engleski

The activation of Toll-like receptor 3 by endogenous ligands released from necrotic cancer cells

Toll-like receptors (TLRs) play a significant role in the innate immune response but they are also expressed in cancer cells where they play a dual role. They can either activate apoptosis or induce the expression of molecules involved in cancer progression and metastasis including cancer metabolic shift. We have previously published that TLR3 activation triggers metabolic reprogramming and the Warburg effect in head and neck cancer. TLRs are generally activated by ligands derived from pathogens (pathogen-associated molecular patterns, PAMPs), however, TLRs also recognize DAMPs (damage-associated molecular patterns) which have an endogenous origin, for example, tissue damage or cell death. Some of the endogenous ligands that are recognized by TLR3 are RNAs that originated from necrotic cells. Here we further explored the pro-tumorigenic role of TLR3. We aimed to determine whether TLR3 can be activated by endogenous ligands derived from cancer cells after their stressing by serum starvation, hypoxia, oxidative stress, and irradiation. We have used reporter cell lines, HEKBlue-TLR3 and HEKBlue-null, to determine the TLR3 signaling pathway activation. Cancer cell lines used in these experiments were of head and neck origin (Detroit 562, FaDu, and SQ20B). We have determined that these cell lines release endogenous ligands after their stress which can activate TLR3 and that these endogenous ligands are localized in exosomes. Additionally, we found that necrotic tumor aspirates derived from patients with head and neck cancer also activate TLR3. Our study signifies the importance of the cancer microenvironment and its influence on cancer development, progression, and metabolism. It also emphasizes that not only exogenous infections activate TLRs but also endogenous ligands already present in the tissue.

Toll-like receptor 3, exosomes, endogenous ligands

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