Cancers are one of the leading causes of mortality in the world. Cellular and physiological mechanisms of cancer development remain not well defined. In vivo models are an attractive  approach for understanding of cancer origin and progression. This review presents current state of experimental in vivo systems including syngeneic models, patient-derived xenografts (PDX), cell line-derived xenografts (CDX) and various animals – humanized and genetically engineered models (GEM). These models provide opportunities for developing patients’ avatars, lifetime visualization of tumor migration and invasion at the organism level, and the evaluation of new therapeutic  methods aimed at primary tumors, metastases, and cancer prevention. We also discuss the problems of choosing the optimal model and potential solutions for their overcoming.

Gastrointestinal stromal tumors (GIST) are most common mesenchymal tumors in gastrointestinal tract which originate from interstitial cells of Cajal and characterized by the mutations in the KIT or PDGFRA tyrosine kinase receptors. Thus, the common therapeutic approach for GIST therapy (including metastatic, recurrent and non-resectable forms) is based on inhibiton of activities of receptor tyrosine kinases indicated above by corresponding receptor tyrosine kinase inhibitors, including first-line therapeutic agent imatinib mesylate – Gleevec. Despite of high efficacy of IM-based therapy, most of GIST patients acquire resistance to this receptor tyrosine kinase inhibitor, which in turn requires second-, third- and fourth-line therapies. The review also describes the common molecular and genetic variants of GIST and the mechanisms of primary and secondary GIST resistance to the targeted-based therapies. In addition, the role of immune microenvironment in GIST and its relationship with tumor’s mutational burden are discussed in detail, thereby illustrating the immunotherapy as one of the attractive future directions for GIST therapy. Lastly, the manuscript provides the information about the ongoing clinical trials of GIST immunotherapy.

Genetic apparatus of human cells is constantly affected by a broad spectrum of mutagenic factors, both exogenous and endogenous. Genetic and epigenetic disorders, which emerge as a result of this influence, become the main cause of the majority of malignant neoplasias. Several different approaches were proposed to prevent these disorders, including the suppression of the activity of mutagenic factors by treatment with certain chemical compounds. Plant polyphenols are promising candidates for the development of chemopreventive drugs, as they exert the ability to regulate the metabolic activation of procarcinogens and modulate the cellular oxidative stress. In the present review, classification of plant phenolic compounds and their interactions  with biological macromolecules are described, along with the molecular mechanisms of their influence on the enzymes and regulatory pathways of phase I xenobiotic metabolism, and the prevention of oxidative stress. Interactions between natural polyphenols and patient’s microbiota is also described.

Adrenocortical cancer is a rare tumor originating from cortical adrenal cells, endowed with aggressive potential, a rapidly progressing course and an unfavorable prognosis. The complexity of early diagnosis of the disease is due to several factors: the variability of clinical manifestations associated with the initial multiregulatory influence of steroid hormones on the body’s homeostasis, the rare occurrence of the tumor and, as a result, the lack of understanding of the molecular mechanisms of its carcinogenesis.

The increased interest in recent years among oncologists and endocrinologists in understanding the fundamental and clinical aspects of adrenocortical cancer and the search for potential targets for new drugs has led to a detailed study of the cellular and molecular genetic mechanisms involved in normal adrenal ontogenesis and their role in tumor transformation. This review presents the currently known molecular genetic processes and their mediating auto-, para-, endocrine factors involved in normal adrenal ontogenesis and carcinogenesis. The paper analyzes results of trials published in international and Russian journals on molecular oncology and endocrinology indexed in the PubMed, CyberLeninka, Web of Science, Science Direct and eLIBRARY databases.

Exosomes are membrane vesicles 30–150 nm in size released by cells upon fusion of multivesicular bodies with the plasma membrane. A distinctive feature of these vesicles is the presence of the surface tetraspanins CD9, CD63, and CD81. The Rab family of small GTPases, including Rab27A and Rab27B, controls various steps in exosome release, including transport of multivesicular bodies and fusion of the multivesicular body to the plasma membrane. It is commonly accepted to date that exosomes are the main carriers of information between cells under physiological conditions, such as mammary development and lactation, and under pathological conditions, such as breast cancer. This review considers the peculiarities of exosome formation, secretion and transport, their composition and role in normal and breast cancer, as well as the prospects for using these vesicles to develop early non-invasive diagnostics and improve the effectiveness of anti-tumor therapy.

Gastric cancer is one of the most common oncological diseases at the present time, so research in this area is very significant and relevant. Immunological checkpoint inhibitors have previously demonstrated  their effectiveness and safety in various solid tumors, however, with regard to stomach cancer, to date, ambiguous results have been presented. Tumor cells express programmed death ligand 1 (PD-L1), which binds to its programmed death receptor 1 (PD-1). Immune defense plays a key role in the initiation and progression of the disease. Understanding the regulatory mechanism of PD-L1 in gastric cancer can lead to significant progress in immunotherapy, as well as contribute to the adequate selection of patients treated with checkpoint inhibitors. In the review, we conducted an in-depth study of PD-L1 expression and regulatory immunosuppressive mechanisms in gastric cancer and methods for assessing PD-L1 status, and also studied the results of current clinical trials in which inhibitors of immunological control points were considered in combination with and without chemotherapy for this oncopathology.

Introduction. The high mortality rate in patients with lung cancer (LC) is due to the lack of highly sensitive diagnostic markers of this disease. Genetic and epigenetic alterations in tumor cells, for example, aberrant microRNA expression, can be proposed. It is known that extracellular/circulating microRNA of biological fluids, in complexes with proteins, or packaged in extracellular vesicles is of interest for the diagnosis of tumor diseases.

Aim. To perform a comparative analysis of miRNA expression in plasma and plasma extracellular vesicles of LC patients and healthy donors. Based on the obtained results, to propose a diagnostic panel to identify patients with LC.

Materials and methods. Blood plasma was obtained from blood samples of healthy donors and LC patients by sequential centrifugation.  Then, a fraction of extracellular vesicles (40–150 nm in size) was isolated from a part of the obtained plasma supernatant by the method of aggregation-precipitation with polyethylene glycol/blue dextran. MicroRNAs were isolated from both blood plasma fractions of patients and healthy donors using guanidine isothiocyanate and octanoic acid. Expression of 17 miRNAs most characteristic for the development of LC according to our and literature data in the above-mentioned blood plasma fractions was analyzed by stem-loop reverse transcription polymerase chain reaction.

Results. 29 and 10 miRNA pairs were differentially expressed in plasma extracellular vesicles and plasma of lung cancer patients and donors. Thus, plasma extracellular vesicles are characterized by greater potential as a source for miRNA based lung cancer diagnostic panels in comparison with blood plasma. Diagnostic algorithm based on aberrant miRNA expression of 8 different miRNAs (miRNA-30e, -1, -125b, -133, -222, -374, -425, -660) composed in 6 pairs was designed. This algorithm allows to diagnose 100 % of patients with lung cancer stages II–IV.

Conclusion. Extracellular plasma vesicles represent a promising source of diagnostically significant microRNAs compared to plasma microRNAs. For the diagnosis of patients with non-small cell lung cancer with 100 % sensitivity and specificity, a panel of 8 microRNAs (6 miRNA pairs) was proposed.

Introduction. The growth of primary breast tumor morbidity in the last ten years and increased number of patients with disseminated breast cancer in the Republic of Kazakhstan require the search for methods of early diagnosis of malignant tumors. Determination of breast cancer markers in epigenetic studies allows to use them as diagnostic signs of the presence of malignant tumor and as predictors of treatment effectiveness in patients with this pathology.

Aim. To perform  a search for therapeutic and prognostic breast cancer markers.

Materials and methods. The study included samples of biological material (peripheral blood) of 50 deemed healthy individuals and 103 patients with locally advanced and disseminated breast cancer receiving special therapy. The following methods were used: blood collection, DNA extraction, creation of DNA methylation profiles, sequencing, statistical data analysis.

Results. The results of search for epigenetic mutations in peripheral blood of patients with breast cancer showed their role as specific diagnostic, therapeutic and prognostic markers with specificity 0.91 % and sensitivity 0.94 %. The hypothesis on therapeutic  significance of identified earlier diagnostic markers in patients  with breast cancer, namely hypermethylation of CpG islands associated with genes JAM3, C17orf64,  MSC, C7orf51  and CpG island associated with intragene part of chromosome 5 (chr5: 77,208,034–77,329,434) was tested and confirmed.

Conclusion. A correlation between DNA methylation characteristics and disease progression during treatment was shown. The study results can be used in clinical practice: epigenetic markers, such as methylation in the CpG islets associated with the JAM3, C17orf64, MSC, C7orf51 genes, and in the CpG islet associated with the intragenic site of chromosome 5 (chr5: 77,208,034–77,329,434) can be used as prognostic markers and therapeutic predictors of breast cancer.

Introduction. Enzyme-linked immunosorbent assay of biochemical markers is one of the most important methods for diagnosing tumors. One of these markers is an inducer of expression of matrix metalloproteases EMMPRIN/CD147. Changes in its expression are associated with the progression of some tumors. This study is the first work devoted to the study of the content of the soluble form of the transmembrane glycoprotein EMMPRIN (sEMMPRIN)  in the blood serum of patients with various bone tumors.

Aim. To study the content of sEMMPRIN in the blood serum of patients with malignant bone tumors, its relationship with the clinical and morphological characteristics of neoplasms and prognosis.

Materials and methods. The study included 88 patients with malignant tumors (osteosarcoma – 37 cases, chondrosarcoma – 39, chordoma – 5, Ewing’s sarcoma – 7) and borderline (11 cases) bone neoplasms, of which 14 patients were under the age of 18 years. The control group consisted of 29 healthy donors, 8 of which were under the age of 18 years. The concentration  of EMMPRIN was determined in the serum of patients and donors with reagents for direct enzyme immunoassay “Human EMMPRIN” (R&D, USA) in accordance with the manufacturer’s instructions and expressed in nanograms (ng) per 1 ml of blood serum. The obtained data were processed using the GraphPad Prizm 9.4 program. When comparing indicators and analyzing their relationships, we used the nonparametric Mann–Whitney and Kruskal–Wallis tests. Overall survival was analyzed using the Kaplan–Meier method.

Results. Our analysis of the sEMMPRIN content in the blood serum of patients with bone tumors did not reveal statistically significant differences between the control group and patients with borderline and malignant tumors, both in adults and in children. At the same time, a trend towards a decrease in the level of sEMMPRIN in the blood serum was noted in the presence of a malignant neoplasm of the bone compared with the corresponding control group. Additionally, we found that the content of sEMMPRIN is associated with age and higher in the group of patients under 18 years of age, both among healthy donors and oncological patients. An analysis of the association of sEMMPRIN content with clinical and morphological characteristics did not reveal statistically significant patterns, however, a trend towards an increase in the level of the marker with disease progression in both studied age groups was observed, which is consistent with other studies conducted on other solid tumors.

Conclusion. ELISA revealed the marker sEMMPRIN in the blood serum of all examined children and adults with borderline malignant bone tumors and healthy donors. At the same time, the levels of sEMMPRIN did not differ between the above groups, however, there was a tendency for a decrease in the concentration of the marker in patients with bone sarcomas compared with the control group, regardless of age.

Introduction. Ovarian cancer (OC) is one of the malignant neoplasms of the female reproductive system with a high mortality rate. Currently used tumor markers of this pathology do not have high sensitivity and specificity. In this regard, promising areas of molecular oncology are the study of the mechanisms of carcinogenesis of OC and the search for new biomarkers of liquid biopsy for early non-invasive diagnosis of neoplasms. It is known that tumor cells actively secrete exosomes into the extracellular space, which include biologically active molecules involved in carcinogenesis and claiming to be diagnostic markers. It was previously shown that microRNA-24 (miR-24) and microRNA-101 (miR-101) are transported as part of exosomes in OC and are involved in the degradation of the extracellular matrix, stromal remodeling, angiogenesis, and cancer cell motility.

Aim. To evaluate the representation and diagnostic significance of miR-24 and miR-101 in plasma exosomes and ascitic fluid of OC patients.

Materials and methods. The study included blood and ascitic fluid samples from OC patients (n = 20) and blood samples from healthy women (n = 19). The exosomal nature of the vesicles was confirmed by transmission electron microscopy, nanotracing analysis, and flow cytometry. After isolation of exosomal RNA, the relative level of miRNA was determined using reverse transcription and real-time polymerase chain reaction.

Results. The highest concentration of exosomes was found in the ascitic fluid of OC patients, while the concentration of exosomes in the blood plasma of these patients was significantly higher than in healthy women. Relative levels of miR-24 and miR-101 in exosomes of blood plasma of healthy women were significantly higher than in exosomes of blood plasma and ascitic fluid of OC patients; at the same time, the levels of these miRNAs in exosomes of plasma and ascitic fluid of patients did not differ significantly.

Conclusion. The results obtained confirm the promise of exosomal miR-101 and miR-24 for the diagnosis of OC by liquid biopsy.

Introduction. Glioblastoma  (GB) is not yet curable despite recent advances in the treatment of other malignant solid tumors. The management of GB is based solely on histopathological features, imaging of the tumor and its genomic analysis (somatic mutations in the isocitrate dehydrogenase genes, methylation status of the O⁶-methylguanine-DNA methyltransferase gene promoter). To adapt the treatment to the most recent tumor evolution, molecular information should be received regularly throughout the course of therapy. However, tumor tissue is often not available for diagnosis as the disease progresses. In this regard, the development of less invasive methods, such as analysis of the proteome of biological fluids of patients, is of particular interest. Cerebrospinal fluid (CSF) is an important source disease biomarkers to monitor the presence and progression of the disease.

Aim. To identify proteomic predictive biomarkers in the CSF of patients with GB.

Materials and methods. During the study, samples of patients’ CSF samples, high-resolution proteomic mass spectrometry, modern biochemical methods and bioinformatic technologies were used.

Results. For the first time, the analysis of proteomes of CSF samples of patients with GB obtained before and 7 days after the removal of the primary tumor was carried out. Potential biomarkers of GB have been identified. After their validation using open databases, 11 proteomic predictive markers of GB (S100A9,  S100A8, PLA2G15, PPIB, LTBP2, VIM, LAMB1, STC1, NRP1, COL6A1, HSPA5)  were selected and their role in the molecular mechanisms of gliomagenesis was assessed. Conclusion. The proposed panel of proteomic predictive CSF biomarkers in GB patients can be further used in the development of test systems for assessing the effectiveness of therapy and early detection of disease relapses.

Introduction. Researchers in the field of oncology have a significant interest in the role of microorganisms in development of malignant neoplasms.

Aim. To study the levels of 2-heptyl-3-hydroxy-4-quinolone (PQS) and 2-heptyl-4-quinolone (HHQ) produced by Pseudomonas aeruginosa in the blood of patients with lung cancer and to analyze the relation between their changes and changes in the level of immunoglobulins and vascular endothelial growth factor (VEGF) in the blood of patients with lung cancer.

Materials and methods.  PQS and HHQ were quantified in the blood of patients using high performance liquid chromatography. The levels of immunoglobulins G (IgG),  secretory immunoglobulin A (s-IgA),  and VEGF in the blood were determined using ELISA.

Results. Analysis have shown that the level of PQS in the blood of patients with lung cancer is 2-fold higher than in the control group. This change is accompanied by a decrease in the level of immunoglobulins IgG, as well as an increase in the content of s-IgA and growth factor VEGF in the blood.

Conclusion. PQS level in the blood of patients with lung cancer is elevated creating conditions aggravating the course of the main disease and worsening its prognosis.