The role of TNF-α in chordoma progression and inflammatory pathways

Güllüoğlu, Şükrü; Tuysuz, Emre Can; Şahin, Mitat; Yaltırık, Cumhur Kaan; Kuşkucu, Ayşegül; Özkan, Ferda; Dalan, Altay Burak; Şahın, Fikrettin; Türe, Uğur; Bayrak, Ömer Faruk

doi:10.1007/s13402-019-00454-y

Cited by 25 publications

(23 citation statements)

References 49 publications

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“…We thus hypothesized that skull base patients with high MPV or PDW may have aberrant levels of cytokines such as interleukin-6 and abnormal inflammatory responses, leading to tumour progression and poor outcomes [32]. Interesting, several cytokines including interleukin-6 and tumor necrosis factor-alpha were reported to be elevated in chordoma patients [41,42], suggesting the potential role of cytokines in chordoma progression. We will explore the levels and prognostic values of these cytokines in skull base chordoma, and their association with platelet associated indexes in the future study.…”

Section: Discussionmentioning

confidence: 99%

Mean platelet volume and platelet distribution width serve as prognostic biomarkers in skull base chordoma: a retrospective study

Bai

Wang

et al. 2020

BMC Cancer

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Background Increasing studies have demonstrated that activated platelets play an essential role in tumour progression. However, the level and prognostic role of platelet indices in chordoma patients remain unclear. The aim of the current study was to characterize the prognostic performance of platelet count (PLT), mean platelet volume (MPV) and platelet distribution width (PDW) in skull base chordoma patients. Methods 187 primary skull base chordoma patients between January 2008 and September 2014 were enrolled in this retrospective study. The optimal cut-off values were determined by X-tile software, and the correlations between PLT, MPV, PDW and clinicopathological features were further analysed. Kaplan-Meier curve and Cox regression analysis were used for survival analysis. Results The values of preoperative PTL, MPV and PDW ranged from 104 to 501 × 109/L, 6.7 to 14.2 fl, and 7.8 to 26.2%, respectively. Elevated PLT was associated with larger tumour volume (p = 0.002). Kaplan-Meier survival analysis revealed that increased MPV and PDW were associated with shorter overall survival (p = 0.022 and 0.008, respectively). Importantly, multivariate Cox analysis demonstrated that elevated PDW was an independent unfavourable predictive factor for overall survival (hazard ratio (HR), 2.154, 95% confidence interval (CI), 1.258–3.688, p = 0.005). Conclusions Our data show that elevated MPV and PDW are associated with poor outcomes in skull base chordoma and that PDW may be helpful to identify patients with high risk.

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Section: Discussionmentioning

confidence: 99%

Mean platelet volume and platelet distribution width serve as prognostic biomarkers in skull base chordoma: a retrospective study

Bai

Wang

et al. 2020

BMC Cancer

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“…Leukemia inhibitory factor (LIF) is a cytokine in the interleukin-6 family whose functions include regulating proliferation of cancer stem cells, like those often found in chordoma ( 48 ). Expression of either TNF-α or LIF in chordoma cell lines promoted cell migration, invasive capabilities, and anchorage-independent growth, demonstrating their pro-tumoral and metastatic potential ( 49 ). Exposure of chordomas to TNF-α upregulates not only its own gene expression but also LIF expression, and vice versa; both cytokines are correlated with increased tumor size, implicating these factors in chordoma growth ( 49 , 50 ).…”

Section: Immune Microenvironmentmentioning

confidence: 99%

“…Immune cell signaling also induces alterations in gene expression in chordoma cells. Epithelial marker expression was downregulated while mesenchymal marker expression was upregulated following exposure to TNF-α, implicating TNF-α in the chordoma epithelial-mesenchymal transition ( 49 ). Differential gene expression analysis post-TNF-α exposure demonstrated upregulation of the phosphoinositide 3-kinase (PI3K)/Akt, Ras, and Ras-related protein 1 (Rap1) signaling pathways, implicated in progression of chordomas and other malignancies, respectively ( 49 , 51 ).…”

Section: Immune Microenvironmentmentioning

confidence: 99%

“…Epithelial marker expression was downregulated while mesenchymal marker expression was upregulated following exposure to TNF-α, implicating TNF-α in the chordoma epithelial-mesenchymal transition ( 49 ). Differential gene expression analysis post-TNF-α exposure demonstrated upregulation of the phosphoinositide 3-kinase (PI3K)/Akt, Ras, and Ras-related protein 1 (Rap1) signaling pathways, implicated in progression of chordomas and other malignancies, respectively ( 49 , 51 ). Pro-angiogenic and anti-apoptotic pathways were also upregulated with longer TNF-α exposure, which may contribute to the survival and metastatic potential of chordomas ( 49 ).…”

Section: Immune Microenvironmentmentioning

confidence: 99%

“…Elevated stroma-tumor ratio was associated with decreased infiltration of effector T-cells and an elevated density of regulatory T cells within the tumor ( 52 ). TNF-α-exposed chordoma cells displayed increased programmed death-ligand 1 (PD-L1) but downregulated T expression; brachyury-targeted treatments may be impacted as a result ( 49 , 50 ). Finally, resistance to cytotoxic chemotherapies also increases in these chordoma cells exposed to LIR and TNF-α ( 49 , 50 ).…”

Section: Immune Microenvironmentmentioning

confidence: 99%

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Translational Windows in Chordoma: A Target Appraisal

et al. 2020

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Chordomas are rare tumors that are notoriously refractory to chemotherapy and radiotherapy when radical surgical resection is not achieved or upon recurrence after maximally aggressive treatment. The study of chordomas has been complicated by small patient cohorts and few available model systems due to the rarity of these tumors. Emerging next-generation sequencing technologies have broadened understanding of this disease by implicating novel pathways for possible targeted therapy. Mutations in cell-cycle regulation and chromatin remodeling genes have been identified in chordomas, but their significance remains unknown. Investigation of the immune microenvironment of these tumors suggests that checkpoint protein expression may influence prognosis, and adjuvant immunotherapy may improve patient outcome. Finally, growing evidence supports aberrant growth factor signaling as potential pathogenic mechanisms in chordoma. In this review, we characterize the impact on treatment opportunities offered by the genomic and immunologic landscape of this tumor.

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Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

Gao,

Huang,

Liu

et al. 2024

J of Cellular Biochemistry

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Despite surgical treatment combined with multidrug therapy having made some progress, chemotherapy resistance is the main cause of recurrence and death of gastric cancer (GC). Gastric cancer mesenchymal stem cells (GCMSCs) have been reported to be correlated with the limited efficacy of chemotherapy in GC, but the mechanism of GCMSCs regulating GC resistance needs to be further studied. The gene set enrichment analysis (GSEA) was performed to explore the glycolysis‐related pathways heterogeneity across different cell subpopulations. Glucose uptake and lactate production assays were used to evaluate the importance of B7H3 expression in GCMSCs‐treated GC cells. The therapeutic efficacy of oxaliplatin (OXA) and paclitaxel (PTX) was determined using CCK‐8 and colony formation assays. Signaling pathways altered by GCMSCs‐CM were revealed by immunoblotting. The expression of TNF‐α in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by western blot analysis and qPCR. Our results showed that the OXA and PTX resistance of GC cells were significantly enhanced in the GCMSCs‐CM treated GC cells. Acquired OXA and PTX resistance was characterized by increased cell viability for OXA and PTX, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of cleaved caspase‐3 and Bax expression, and increased levels of Bcl‐2, HK2, MDR1, and B7H3 expression. Blocking TNF‐α in GCMSCs‐CM, B7H3 knockdown or the use of 2‐DG, a key enzyme inhibitor of glycolysis in GC cells suppressed the OXA and PTX resistance of GC cells that had been treated with GCMSCs‐CM. This study shows that GCMSCs‐CM derived TNF‐α could upregulate the expression of B7H3 of GC cells to promote tumor chemoresistance. Our results provide a new basis for the treatment of GC.

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The role of TNF-α in chordoma progression and inflammatory pathways

Cited by 25 publications

References 49 publications

Mean platelet volume and platelet distribution width serve as prognostic biomarkers in skull base chordoma: a retrospective study

Mean platelet volume and platelet distribution width serve as prognostic biomarkers in skull base chordoma: a retrospective study

Translational Windows in Chordoma: A Target Appraisal

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

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