In a continuous search for the improvement of antitumor therapies, the inhibition of the Wnt signaling pathway has been recognized as a promising target. The altered functioning of the Wnt signaling in human tumors points to the strategy of the inhibition of its activity that would impact the clinical outcomes and survival of patients. Because the Wnt pathway is often mutated or epigenetically altered in tumors, which promotes its activation, inhibitors of Wnt signaling are being intensively investigated. It has been shown that knocking down specific components of the Wnt pathway has inhibitory effects on tumor growth in vivo and in vitro. Thus, similar effects are expected from the application of Wnt inhibitors. In the last decades, molecules acting as inhibitors on the pathway’s specific molecular levels have been identified and characterized. This review will discuss the inhibitors of the canonical Wnt pathway, summarize knowledge on their effectiveness as therapeutics, and debate their side effects. The role of the components frequently mutated in various tumors that are principal targets for Wnt inhibitors is also going to be brought to the reader’s attention. Some of the molecules identified as Wnt pathway inhibitors have reached early stages of clinical trials, and some have only just been discovered. All things considered, inhibition of the Wnt signaling pathway shows potential for the development of future therapies.

Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.

Epithelial to mesenchymal transition (EMT), which is characterized by the reduced expression of E-cadherin and increased expression of N-cadherin, plays an important role in the tumor invasion and metastasis. Classical Wnt signaling pathway has a tight link with EMT and it has been shown that nuclear translocation of β-catenin can induce EMT. This research has showed that genes that are involved in cadherin switch, CDH1 and CDH2, play a role in meningioma progression. Increased N-cadherin expression in relation to E-cadherin was recorded. In meningioma, transcription factors SNAIL, SLUG, and TWIST1 demonstrated strong expression in relation to E- and N-cadherin. The expression of SNAIL and SLUG was significantly associated with higher grades (p = 0.001), indicating their role in meningioma progression. Higher grades also recorded an increased expression of total β-catenin followed by an increased expression of its active form (p = 0.000). This research brings the results of genetic and protein analyzes of important molecules that are involved in Wnt and EMT signaling pathways and reveals their role in intracranial meningioma. The results of this study offer guidelines and new markers of progression for future research and reveal new molecular targets of therapeutic interventions.

A collection of intracranial astrocytomas of different malignancy grades was analyzed for copy number aberrations (CNA) in order to identify regions that are driving cancer pathogenesis. Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) and bioinformatics utilizing a Bioconductor package, Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID software. Altogether, 1438 CNA were found of which losses prevailed. On our total sample, significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11, 22q12.3 remained significant even at 0.05 q-value. When divided into malignancy groups, the regions identified as significantly deleted in high grades were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while amplified were: 3q28; 12q13.3 and 21q22.3. Low grades comprised significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 indicating their involvement in early stages of tumorigenesis. Significantly enriched pathways were: PI3K-Akt, Cytokine-cytokine receptor, the nucleotide-binding oligomerization domain (NOD)–like receptor, Jak-STAT, retinoic acid-inducible gene (RIG)-I-like receptor and Toll-like receptor pathways. HPV and herpex simplex infection and inflammation pathways were also represented. The present study brings new data to astrocytoma research amplifying the wide spectrum of changes that could help us identify the regions critical for tumorigenesis.

In the present study, we investigated genetic and epigenetic changes and protein expression levels of negative regulators of Wnt signaling, DKK1, DKK3, and APC as well as glycogen synthase kinase 3 (GSK3β) and β-catenin in 64 human astrocytomas of grades II–IV. Methylation-specific PCR revealed promoter methylation of DKK1, DKK3, and GSK3β in 38%, 43%, and 18% of samples, respectively. Grade IV comprised the lowest number of methylated GSK3β cases and highest of DKK3. Evaluation of the immunostaining using H-score was performed for β-catenin, both total and unphosphorylated (active) forms. Additionally, active (pY216) and inactive (pS9) forms of GSK3β protein were also analyzed. Spearman’s correlation confirmed the prevalence of β-catenin’s active form (r_s = 0.634, p < 0.001) in astrocytoma tumor cells. The Wilcoxon test revealed that astrocytoma with higher levels of the active pGSK3β-Y216 form had lower expression levels of its inactive form (p < 0.0001, Z = −5.332). Changes in APC’s exon 11 were observed in 44.44% of samples by PCR/RFLP. Astrocytomas with changes of APC had higher H-score values of total β-catenin compared to the group without genetic changes (t = −2.264, p = 0.038). Furthermore, a positive correlation between samples with methylated DKK3 promoter and the expression of active pGSK3β-Y216 (r_s = 0.356, p = 0.011) was established. Our results emphasize the importance of methylation for the regulation of Wnt signaling. Large deletions of the APC gene associated with increased β-catenin levels, together with oncogenic effects of both β-catenin and GSK3β, are clearly involved in astrocytoma evolution. Our findings contribute to a better understanding of the etiology of gliomas. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations.

In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active β-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway.