Necrotic Cells from Head and Neck Carcinomas Release Biomolecules That Are Activating Toll-like Receptor 3

Scientific paper - Original scientific paper

• Author: Tea Vasiljević
• Author: Marko Tarle
• Author: Koraljka Hat
• Author: Ivica Lukšić
• Author: Martina Mikulandra
• Author: Pierre Busson
• Author: Tanja Matijević Glavan
• Author's institution: University of Zagreb; School of Medicine; (Department of Maxillofacial Surgery and Dentistry)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Surgery

Abstract (english)

Tumor necrosis is a recurrent characteristic of head and neck squamous cell carcinomas (HNSCCs). There is a need for more investigations on the influence of biomolecules released by these necrotic foci in the HNSCC tumor microenvironment. It is suspected that a fraction of the biomolecules released by necrotic cells are damage-associated molecular patterns (DAMPs), which are known to be natural endogenous ligands of Toll-like receptors (TLRs), including, among others, proteins and nucleic acids. However, there has been no direct demonstration that biomolecules released by HNSCC necrotic cells can activate TLRs. Our aim was to investigate whether some of these molecules could behave as agonists of the TLR3, either in vitro or in vivo. We chose a functional approach based on reporter cell exhibiting artificial TLR3 expression and downstream release of secreted alkaline phosphatase. The production of biomolecules activating TLR3 was first investigated in vitro using three HNSCC cell lines subjected to various pronecrotic stimuli (external irradiation, serum starvation, hypoxia and oxidative stress). TLR3 agonists were also investigated in necrotic tumor fluids from five oral cancer patients and three mouse tumor grafts. The release of biomolecules activating TLR3 was demonstrated for all three HNSCC cell lines. External irradiation was the most consistently efficient stimulus, and corresponding TLR3 agonists were conveyed in extracellular vesicles. TLR3-stimulating activity was detected in the fluids from all five patients and three mouse tumor grafts. In most cases, this activity was greatly reduced by RNAse pretreatment or TLR3 blocking antibodies. Our data indicate that TLR3 agonists are consistently present in necrotic fluids from HNSCC cells and mainly made of dsRNA fragments. These endogenous agonists may induce TLR3, which might lead to a protumorigenic effect. Regarding methodological aspects, our study demonstrates that direct investigations—including functional testing—can be performed on necrotic fluids from patient tumors.

• Keywords (english): Animals; Head and Neck Neoplasms; Humans; Mice; Necrosis / metabolism; Squamous Cell Carcinoma of Head and Neck; Toll-Like Receptor 3 / metabolism; Toll-Like Receptor 9; Toll-Like Receptors; Tumor Microenvironment
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Published version
• Journal title: International Journal of Molecular Sciences
• Numbering: vol. 24, no. 20, 15269
• e-ISSN: 1422-0067
• DOI: https://doi.org/10.3390/ijms242015269
• URN:NBN: urn:nbn:hr:105:413702
• Publication: 2023-10-17
• Project: Number: IP-2020-02-4225; Title (croatian): Toll-like receptor 3 u razvoju i liječenju tumora glave i vrata: uloga endogenih liganada; Title (english): Toll-like receptor 3 in the development and treatment of human head and neck cancer: the role of endogenous ligands; Acronym: TollTreatTum; Leader: Tanja Matijević Glavan; Jurisdiction: Croatia; Funding stream: Research Projects
• Document URL: https://www.mdpi.com/1422-0067/24/20/15269
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-05-10 07:57:19