Cancer stem cells may be a source of malignant tumors as well as their relapses after treatment and metastases. They share many features with normal tissue stem cells but also possess mutations and other genetic and epigenetic changes that make them tumorigenic and resistant to conventional cancer therapies. The source of cancer stem cells is discussed: they may originate from normal tissue stem cells as a result of their mutations or deregulation of signaling pathways or alternatively from differentiated tumor cells as a result of dedifferentiation during tumor development. Cancer stem cells reside in a special tumor microenvironment (niche) that regulates their functions. A number of signaling pathways and molecules participate in regulating cancer stem cells features. And although there are some inconsistencies concerning cancer stem cells, their existence may change our view on cancer progression and help to develop new strategies of cancer treatment.

The embryonic development and carcinogenesis are controlled by many transcription factors. The regulatory systems involved in embryogenesis of an organ are also involved in the tumor development in the same organ. FOX family proteins are transcription factors, which play a key role in these processes. The pioneering factors of the FOXA subfamily act at the very early stages of the embryonic development by interacting with condensed chromatin and thereby enabling the expression of the formerly silent important transcription factors. The role of these factors in tumor development is currently not fully elucidated, although recent studies indicate the important contribution of the FOXA subfamily proteins at the early stages of carcinogenesis. This review is restricted to the role of the FOXA factors in embryogenesis of the pancreas and their significance in the development of the pancreatic ductal adenocarcinoma.

This review was devoted to the use of the versatile component oftumoral stroma (fibroblast activation protein, FAP) as a target of the versatile tumor therapy. The tumor is a coevolution system, which includes the microenvironment or reactive stroma differing from the normal tissue by the phenotypic and genotypic features. Important elements of the tumor microenvironment are cancer-associated fibroblasts (CAFs), which contain typical marker FAP (serine proteinase with the enzymatic activity of dipeptidyl peptidase and endopeptidase). According to the literature, more than 90% of tumors contain FAP-positive activated fibroblasts. FAP is virtually absent in normal tissues, but it is present in the embryonic and tumor tissues, which makes it a selective and versatile model. In this work, basic approaches to affecting the CAF using FAP as a target were discussed. The use of FAP as a target provides an important advantage: its proteolytic activity can be used along with the protein-targeted agents. The main directions in the therapeutic use of FAP were discussed in this work.

One of the regulators of gene expression at the post-transcriptional level are miRNAs. Due to its multifunctionality, these molecules are considered as potential targets for controlling the biological behavior of tumor cells. To date, several thousand types of microRNAs have been identified and their expression profiles have shown significant during malignant transformation of cells. In this study, we have investigated the effect of miR-106a functional inhibition on the growth, viability and apoptosis of melanoma cells. Comparative analysis of expression profiles in melanona cells and in cells of melanocytic nevi identified by the use of microarray has revealed a significant increase in the miRNA expression level in melanoma cells. Despite this, inhibition of this molecule in melanoma cells has no antitumor effect on cell proliferation, viability, migration activity and apoptosis of melanoma cells, but increases invasive activity and the ability to form colonies. The paper discusses the importance of evaluating changes in miRNA levels in melanoma and other malignancies, relationship îf miR-106a with the pathogenesis of melanoma, as well as the possible role of miR-106a in other pathologies.

Although there is a progress in understanding the causes and consequences of genetic and epigenetic changes in glioma malignant transformation, many details remain obscure and need further investigation. It is known that process of malignant transformation of gliomas is accompanied by gradual loss of LGI1 gene expression. However, genetic defects causing LGI1 inactivation have not been revealed. In this paper, we have analyzed the LGI1 gene expression in primary cultures of malignant gliomas, and compared these data with epigenetic indicators of transcriptional activity — posttranslational H3 histone modifications. We have show the presence of an epigenetic marker of gene repression H3K9me3 near the site of LGI1 transcription initiation in most (5 from 6) studied gliomas. There was not LGI1 expression in these gliomas. Only one glioma showed LGI1 expression, and in this glioma there was no association of LGI1gene with H3K9me3 modification. Thus, we are the first to show a correlation between LGI1 gene expression and the epigenetic indicator H3K9met3 in malignant gliomas. Marker of actively transcribed chromatin Í3K4àñ have not been found in this area of the genome. The data obtained strongly suggest the possibility of gene LGL1 inactivation by epigenetic mechanism: modified «histone code».

Microribonucleic acids (miRNAs) are a class of noncoding RNAs that regulate posttranscriptional gene expression. These molecules are regulators of cell proliferation, metabolism, apoptosis, and differentiation. MiRNAs are not degraded by RNAases and their concentrations can be measured in different body fluids, including serum. The expression of miRNAs varies in intact tissues and tumors, including pituitary adenomas. Pituitary tumors are encountered in 22.5% of the population and, in a number of cases, may be asymptomatic, but in case of invasion or/and hormone overproduction, their clinical presentation is severe with multiple symptoms leading to disability and even death. The mechanisms for the development and progression of pituitary tumors and the markers for remission and recurrence have not been adequately investigated. This literature review discusses the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers.

The aim was to study bioinformatics involvement of candidate genes of cytokines in the formation of large fibroids in women with uterine cancer in older age groups. Genotyping of 15 molecular genetic markers cytokines was performed in 120 patients with uterine myoma with large myoma nodes and 107 patients with myoma nodes of small size. The study found that genetic risk factors for fibroids with large uterine fibroids are two combinations of genetic variants: G SDF-1, CC IL-1β, A RANTES (OR=5,56) and A RANTES with genotype CC IL-1β (OR=4,60). 12 of 15 polymorphic loci studied in various combinations (8 revealed significant combinations) have protective value in the formation of large fibroids with uterine cancer (OR=0,09-0,31).

Telomerase is a ribonucleoprotein enzyme that elongates telomeres and therefore maintains chromosomal stability in germline, and in the majority of cancer cells, during cell doubling. However, up to 30 % of human tumors of different types do not express telomerase, but instead use an alternative lengthening of telomeres (ALT). Here authors show that human tumor-derived ALT cell lines express a LINE-1 (L1) retrotransposon, which suggests its participation in telomere maintenance, possibly by a «slippage» mechanism of telomeric DNA synthesis. Moreover, suppression of the L1 encoded reverse transcriptase activity using an antisense strategy, or treatment of the ALT cells with the reverse transcriptase inhibitor 3'-azido-2',3'-dideoxythymidine (AZT), induces progressive telomere loss, arrest in G2-phase of the cell cycle, and, eventually, in cancer cell death. This finding suggests an exciting opportunity for the cure of up to 30 % of cancer cases.

The RNA-seq approach for prostate cancer candidate RNA biomarkers screening in plasma and urine obtained by minimally invasive or noninvasive methods is proved to be feasible. Significant amount of RNA biomarkers associated with prostate cancer according to the literature were found in plasma and urine samples obtained from patients with benign prostatic hyperplasia (BPH). The number of detected markers was shown to vary in accordance with method of library preparation used for transcriptome profiling. The detection of known RNA biomarkers for prostate cancer in urine and plasma samples shows the feasibility of such method for minimally invasive diagnostics. The fact of presence of the same RNA biomarkers in samples from patients with BPH suggests their possible lack of specificity and confirms the need for further research in this area.

Hallmark of neuroblastoma is an ability of this malignant tumor to undergo spontaneous regression or differentiation into benign tumor during any stage of the disease, but it is little known about mechanisms of these phenomena. We studied effect of receptor tyrosine kinase receptor KIT on expression of genes, which may be involved in tumor spontaneous regression. Downregulation of KIT expression by RNA interference in SH-SY5Y cells causes suppression of neurotrophin receptor NGFR expression that may promote the loss of sensibility of cells to nerve growth factors, also it causes upregulation of TrkA receptor expression which can stimulate cell differentiation or apoptosis in NGF dependent manner. Furthermore there is an upregulation of genes which stimulate malignant cell detection by immune system, such as genes of major histocompatibility complex HLA class I HLA-B and HLA-C, and interferon-γ receptors IFNGR1 and IFNGR2 genes. Thus KIT can mediate neuroblastoma cell sensibility to neurotrophins and immune system components--two factors directly contributing to spontaneous regression of neuroblastoma.

In this study we evaluated c-kit, VEGFA, and MYC gene expression level in seven neuroblastoma stable cell lines: SK-N-SH, SK-N-BE, SK-N-AS, SH-SY5Y, Kelly, IMR-32, and LAN-1. Expression levels of these genes can serve as diagnostic factors of cancer progression, and proteins encoded by these genes are promising targets for neuroblastoma treatment. SH-SY5Y and SK-N-AS cells have highest MYC expression and the same VEGFA expression, although SH-SY5Y has 10 times higher c-kit expression than SK-N-AS cells. Both IMR-32 and LAN-1 cells have low MYC expression level, but differ in c-kit expression, IMR-32 has significantly higher c-kit expression, than any other neuroblastoma cell line. LAN-1 on the other hand has the highest VEGFA expression. These data suggest that MYC, c-kit, and VEGFA genes can play different roles in development and progression of neuroblastoma depending on other activated molecular mechanisms in malignant cells.

Melanoma is the most lethal malignancy of skin, which is comprised of clinically relevant molecular subsets defined by specific "driver" mutations in BRAF, NRAS, and KIT genes. Recently, the better results in melanoma treatment were obtained with the mutation-specific inhibitors that have been developed for clinical use and target only patients with particular tumor genotypes. The aim of the study was to characterize the spectrum of "driver" mutations in melanoma subtypes from 137 patients with skin melanoma and 14 patients with mucosal melanoma. In total 151 melanoma cases, the frequency of BRAF, NRAS, KIT, PDGFRA, and KRAS mutations was 55.0, 10.6, 4.0, 0.7, and 0.7%, respectively. BRAF mutations were found in 69% of cutaneous melanoma without UV exposure and in 43% of cutaneous melanoma with chronic UV exposure (p=0.045), rarely in acral and mucosal melanomas. Most of melanomas containing BRAF mutations, V600E (92%) and V600K (6.0%) were potentially sensitive to inhibitors vemurafenib and dabrafenib. NRAS mutations were more common in cutaneous melanoma with chronic UV exposure (26.0%), in acral and mucosal melanomas; the dominant mutations being Q61R/K/L (87.5%). KIT mutations were found in cutaneous melanoma with chronic UV exposure (8.7%) and mucosal one (28.6%), but not in acral melanoma. Most of KIT mutations were identified in exon 11; these tumors being sensitive to tyrosine kinase inhibitors. This is the first monitoring of BRAF, NRAS, KIT, PDGFRA, and KRAS hotspot mutations in different subtypes of melanoma for Russian population. On the base of data obtained, one can suppose that at the molecular level melanomas are heterogeneous tumors that should be tested for "driver" mutations in the each case for evaluation of the potential sensitivity to target therapy. The obtained results were used for treatment of melanoma patients.

Several polymorphisms in melanocortin-1 receptor (MC1R) gene are shown to have associations with melanoma risk. In particular, rs1805007, rs1805008, and rs1805009 mutations causing the corresponding R151C, R160W, and D294H changes and associated with the phenotype ("red-hair mutations") are connected with melanoma and non-melanoma skin cancer risks. The work describes the approach to detect these polymorphisms based on primer extension reaction with the following dual bioluminescent assay. Model plasmids with polymorphic MC1R fragments as well as several clinical DNA samples were tested using the developed technique. The results were in good correlation with those obtained by Sanger sequencing.

Acute lymphoblastic leukaemia (ALL) is the most common subtype of childhood cancer. Detection of a specific gene rearrangement allows the identification of prognostically relevant subgroups in childhood B-ALL. There are four common gene rearrangements which are widely studied to see prognostical values (TEL-AML1, BCR-ABL, E2A-PBX1, MLL-AF4) in childhood B-ALL. In this study we show the prevalence of these common gene rearrangements and also explain the way to identify some rare breakpoints which also occur in these gene rearrangements. 97 samples received for diagnosis from paediatric B-ALL patients were included in this study. Qualitative reverse transcriptase PCR was used for detection of the TEL-AML1-t(12;21), E2A-PBX1-t(1;19), BCR-ABL1-t(9;22) and MLL-AF4 t(4;11) fusion transcripts. Unusually sized amplicons were confirmed by FISH and DNA sequencing to confirm atypical breakpoints. Amongst the paediatric B-ALL samples t(12;21), was detected in (∼20%), t(9;22), was detected in (∼8%), t(1;19) was detected in (∼9%) and t(4;11) was detected in 2 cases. t(12;21) with intron 1of the AML1 gene was detected as the most common gene rearrangement in paediatric ALL, whereas one rare form of the TEL-AML1 breakpoint in which TEL is fused with intron 2 of AML1 was also observed. In the t(9;22) breakpoints e13a2, e14a2 and e1a2 were detected as the common breakpoints. Two atypical and rare breakpoint of t(9;22) were detected namely e6a2 and e13a3 in paediatric ALL. TEL-AML1 was found to be the most common translocation in Paediatric B-ALL. Identification of the rare breakpoints through RT-PCR technique requires designing of PCR in such a way that it can detect these rare breakpoints also.

Enhancers make up a huge class of genome regulatory elements that play an important role in the formation and maintenance of specific patterns of gene transcriptional activity in all types of cells. In recent years, high-throughput methods for the genome-wide epigenetic analysis of chromatin have made it possible to identify structural and functional features of enhancers and their role in the spatial and functional organization of the genome and in the formation and maintenance of cell identity, as well as in the pathogenesis of certain diseases. Special attention has been focused on genome regions called super-enhancers, or stretch enhancers, which consist of clusters of elements with properties of classic enhancers. This review considers current data on specific properties of super-enhancers and their role in the formation of interconnected autoregulatory circuits with positive feedback that regulates the most important genes, the activity of which underlies the formation and maintenance of specialized cellular functions.

The article presents the data on the structure and mechanisms of β-catenin functioning. The basic aspects of the role of β-catenin in malignant transformation have been studied at various tumors. Primary structure of β-catenin allows it to interact with many factors and ligands, including transcription factors, α-catenin, cadherin, Axin, Rho family GTPases, Bcl9 et al. This interaction is the base for β-catenin's intracellular multi-functioning. The review presents data on the participation of β-catenin in the mechanisms of adhesion, regulation of RNA metabolism, formation contacts with the cytoskeleton and its role in the canonical Wnt signaling pathway, marked examples pro-inflammatory and anti-inflammatory effects of β-catenin. The β-catenin involvement in malignant transformation and progression of certain tumors is not in doubt. The data on the changes in β-catenin expression in the given examples of colon cancer, prostate cancer, different forms of thyroid cancer and hepatocellular carcinoma are presented with the prospects of its use as a marker and a predictor of malignant transformation. Continued research in this area will not only make use of β-catenin as a potential predictor of malignant tumors, but also to develop approaches to targeted therapy.

Recent data on adult stem cells are reviewed. According to the present dominant paradigm, it is most probable that cancer predisposition arises or cancer is initiated in these cells.

The database of publications on molecular epidemiology of RET/PTC rearrangements in sporadic and radiogenic thyroid papillary carcinoma has been formed (197 sources at the end of 2014; coverage of 100%). Based on this database a pooled analysis of data on the rates of RET/PTC1, RET/PTC3 and RET/PTC in total was conducted. Statistical approach involves a simple pooling, as well as calculations on the models of random and fixed effects. Since almost all the strata were characterized by heterogeneity, simple pooling and random effect models were adequate. Calculations using both models led to almost identical results. For rates of RET/PTC1, RET/PTC3 and RET/PTC in total with respect to formed carcinoma striations the following values (pooling, in %) were obtained: sporadic, total--13.2; 8.9; 21.2; sporadic, adults--13.3; 9.9; 21.1; sporadic, children--22.4; 17.5; 44.5; radiogenic, total--20.9; 20.3; 40.4; radiotherapy (exposure in childhood)--31.1; 11.8; 42.5; children affected after the Chernobyl accident--19.9; 23.6; 46.1; radiological incidents (exposure in adulthood)--19.9; 7.7; 18.4. Statistically proven is the reliability of differences of carcinoma indicators for children compared with adults (both sporadic and radiogenic tumors) and for radiogenic cancer compared with sporadic. The greatest increase in rate after irradiation was found for RET/PTC1, previously characterized in vitro as one of radiogenic types of RET/PTC.

The major features of extracellular vesicles secreted by mammalian cells are considered. Cell activation caused by formation of pathology stimulates the secretion acutely. The vesicles (exosomes, microvesicles) are enriched with annexin V, tetraspanin, miRNA. Exosomes are enriched especially by integrins, heat shock proteins. Microvesicles contain elevated amounts of tissue factors, phosphatidylserine, mRNA. The vesicles carry information about the pathological process, and microvesicles contain more proteins characteristic of inflammation and death than exosomes. They are important mediators of inflammation and infection in the body, have different effects on the immune system and the processes of carcinogenesis and neurodegeneration. However, antigenic profiles of extracellular vesicles differ not profoundly in various pathologies and so far they help diagnostics limitedly. The vesicles carry signals of genetic reprogramming of the cells and epigenetic stimulation, connected with both protein factors and mRNA and miRNA. Profiles of miRNA vesicles produced by the various pathological sources are studied actively and are useful as indicators of source and stage of cancer. Some ways of therapeutic use of the vesicles are also considered.

Pheochromocytoma (PCC)/paraganglioma is a catecholamine-secreting tumor of the paraganglion. The hereditary variants of PCC have been previously considered to occur in 10% of cases. The latest researches have clearly demonstrated that the hereditary cause of chromaffin tumors is revealed in a much larger number of patients. There have been the most investigated NF, RET, VHL, SDHD, SDHC, and SDHB gene mutations. New EGLN1/PHD2, KIF1B, SDH5/SDHAF2, IDH1, TMEM127, SDHA, MAX, and HIF2A gene mutations have been recently discovered. This review describes new ideas of the genetic bases of PCC. The authors discuss criteria for patient referral for genetic examination on the basis of the phenotypic.manifestations of mutations, such as a malignant course, bilateral adrenal lesion, and age at disease manifestations. Recommendations are determined for carriers to screen for the components of hereditary pathology.