The association between the wnt signaling pathway and apoptosis has become more firmly established in the recent scientific literature. Many reports indicate that the wnt signaling pathway regulates ...apoptosis through a variety of mechanisms.The activity of wnt signaling according to specific cellular environment stimuli can either foster or restrain the processes of apoptosis. Wnt signaling regulates the early and late stages of apoptosis in both development and cellular injury in populations of neurons, endothelial cells, vascular smooth muscle cells and cardiomyocytes.In this review I draw attention to genes and proteins of the wnt signaling pathway involved in apoptosis and describe some of their functional effects.
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The acquisition of genomic instability is one of the key characteristics of the cancer cell, and microsatellite instability (MSI) is an important segment of this phenomenon. This review aims to ...describe the mismatch DNA repair (MMR) system whose deficiency is responsible for MSI and discuss the cellular roles of MMR genes. Malfunctioning of the MMR repair pathway increases the mutational burden of specific cancers and is often involved in its etiology, sometimes as an influential bystander and sometimes as the main driving force. Detecting the presence of MSI has for a long time been an important part of clinical diagnostics, but has still not achieved its full potential. The MSI blueprints of specific tumors are useful for precize grading, evaluation of cancer chance and prognosis and to help us understand how and why therapy-resistant cancers arise. Furthermore, evidence indicates that MSI is an important predictive biomarker for the application of immunotherapy.
On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the ...survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the infiltrative capability of gliomas, as well as its resistance to therapy, recurrence and aggressive behavior, lies in a small subset of tumor-initiating cells that behave like stem cells and are known as glioma cancer stem cells (GCSCs). They are responsible for tumor plasticity and are influenced by genetic drivers. Additionally, GCSCs also display greater migratory abilities. A great effort is under way in order to find ways to eliminate or neutralize GCSCs. Many different treatment strategies are currently being explored, including modulation of the tumor microenvironment, posttranscriptional regulation, epigenetic modulation and immunotherapy.
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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.
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This reprint encompasses a number of articles that focus on the molecular blueprint of brain tumors. A collection of relevant papers in the rapidly expanding field of brain tumor molecular genetics ...broadens our knowledge about the biology of brain tumors, and inspires further studies that will improve the diagnosis and clinical management of brain tumors. Due to the great heterogeneity of brain tumors it is important to research and understand every aspect of their initiation, progression and metastasis in order to design better diagnostic and therapeutic approaches for their clinical management and patient benefit.
Here, we present a rarely seen example of bilateral meningiomas exhibiting different malignancy grades, I (meningothelial) and II (atypical), recorded in a 72-year-old patient. The presence of two ...separated lesions of different grades in a single patient can elucidate meningioma progression. To this end, the involvement of specific protein markers of epithelial to mesenchymal transition (EMT), the process responsible for progression, was tested in both tumors. Protein expression status of specific epithelial (E-cadherin) and mesenchymal markers (N-cadherin, SNAIL&SLUG and TWIST1) was investigated. Furthermore, markers that are connected to Wnt signaling pathway-beta-catenin, GSK3beta and DVL1-were also analyzed. For signs of neurofibromatosis and schwanomatosis genetic testing was performed. Immunohistochemistry evaluated by immunoreactivity score (IRS) was used to determine the signal strengths and proteins' location. Our results indicated that, in comparison to the grade I tumor, mesenchymal markers SNAIL and SLUG were upregulated in the atypical meningioma. TWIST1, beta-catenin and GSK3beta were upregulated in both grades, while E-cadherin was partially lost. A pronounced cadherin switch could not be established; however, N-cadherin showed widespread tissue presence. Genetic testing did not detect changes of
or
genes denying germline origin of the lesions. The rare presence of two different grades in one patient elucidate previously unknown molecules involved in meningioma progression.
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This review presents current knowledge on the molecular biology of retinoblastoma (RB). Retinoblastoma is an intraocular tumor with hereditary and sporadic forms. 8,000 new cases of this ocular ...malignancy of the developing retina are diagnosed each year worldwide. The major gene responsible for retinoblastoma is RB1, and it harbors a large spectrum of pathogenic variants. Tumorigenesis begins with mutations that cause RB1 biallelic inactivation preventing the production of functional pRB proteins. Depending on the type of mutation the penetrance of RB is different. However, in small percent of tumors additional genes may be required, such as MYCN, BCOR and CREBBP. Additionally, epigenetic changes contribute to the progression of retinoblastoma as well. Besides its role in the cell cycle, pRB plays many additional roles, it regulates the nucleosome structure, participates in apoptosis, DNA replication, cellular senescence, differentiation, DNA repair and angiogenesis. Notably, pRB has an important role as a modulator of chromatin remodeling. In recent years high-throughput techniques are becoming essential for credible biomarker identification and patient management improvement. In spite of remarkable advances in retinoblastoma therapy, primarily in high-income countries, our understanding of retinoblastoma and its specific genetics still needs further clarification in order to predict the course of this disease and improve therapy. One such approach is the tumor free DNA that can be obtained from the anterior segment of the eye and be useful in diagnostics and prognostics.
E-cadherin tumor suppressor genes are particularly active area of research in development and tumorigenesis. The calcium-dependent interactions among E-cadherin molecules are critical for the ...formation and maintenance of adherent junctions in areas of epithelial cell-cell contact. Loss of E-cadherin-mediated-adhesion characterises the transition from benign lesions to invasive, metastatic cancer. Nevertheless, there is evidence that E-cadherins may also play a role in the wnt signal transduction pathway, together with other key molecules involved in it, such as beta-catenins and adenomatous poliposis coli gene products.The structure and function of E-cadherin, gene and protein, in normal as well as in tumor cells are reviewed in this paper.
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Key regulators of the Wnt signalling, DVL1, DVL2 and DVL3, in astrocytomas of different malignancy grades were investigated. Markers for DVL1, DVL2 and DVL3 were used to detect microsatellite ...instability (MSI) and gross deletions (LOH), while immunohistochemistry and immunoreactivity score were used to determine the signal strengths of the three DVL proteins and transcription factors of the pathway, TCF1 and LEF1. Our findings demonstrated that MSI at all three DVL loci was constantly found across tumour grades with the highest number in grade II (P = 0.008). Collectively, LOHs were more frequent in high‐grade tumours than in low grade ones. LOHs of DVL3 gene were significantly associated with grade IV tumours (P = 0.007). The results on protein expressions indicated that high‐grade tumours expressed less DVL1 protein as compared with low grade ones. A significant negative correlation was established between DVL1 expression and malignancy grades (P < 0.001). The expression of DVL2 protein was found similar across grades, while DVL3 expression significantly increased with malignancy grades (P < 0.001). The signal strengths of expressed DVL1 and DVL3 were negatively correlated (P = 0.002). However, TCF1 and LEF1 were both significantly upregulated and increasing with astrocytoma grades (P = 0.001). A positive correlation was established between DVL3 and both TCF1 (P = 0.020) and LEF1 (P = 0.006) suggesting their joint involvement in malignant progression. Our findings suggest that DVL1 and DVL2 may be involved during early stages of the disease, while DVL3 may have a role in later phases and together with TCF1 and LEF1 promotes the activation of Wnt signalling.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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