Towards new therapies for glioblastoma treatment: role of Dkk-3 and Claudin-5.

Background Glioblastomas (GBM) are highly aggressive brain tumors commonly treated with a combination of surgery, radiation therapy, and systemic chemotherapy. However, despite recent improvement in the multimodality approach, patient median survival times range between 3 and 30 months. New data by genomic approaches have allowed the subdivision of GBM into molecular subtypes, allowing us, in this way, to identify new targets. An important role in carcinogenesis is played by Dickkopf protein-related 3, which is involved in embryonic development through its interaction and modulation of the Wnt pathway. The expression of the REIC/Dkk-3 gene is down-regulated in many tumor cell lines and could contribute to the immunomodulatory properties of the tissue microenvironment. The mutations of Wnt pathway are of clinical importance, because they lead to the onset of several cancers, including brain tumors, being also involved in tumor angiogenesis. The Wnt signaling contributes also to activity of the claudins, that are critical components of tight junctions (TJ), implicated in blood-brain barrier (BBB) formation, whose expression was altered in cerebral microvessels of human GBM. Material and Methods In the present study we investigated the Wnt-signaling-mediated role of Dkk-3 and claudin-5 in vitro on GBM cell lines, and in the histopathological study on tissues of 30 WHO grade IV GBM patients. Results We evidenced that the expression of Dkk-3 was higher in normal human astrocytes cell line (NHA) used as control compared to human GBM tissues. Similarly, intracellular claudin-5 expression was significantly lower in U-138MG, A-172, LN-18 and LN-229 cell lines, while NHA cells significantly expressed claudin-5. Conclusion Dkk-3 is able to regulate the WNT pathway, while the claudin-5 appears to interfere in maintaining the integrity of BBB permeability. By molecular analysis, our findings suggest a key role of Dkk-3 protein in GBM, as a potential tumor suppressor, evidenced by its reduced expression in tumor tissues. In addition, the down-regulation of claudin-5 observed confirms the protective role of BBB to maintain its integrity. Our research clearly demonstrated that Dkk-3 in GBM had pro-apoptotic effects up-regulating both intrinsic and extrinsic apoptotic pathways. The restoration of the levels of these proteins could induce a slowdown in tumor progression. We hypothesize that a more complete evaluation of the role of these proteins might suggest interesting new molecular targets for future therapeutic protocols.