Sukru Gulluoglu1,2, Emre Can Tuysuz1,2, Mesut Sahin3, Cumhur Kaan Yaltirik4, Aysegul Kuskucu1, Ferda Ozkan5, Altay Burak Dalan6, Fikrettin Sahin2, Ugur Ture4, Omer Faruk Bayrak7. 1. Department of Medical Genetics, Yeditepe University Medical School, Koftuncu Sok. Acıbadem Mah. Istek Vakfi Kat: 3 34718 No: 57/1 Kadikoy, 34755, Istanbul, Turkey. 2. Department of Biotechnology, Institute of Science, Yeditepe University, 34755, Istanbul, Turkey. 3. Department of Nanoscience and Nanoengineering, Institute of Science, Ataturk University, 25240, Erzurum, Turkey. 4. Department of Neurosurgery, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey. 5. Department of Medical Pathology, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey. 6. Department of Biochemistry, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey. 7. Department of Medical Genetics, Yeditepe University Medical School, Koftuncu Sok. Acıbadem Mah. Istek Vakfi Kat: 3 34718 No: 57/1 Kadikoy, 34755, Istanbul, Turkey. ofbayrak@yeditepe.edu.tr.
Abstract
PURPOSE: Chordomas are highly therapy-resistant primary bone tumors that exhibit high relapse rates and may induce local destruction. Here, we evaluated the effects of tumor necrosis factor-alpha (TNF-α) on chordoma progression and clinical outcome. METHODS: Chordoma cells were treated with TNF-α after which its short- and long-term effects were evaluated. Functional assays, qRT-PCR and microarray-based expression analyses were carried out to assess the effect of TNF-α on chemo-resistance, epithelial to mesenchymal transition (EMT), migration, invasion and cancer stem cell-like properties. Finally, relationships between TNF-α expression and clinicopathological features were assessed in a chordoma patient cohort. RESULTS: We found that TNF-α treatment increased the migration and invasion of chordoma cells. Also, NF-κB activation was observed along with increased EMT marker expression. In addition, enhanced tumor sphere formation and soft agar colony formation were observed, concomitantly with increased chemo-resistance and CD338 marker expression. The TNF-α and TNFR1 expression levels were found to be significantly correlated with LIF, PD-L1 and Ki67 expression levels, tumor volume and a short survival time in patients. In addition, a high neutrophil to lymphocyte ratio was found to be associated with recurrence and a decreased overall survival. CONCLUSIONS: From our data we conclude that TNF-α may serve as a prognostic marker for chordoma progression and that tumor-promoting inflammation may be a major factor in chordoma tumor progression.
PURPOSE:Chordomas are highly therapy-resistant primary bone tumors that exhibit high relapse rates and may induce local destruction. Here, we evaluated the effects of tumor necrosis factor-alpha (TNF-α) on chordoma progression and clinical outcome. METHODS:Chordoma cells were treated with TNF-α after which its short- and long-term effects were evaluated. Functional assays, qRT-PCR and microarray-based expression analyses were carried out to assess the effect of TNF-α on chemo-resistance, epithelial to mesenchymal transition (EMT), migration, invasion and cancer stem cell-like properties. Finally, relationships between TNF-α expression and clinicopathological features were assessed in a chordomapatient cohort. RESULTS: We found that TNF-α treatment increased the migration and invasion of chordoma cells. Also, NF-κB activation was observed along with increased EMT marker expression. In addition, enhanced tumor sphere formation and soft agar colony formation were observed, concomitantly with increased chemo-resistance and CD338 marker expression. The TNF-α and TNFR1 expression levels were found to be significantly correlated with LIF, PD-L1 and Ki67 expression levels, tumor volume and a short survival time in patients. In addition, a high neutrophil to lymphocyte ratio was found to be associated with recurrence and a decreased overall survival. CONCLUSIONS: From our data we conclude that TNF-α may serve as a prognostic marker for chordoma progression and that tumor-promoting inflammation may be a major factor in chordoma tumor progression.
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