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

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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.

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Acknowledgements

We thank Dr. Kadir Caner Akdemir for assistance in evaluating the microarray data using ingenuity pathway analysis and Utku Ozbey for help with Western blotting. We also thank Julie Yamamoto for her editorial assistance. This study was supported by TÜBİTAK (grant number: 112S485) and Yeditepe University Hospital.

Funding

This study was supported by TÜBİTAK (grant number: 112S485) and Yeditepe University Hospital.

Author information

Author notes

  1. Sukru Gulluoglu and Emre Can Tuysuz contributed equally to this work.

Authors and Affiliations

  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

    Sukru Gulluoglu, Emre Can Tuysuz, Aysegul Kuskucu & Omer Faruk Bayrak

  2. Department of Biotechnology, Institute of Science, Yeditepe University, 34755, Istanbul, Turkey

    Sukru Gulluoglu, Emre Can Tuysuz & Fikrettin Sahin

  3. Department of Nanoscience and Nanoengineering, Institute of Science, Ataturk University, 25240, Erzurum, Turkey

    Mesut Sahin

  4. Department of Neurosurgery, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey

    Cumhur Kaan Yaltirik & Ugur Ture

  5. Department of Medical Pathology, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey

    Ferda Ozkan

  6. Department of Biochemistry, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey

    Altay Burak Dalan

Authors
  1. Sukru Gulluoglu
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  10. Omer Faruk Bayrak
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Corresponding author

Correspondence to Omer Faruk Bayrak.

Ethics declarations

The study was approved by the institutional review board of Yeditepe University Hospital (IRB 98-3943B and 101-4621B), and written informed consent was obtained from all participants. The study was performed in accordance with the Declaration of Helsinki.

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Electronic supplementary material

Supplementary Fig. 1

General summary of ingenuity pathway analysis for one week TNF-α-treated chordoma cells versus control cells. (PNG 112 kb)

High Resolution (TIF 132 kb)

Supplementary Fig. 2

General summary of the ingenuity pathway analysis for LT-TNF-treated chordoma cells versus control cells. (PNG 119 kb)

High Resolution (TIF 142 kb)

Supplementary Fig. 3

IPA causal networks generated for long- and short-term-treated chordoma samples. TNF-α treatment elevated pathways relevant to tumor-promoting inflammation and tumor progression in chordoma cells A) Legend for the created causal prediction networks. B) Gene expression networks related to elevated inflammatory response with functions such as the activation of antigen-presenting cells, myeloid cell recruitment of phagocytes and the immune response of short-term TNF-α-treated cells. C) Gene expression networks related to the pathways of cellular movement, migration, and invasion and leukocyte infiltration in short-term TNF-α-treated cells. D) Gene expression networks related to macrophage recruitment in short-term TNF-α-treated cells. E) Gene expression networks related to tumor cell invasion and endothelial branching in LT-TNFα samples. F) Gene expression networks related to cellular movement in LT-TNFα samples. G) Gene expression networks related to the downstream VEGFA gene network in LT-TNFα-treated cells. (PDF 877 kb)

Supplementary Fig. 4

Immunohistochemical (IHC) TNF-α and TNFR1 staining of chordoma tissues. Representative images showing the low, moderate and high expression of both TNF-α and TNFR1 in chordoma tissues. Scale bar =100 μm. (PNG 596 kb)

High Resolution (TIF 848 kb)

Supplementary Table 1

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Gulluoglu, S., Tuysuz, E.C., Sahin, M. et al. The role of TNF-α in chordoma progression and inflammatory pathways. Cell Oncol. 42, 663–677 (2019). https://doi.org/10.1007/s13402-019-00454-y

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