Research Papers:

TLR-4/Wnt modulation as new therapeutic strategy in the treatment of glioblastomas

Giovanna Casili, Maria Caffo, Michela Campolo, Valeria Barresi, Gerardo Caruso, Salvatore M. Cardali, Marika Lanza, Raffaella Mallamace, Alessia Filippone, Alfredo Conti, Antonino Germanò, Salvatore Cuzzocrea and Emanuela Esposito _

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Oncotarget. 2018; 9:37564-37580. https://doi.org/10.18632/oncotarget.26500

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Giovanna Casili1, Maria Caffo2, Michela Campolo1, Valeria Barresi3, Gerardo Caruso2, Salvatore M. Cardali2, Marika Lanza1, Raffaella Mallamace4, Alessia Filippone1, Alfredo Conti2, Antonino Germanò2, Salvatore Cuzzocrea1 and Emanuela Esposito1

1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy

2Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Unit of Neurosurgery, University of Messina, Messina, Italy

3Department of Human Pathology, University of Messina, Messina, Italy

4Unit of Anesthesia, University of Messina, Messina, Italy

Correspondence to:

Emanuela Esposito, email: [email protected]

Keywords: glioblastomas; TLR-4; Wnt; Dkk-3; claudin-5

Received: February 19, 2018     Accepted: December 13, 2018     Published: December 25, 2018


Purpose: Glioblastomas are highly aggressive brain tumors. Various pathways are involved in gliomagenesis, among which the Wingless (Wnt) signaling. Dickkopf protein-related protein 3 (Dkk-3) interacts with proteins of Wnt pathwayas inhibitor. The Wnt signaling contributes to activity of the claudins, that are critical components of tight junctions, whose expression was altered selectively in cerebral microvessels of glioblastoma. The aim of this study was to determine the role of Wnt pathways in the regulation of tumor growth, apoptosis process by targeting Dkk-3, tight junctions alteration involving claudin-5, suggesting possible therapeutic interactions involving Wnt/Toll-like receptors (TLRs) pathways.

Results: We showed a significant decreasing of Dkk-3 and claudin-5 in human glioblastoma cell lines, as well as in U-87 MG xenograft tumors and in glioblastoma human patient’s tissues, with an involvement of the apoptosis process. Also, an interesting TLR-4/Wnt modulation highlighted that the absence of TLR-4 determined resistance to the tumor onset.

Conclusions: We concluded that combined modulation of Wnt/Dkk-3/claudin-5 and TLR-4 pathways, simultaneously targeting apoptosis and survival signaling defects, might shift the balance from tumor growth stasis to cytotoxic therapeutic responses, flowing in greater therapeutic benefits.

Methods: In the present study we investigated the expression of Dkk-3, claudin-5, apoptosis markers and TLR-4 receptor protein levels in in vitro studies on U-138MG, A-172, LN-18 and LN-229 human glioblastoma cell lines, and in vivo study using TLR-4 KO mice and in glioblastoma human patient’s tissues.

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