cell migration, and thus suppresses tumor growth and invasion [7][8][9][10][11][12]. TTFields therapy also ablates the primary cilia on GBM cells that promote tumor growth and chemoresistance to TMZ and induces nuclear envelope disruption and the subsequent release of naked micronucleus clusters, which activate several types of inflammasomes to induce anticancer immunity in GBMs [13][14][15]. The Food and Drug Administration (FDA) of the United States approved the use of TTFields for the treatment of recurrent GBMs (rGBMs) in 2011 and for ndGBMs in 2015 due to the promising results that it had comparable effects with the use of the physician's best choice (PBC) for rGBMs (EF-11) and promoted improved survival relative to the standardized Stupp protocol for ndGBMs [4,5,16]. ...
... Additionally, TTFields downregulates the expression levels of VEGF, HIF1-α, MMP2, and MMP9, which are the basis of tumor growth, invasion, metastasis, and recidivism, respectively [12]. Cilia are present in more than 30% of glioma cells and play a role in promoting cancer growth, migration, differentiation, and TMZ chemoresistance [14,61,62]. Shi et al. [15] found that TTFields exerted suppressing effects on primary cilia in both low-and high-grade glioma cell lines but fewer effects on normal astrocytes and neurons. ...
Tumor-treating fields (TTFields), a noninvasive and innovative therapeutic approach, has emerged as the fourth most effective treatment option for the management of glioblastomas (GBMs), the most deadly primary brain cancer. According to on recent milestone randomized trials and subsequent observational data, TTFields therapy leads to substantially prolonged patient survival and acceptable adverse events. Clinical trials are ongoing to further evaluate the safety and efficacy of TTFields in treating GBMs and its biological and radiological correlations. TTFields is administered by delivering low-intensity, intermediate-frequency, alternating electric fields to human GBM function through different mechanisms of action, including by disturbing cell mitosis, delaying DNA repair, enhancing autophagy, inhibiting cell metabolism and angiogenesis, and limiting cancer cell migration. The abilities of TTFields to strengthen intratumoral antitumor immunity, increase the permeability of the cell membrane and the blood–brain barrier, and disrupt DNA-damage-repair processes make it a promising therapy when combined with conventional treatment modalities. However, the overall acceptance of TTFields in real-world clinical practice is still low. Given that increasing studies on this promising topic have been published recently, we conducted this updated review on the past, present, and future of TTFields in GBMs.
... Vascular endothelial cells in the tumor microenvironment may provide SHH to further activate HH signaling pathways, thereby promoting GSC properties. QKI, Quaking homolog; DRP5, dihydro pyrimidine-associated protein 5; SHH, Sonic Hedgehog; GBM, glioblastoma; SMO, smoothened; Gli, glioma-associated oncogene; GSC, glioblastoma stem cells; ID1, differentiation inhibitor 1; NS, microenvironmental nutritional stress; DLG5, discs large homolog 5. resistance (112). A previous study reported that the development of resistance to acquired kinase inhibitors is associated with upregulation of PC, uncontrolled PC length and abnormal activation of SHH signaling. ...
Glioblastoma (GBM) is the most common and fatal malignant tumor type of the central nervous system. GBM affects public health and it is important to identify biomarkers to improve diagnosis, reduce drug resistance and improve prognosis (e.g., personalized targeted therapies). Hedgehog (HH) signaling has an important role in embryonic development, tissue regeneration and stem cell renewal. A large amount of evidence indicates that both normative and non-normative HH signals have an important role in GBM. The present study reviewed the role of the HH signaling pathway in the occurrence and progression of GBM. Furthermore, the effectiveness of drugs that target different components of the HH pathway was also examined. The HH pathway has an important role in reversing drug resistance after GBM conventional treatment. The present review highlighted the relevance of HH signaling in GBM and outlined that this pathway has a key role in the occurrence, development and treatment of GBM.
... H uman glioblastoma (GBM) is a grade-IV diffuse glioma and represents the most frequent malignant primary brain tumor with an extremely poor prognosis [1] . Although the current therapies, including a maximum surgical resection followed by temozolomide (TMZ) in combination with ionizing radiation (IR), show an effective response, tumor recurrence invariably occurs for most patients with a median overall survival of 15 months and a 5-year survival rate of less than 5% [2] . Given the complex development of therapeutic resistance in GBM and controversial therapeutic efficacy [3] , a comprehensive understanding of the resistance mechanism implicated in the cellular response to TMZ and/or IR is necessary to exploit new therapies to improve the outcome of the current GBM therapy. ...
Objective:
To investigate the function of primary cilia in regulating the cellular response to temozolomide (TMZ) and ionizing radiation (IR) in glioblastoma (GBM).
Methods:
GBM cells were treated with TMZ or X-ray/carbon ion. The primary cilia were examined by immunostaining with Arl13b and γ-tubulin, and the cellular resistance ability was measured by cell viability assay or survival fraction assay. Combining with cilia ablation by IFT88 depletion or chloral hydrate and induction by lithium chloride, the autophagy was measured by acridine orange staining assay. The DNA damage repair ability was estimated by the kinetic curve of γH2AX foci, and the DNA-dependent protein kinase (DNA-PK) activation was detected by immunostaining assay.
Results:
Primary cilia were frequently preserved in GBM, and the induction of ciliogenesis decreased cell proliferation. TMZ and IR promoted ciliogenesis in dose- and time-dependent manners, and the suppression of ciliogenesis significantly enhanced the cellular sensitivity to TMZ and IR. The inhibition of ciliogenesis elevated the lethal effects of TMZ and IR via the impairment of autophagy and DNA damage repair. The interference of ciliogenesis reduced DNA-PK activation, and the knockdown of DNA-PK led to cilium formation and elongation.
Conclusion:
Primary cilia play a vital role in regulating the cellular sensitivity to TMZ and IR in GBM cells through mediating autophagy and DNA damage repair.
Background
Recent studies have validated the role of Pericentriolar Material 1 (PCM1) in several malignant tumour cell lines, but its specific biological function in lung adenocarcinoma (LUAD) remains unclear.
Objective
To address this gap, this study analyzed 411 LUAD and control samples to evaluate the prognostic value of PCM1 using Cox regression analysis.
Methods
Multiple genes co-expressed with PCM1 were also analyzed to investigate the biological processes and roles involved in PCM1. An endogenous competitive network with PCM1 as the key gene was constructed to uncover its regulatory and competitive relationships in LUAD. The study further explored the immunological characteristics of PCM1 in different expression groups based on immune infiltration analysis.
Results
These findings indicated that higher PCM1 expression levels were associated with better survival prognoses, possibly due to its antagonistic effects on RHOC. Immunological infiltration analysis revealed a significant correlation between PCM1 and various immune cell infiltration levels, including CD4+ T cells, naïve B cells, M2 macrophages, and mast cells. However, there was no significant relationship between PCM1 and MSI, TMB, or stemness, although it was positively correlated with m6A genes. Patients with lower PCM1 expression responded better to CTLA-4 therapy. The study also estimated that some chemotherapeutic and targeted agents might be effective in treating patients with high PCM1 levels. PCM1 was mainly expressed in the cytoplasmic and membranous structures.
Conclusion
PCM1 shows potential as a prognostic biomarker for LUAD due to its strong correlation with immune cell infiltration and its ability to enhance anticancer treatment sensitivity.
