Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer that is mainly diagnosed at advanced stages. Since molecular markers that are currently used in clinical practice are not sensitive enough for effective diagnosis of HCC, active search of new biomarkers is underway. Usе of minimally invasive liquid biopsy allows to detect specific markers of tumor growth and particularly alterations  of gene methylation patterns in cell-free DNA distinctive for HCC, in biological liquids of patients. In the present review the most promising diagnostic and prognostic methylation biomarkers that were detected in cell-free DNA of HCC patients are being considered.

Macrophages are the key cells of the innate immune system. One of the main functions of macrophages is the regulation of inflammation. Being common in all tissues and organs of the human body, tissue macrophages control their condition and guarantee a timely and effective response to damage, pathogen penetration or cell transformation. After eliminating the cause of inflammation, macrophages initiate the processes of healing and restoration of tissue homeostasis. At the end of the 20^th century, the concept of macrophage activation dichotomy was proposed, which divided them into classically (M1) and alternatively (M2) activated ones. The development of this concept has led to the description of a wide variety of macrophage phenotypes. At the same time, M2 continues to be considered a prototype of tumor associated macrophages (TAM).

TAM represent one of the most important cell types in the tumor microenvironment. Like all macrophages, they have a certain level of heterogeneity and plasticity, which develop under the influence of cytokines and growth factors produced by tumor cells. TAM, in turn, produces growth factors, cytokines and extracellular matrix components that support the progression of the tumor and increase its malignant potential. Numerous clinical studies have shown that the amount of TAM is often correlated with a poor prognosis of the disease. TAM perform a large number of functions necessary to maintain tumor progression. They are capable of stimulating angiogenesis and reorganization of the vascular system. Since the role of TAM in tumor development has become apparent, various attempts have been made to use them in the clinic.  It can be confidently asserted that various TAM markers are very attractive as diagnostic and prognostic markers of various tumors, and also as promising targets for the development of new targeted therapeutic agents.

Bispecific antibody molecules contain two different antigen-binding centers. Particular interest in bispecific antibodies is due to their therapeutic application. Two preparations of therapeutic bispecific immunoglobulins, approved for use in the US and European countries, are aimed at the treatment of cancer. Studies published in recent years are devoted to various methods of obtaining monoclonal bispecific antibodies, to study their physicochemical properties, biological activity, preclinical and clinical trials. This paper reviews different approaches  to the production of antitumor bispecific immunoglobulins, as well as the prospects for their practical application.

The presented review is devoted to the analysis of molecular mechanisms of action for different natural DNA-tropic compounds with established tumor preventive activity. Here we present their cancer preventive effects observed in vivo, mechanisms of DNA binding, influence on epigenetic regulation and “housekeeping” protein function. Additionally, the influence of these compounds on DNA helix parameters is discussed that should impact on epigenetic regulation of gene expression and formation of topologically associated domains.

The basic characteristics of tumours are ability for invasiveness and metastasis. These properties are realized due to destruction of intercellular matrix caused with acidification of intercellular area stimulated with transition from tissue respiration to glycolysis. The transition  to glycolysis in tumor cells is observed not only during hypoxic state how is realized in normal cells but also during oxygenation (Warburg  effect). It is accepted that by any carcinogenic action the activation of oncogenes or inactivation of genes – supressors occurs. As a result  it is permanent expression of oncoproteins and stimulation of tumour development. Different oncoproteins operate in different regulation systems at that they cause the same effect – tumour development.

It is assumed that oncoproteins are not the ultimate factor in tumour development but there are existed some common element which is activated by different oncoproteins. In this review it is assumed that common element is HIFα (hypoxia-inducible factor α) transcription factor and it is discussed the mechanisms its activation by oncoproteins takes place in different signal systems.

Тhe protein TRIM16 is involved in key intracellular processes, such as proliferation, cell differentiation and programmed death, including intrinsic and extrinsic apoptosis, autophagy-dependent cell death and immunogenic cell death. The TRIM16 protein acts the proteins TPD43, Gli-1, RARβ, Snail components and MAPK signaling pathway, cadherins, caspases and is also associated with the regulation  of the immune system via direct and indirect mechanisms. The influence of TRIM16 protein on the pathogenesis of hormone-dependent tumors is well-known. Further study of the TRIM16 role in the development and progression of malignant neoplasms will form the basis for  the development of new methods for predicting the course of the malignant process.

Proteins of the superfamily of small guanosine triphosphate hydrolase (GTPase) perform various functions: from the control of cell proliferation to the regulation of vesicular transport. The superfamily of small GTPase Ras includes more than 150 proteins, devided to 5 major families (Arf, Ran, Rho, Ras and Rab), and plays an important role in carcinogenesis. Compared to the other families, the Rab family was investigated by relatively small number studies, which does not equally reflect their role in malignant transformation processes. In our review  we have focused on both the subfamily Rab3 and its poorly investigated member Rab3B. Recent findings allow to consider Rab3B not only  as a promising diagnostic or prognostic marker for several types of neoplasms, but also is a potential target for antitumor therapy. Our analysis of publicly available transcriptional databases revealed that kidney, lung and liver cancer patients with low Rab3B gene expression demonstrate a better overall five-year survival.

The initiation of carcinoma progression is attributed to significant disorders in the synthesis of macromolecules that affect physiological processes in the epithelial cells of oral mucosa. It is known that the integrin family receptors are crucial for regenerative and reparative functions of the normal epithelium. In addition to their well-established physiological role, some types of integrins are the major determinants of malignant transformations. In particular, the results of recent studies in molecular oncology reveal the importance of αv integrins in the pathogenesis of carcinomas, including oral squamous cell carcinoma. This review aims to analyse the significance of αv integrins in the key processes of malignant growth and metastasis of oral squamous cell carcinoma. The prospects of using αv integrins as prognostic molecular markers and targets for developing novel diagnostic and therapeutic methods in the management of oral cancer are discussed.

The Wnt-signaling pathway regulates various biological processes, such as embryonic development, self-renewal, proliferation, differentiation and migration of stem cells. The Wnt-signaling is involved in tumor progression by aberrant activation in stem-like cells, called cancer stem cells, in different kinds of tumor, including multiform glioblastoma. The Wnt-signaling promotes stemness, invasion, metastasis, therapeutic and immune resistance of cancer stem cells in multiform glioblastoma. To summarize, targeting the Wnt-signaling pathway as an oncogenic driver is the future hope for effective therapy of glioblastoma for which current standard therapy is not effective.

In this review, we focused on functions of the Wnt-signaling in cancer stem cells and involvement of the Wnt-signaling pathway in gliomagenesis.

Objective: to the study of the vimentin aberrant expression in the carcinoid tumors of lung, which is a rare group of epithelial neuroendocrine neoplasms with common morphological characteristics and highly variable clinical course.

Materials and methods. Vimentin expression was studied using immunohistochemical analysis in neoplasms of 34 patients with lung carcinoid tumors, which included 17 cases in the categories of typical and atypical carcinoids.

Results. Overall positive cytoplasmic immunoreactivity was observed in 9 (26.5 %) of the 34 studied tumors. Staining for vimentin was positive in 2 (11.8 %) of typical carcinoid and in 7 (41.2 %) of atypical carcinoid specimens. Expression of vimentin was more often observed  in the atypical carcinoids category and was significantly associated with increased grade (p = 0.05), and cell proliferation taking into account the Ki-67 index (p = 0.008).

Conclusion. These results suggest that expression of vimentin as an epithelial-mesenchymal transition-related marker plays an important role in the progression of carcinoid tumors. It may prove useful for diagnostic purposes, and also be used as a potential criterion for prognosis assessment of this type of tumors.

Background. Overexpression of the human papillomavirus oncogenes E6 and E7 is a major factor in initiation and progression of HPV-induced tumors. Inactivation of negative regulatory function of E2 protein – the main viral transcription and replication regulator – is considered to be an important mechanism leading to the viral oncogenes overexpression. It is known that the loss of E2 functions occurs due to disruption of E2 open reading frame during the viral DNA integration into a cell genome in a part of HPV-positive tumors. An alternative mechanism of E2 function blocking in tumors retained its expression can be methylation of the HPV regulatory region, since it is known that E2 is incapable to bind its methylated binding sites.

The study objective is to analyze methylation of the HPV16 regulatory region and expression of the viral E6 and E7 oncogenes in E2 expressing or non-expressing clinical samples of cervical cancer.

Results. It has been demonstrated that the level of the HPV16 URR methylation in E2-expressing lesions is significantly higher than that in non-expressing cervical cancer lesions. Demethylation of the HPV16 promoter in cervical cell line Caski is followed by decrease of the viral E6 и E7 oncogenes mRNA levels, supporting the hypothesis that methylation is necessary for effective E6 and E7 transcription and indicates on restitution of E2 regulatory function in E2-expressing cervical cancer cells.

Conclusion. These data suggest that methylation of E2 binding sites in HPV16 regulatory region blocking E2 protein binding represents an important mechanism ensuring high level of the viral E6 and E7 oncogenes expression.

The objective is to evaluate the level of ADAM10 and ADAM17 (a disintegrin and metalloproteinase) proteases, as well as 20S-proteasomes in blood plasma exosomes of patients with colorectal cancer.

Materials and methods. The study included 60 patients with colorectal cancer (T2–4N0–2M0–1) and 10 control patients. The material for the study was EDTA blood plasma. Exosomes of blood plasma were isolated by ultrafiltration with ultracentrifugation. The level of tetraspanin-associated (ADAM10 and ADAM17) and tetraspanin-non-associated (20S-proteasome) proteases was evaluated by flow cytometry and Western blotting.

Results. A twice negative subpopulation (ADAM10–/ADAM17–) predominated in blood plasma exosomes of colorectal cancer patients and control patients. The level of ADAM10+/ADAM17– exosomes was significantly higher in the exosomes of the plasma of control patients. There were no significant differences between the ADAM10/ADAM17 subpopulations and the 20S-proteasome level, depending on sex, age and tumor grade. A decrease in the ADAM10+/ADAM17– subpopulation was found in patients with metastatic colorectal cancer with hematogenous metastases compared with patients with T2–4N1–2M0 and 20S-proteasome compared to T2–4N0M0. A decrease in ADAM10–/ ADAM17+ exosomes and 20S-proteasomes level was found in exosomes of patients with colorectal cancer with a metabolic syndrome  in comparison with patients without metabolic disorders.

Background. The non-canonical activity of retinoic acid (RA) was discovered relatively recently and consists in the rapid activation of intracellular signaling pathways by the mechanisms not related to the transcriptional activity of the RA nuclear receptors. Separate data suggest that this activity can stimulate the processes of malignancy and contribute to the formation of tumor cell resistance to RA as a therapeutic agent. However, little is known about the mechanisms of this activity. It is also unclear how universal this effect is; does the RA-dependent activation of different signaling protein kinases occur in the same cells, and whether activation of these kinases is interrelated.

Materials and methods: cultivation of non-small cell lung cancer cells and neuroblastoma cells under standard conditions and with incubation with all-trans retinoic acid (ATRA); immunoblotting.

Results. Here we studied the effect of ATRA on the activation of Akt and Erk1/2 protein kinases depending on the incubation time. The analysis revealed RA-dependent activation of both kinases in all studied non-small cell lung cancer and neuroblastoma cell lines. Activation of Akt and Erk1/2 occurred at five minutes of incubation, which corresponds to the non-transcriptional (non-canonical) activity of the RA, however, further activation kinetics of the two kinases differed essentially.

Conclusion. We found that ATRA causes rapid activation of Erk1/2 and Akt protein kinases in both non-small cell lung cancer and neuroblastoma cells. The differences in the kinetics of RA-dependent stimulation of these two kinases suggest that their activation is mediated by independent mechanisms.

Background. PRAME gene spontaneous expression is frequently observed in a cancer cell. The protein encoded by this gene increases  the viability of tumour cell. NF-κB signalling pathway takes part in PRAME upregulation. It proposes, that stress conditions may increase the expression level of PRAME in the tumour cell and increase cell’s viability after it. We hypothesized that this phenomenon determines chemoresistance of PRAME-expressing cell, which can be overcome by NF-κB inhibitors, such as bortezomib.

Materials and methods. We incubated A875 melanoma cells with cisplatin, bortezomib and dexamethasone, as well as with a mixture  of cisplatin with bortezomib and cisplatin with dexamethasone within 24 hours. To assess the cytotoxicity of these combinations MTT-test was used. For evaluation of PRAME expression level, real-time polymerase chain reaction was used. All data were analyzed with Wilcoxon test for coupled samples.

Results. It was found that cisplatin and dexamethasone increased an expression level of PRAME compared to control (p <0.03). The addition of dexamethasone to cisplatin reduced cytotoxic effect of cisplatin. Bortezomib has a cytotoxic effect, but it did not increase the activity  of PRAME gene (p = 0.12). PRAME gene activity in cells incubated with a mixture of cisplatin and bortezomib was observed at a lower level in comparison with cells incubated with cisplatin (p = 0.0277).

Conclusion. The results of experiments show that an increase of PRAME expression level reduces the sensitivity of melanoma cells to the cytotoxic effect of cisplatin. PRAME activity increases under stress conditions. Using of bortezomib can inhibit the growth of PRAME expression and makes the tumour cell more vulnerable to cytotoxic agents. On the other hand, dexamethasone may increase a resistance  of PRAME-expressing cell to cytotoxic effects.