Abstract 1458: Toll-like receptors 1, 2, 4 and 6 expression levels in diffusely infiltrative astrocytomas

Abstract

Abstract Toll-like receptors (TLRs) are the first receptors of the immune system that identify disturbances in homeostasis, capable of recognizing molecules associated to cell and tissue damage. TLRs signaling pathway activates inflammatory transcription factors, mainly Nuclear Factor-kappa B (NF-kB) and Interferon Regulatory Factors (IRF3/7). Due to their importance in inflammatory process, TLRs are research hot targets for therapy in several diseases, including cancer. This study aims to analyze TLRs (1, 2, 4 and 6) expressions in human diffusely infiltrative astrocytomas, WHO grades II to IV of malignancy (AGII-AGIV), and correlate their expressions among them and with the clinical outcome of AGIV (glioblastoma, GBM) patients. TLRs mRNA levels were evaluated by qRT-PCR in 143 astrocytoma samples and 22 non-neoplastic (NN) brain specimens from epilepsy surgery. Upregulated mRNA levels of all studied TLRs were observed in astrocytomas compared to NN cases (p<0.05), except for TLR2 in AGII. TLR1 and TLR2 median expression values increased according to astrocytoma malignancy. TLRs mRNA expressions presented positive correlation with significance (p<0.05) in all grades of astrocytoma, except for TLR2 and TLR4 in AGIII. Strong associations (r<0.7) were detected with TLR1-TLR2 mRNA expressions among AGII, AGIII and AGIV, TLR1-TLR4 in AGIII, and TLR6-TLR1 in AGII. In GBM patients, TLR2 upregulation was associated to better outcome with longer overall survival (p<0.007). The same was verified for concomitant upregulation of TLR1, 2 and 4 (p<0.05). Aiming to analyze the distribution of these receptors in different cells present in the tumor, we performed immunofluorescence staining of GBM cell lines (A172 and U87MG). All TLRs were detected in both cell lines, indicating that their expression were not limited to immune cells. The current literature has described controversial roles for the TLRs in cancer, either activating an anti-inflammatory condition leading to tumor progression or a pro-inflammatory state leading to tumor abrogation. TLRs distribution among different cells in the tumor environment might be relevant for the inflammatory process. Our findings of TLRs on tumor cells may suggest a tendency towards an anti-inflammatory state. The comprehension of TLRs role in each cell type, that compose the tumor, may help to determine the signaling pathways involved in diffusely infiltrative astrocytoma progression, and potential new therapeutic strategies. Citation Format: Isabele F. Moretti, Daiane Gil Franco, Roseli Silva, Thais F. Galatro, Sueli M. Oba-Shinjo, Suely K.N. Marie. Toll-like receptors 1, 2, 4 and 6 expression levels in diffusely infiltrative astrocytomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1458.