Sex hormones, regulating normal physiological processes of most tissues and organs, are considered to be one of the key factors in the development and progression of the reproductive system cancer. Recently, the importance of the system for post-transcriptional control of gene expression mediated by short single-stranded RNA molecules (microRNA) became evident. This system is involved in regulation of normal physiological processes and in the pathogenesis of many diseases, including cancer. In review we discuss the relationship between the two regulatory systems – sex hormones and microRNAs. The relationship of these systems is considered in the context of two tumors – breast and prostate cancer. In particular, the history of research on the role of sex hormones in the pathogenesis of breast cancer and prostate cancer is briefly covered. Additionally, modern scientific data on the biogenesis and biological role of microRNAs are presented in more detail. In the cells of the hormone-sensitive tissues, sex hormones regulate the microRNA-mediated machinery of gene expression control by two known ways: specifically, affecting the activity of individual microRNA molecules and non-specifically by altering the efficiency of microRNA biogenesis and activity of RNA-induced silencing complex. This downstream regulatory network substantially enhances biological effects of sex hormones at physiological conditions. Malignant transformation leads to a distortion of the regulatory effects of sex hormones that crucially influence the system of microRNA-regulated post-transcriptional control of gene expression. The most established and clinically significant example of such phenomenon is the loss of sensitivity of cells to the regulatory action of these hormones. As a consequence, cancer cells acquire the ability to active proliferation without stimulation with sex hormones. This effect is partly mediated by microRNAs. Also, relevant experimental data indicating the involvement of microRNAs in the phenomenon of breast cancer and prostate cancer cells hormone resistance are discussed in the review.

Conception of the possible primary role of microRNAs in the process of malignant transformation and distortion of hormonal regulation is based on a smaller number of scientific reports. In general, in accordance with the main biological role of microRNAs, latter may affect sex hormones function via interaction with the mRNAs of hormone receptors and inhibition of their synthesis. As a result, the effect of many microRNA is converging on the single mRNA, results in suppression of corresponding protein function and, in the end, leads to inhibition of regulatory cascade downstream of sex steroids.

Finally, the analysis of the fundamental aspects of sex hormones – microRNA interplay is supplemented by brief overview of clinically significant problems. The prospects for development and introduction into clinical practice innovative methods of diagnosis, prediction and optimization of therapy of breast and prostate cancers are discussed as well.

Investigation of the pathogenesis and factors effecting recurrence, progression and drug resistance in acute leukemia (AL) remains a major challenge for hematology and other related areas. The role of more than 50 genes and proteins in the AL pathogenesis has been shown, including the well-studied tumor suppressor (CDKN2A/CDKN2B, RB1, PTEN, p53), and classical fusion genes (BCR/ABL1, TEL/AML1, E2A/PBX, MLL translocations). In addition, high frequency of aberrations in genes responsible for lymphoid differentiation have been identified such as transcription factors (PAX5, IKZF1 and EBF1), transcriptional regulation of the genes (ETV6, ERG), and signaling pathways of antigen receptors (BTLA, CD200, TOX, BLNK, VPREB1), as well as genes involved in chemoresistance of leukemia cells (NR3C1). In recent studies, Ikaros abnormalities have been reported to be frequently associated with AL. Ikaros is a member of a Kruppel-like family of zinc finger transcription factors that also includes IKZF2 (Helios), IKZF3 (Aiolos), Eos and Pegasus, and encoded by the IKZF1 gene. In hematopoietic cells Ikaros functions as a transcription factor, a key protein controlling T-, B-, NK-, and dendritic cells early differentiation. At the early hematopoiesis stages, it represses the myeloid and erythroid lineages, and stimulates the lymphoid differentiation. Ikaros also normally modulates immune response and plays role of a tumor suppressor in lymphoid malignances. Data from numerous clinical studies confirmed an association between the presence of IKZF1 aberrations and B-cell and, to a lesser extent, T-cell acute lymphoblastic leukemia (ALL) development. Besides, loss of Ikaros function was associated with progression of myeloproliferative diseases to acute myeloid leukemia (AML) in children. From clinical point of view, particular intragenic IKZF1 deletions and a short (non-functional) protein Ikaros isoforms, which may occur as a result of intragenic deletions or aberrant splicing, are the most significant features. These mutations of IKZF1 gene and Ikaros aberrant expression play a key role in the lymphoid transformation, tumor progression, and may cause development of leukemic cells chemoresistance. Therefore, IKZF1 aberrations should be taken into account as a valuable prognostic marker for risk groups stratification, poor outcome and low survival rare. This review compiles currently available data regarding the frequency and variants of the IKZF1 (Ikaros) aberrations, and the use of them in diagnostics of all types of leukemia and minimal residual disease detection. Although Ikaros has already applied in clinical studies, a growing number of questions  still remain unanswered. Molecular biology of IKZF1 expression and splicing regulation is not well understood. Clinical value of point mutations and subclonal deletion in IKZF1 locus should be elucidated. Prognostic significance of intragenic deletions and aberrant splicing is necessary to clarify for different groups of ALL patients, in connection with other genetic markers and therapy protocol. More detailed clinical analysis required for proving IKZF1 impact on probability of relapse, improving patients, risk stratification and application of minimal residual disease.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in key cellular functions and cancerogenesis. Nowadays FGFR and their ligands are one of the most investigated markers in oncology and targets for specific therapy. There are a lot of clinical trials in on- cology include drugs with anti-FGFR activities. The most of these drugs are tyrosine kinase inhibitors and monoclonal antibodies. When we say about therapeutic effects on the FGFR signaling pathway, we say about opportunity not only block the ligands and FGFRs, but the under- lying molecular and signaling pathways activated by FGFRs. Nowadays the number of tyrosine kinase inhibitors selectively blocking FGFRs is extremely small. Typically, tyrosine kinase inhibitors can block a wide range of targets. Some of these inhibitors have entered in clinical practice in the treatment of metastatic tumors of different localizations, others are in clinical trials. On August 2014, 74 studies investigating inhibitors of FGFRs are registered on clinicaltrials.gov. A number of marketed drugs at high concentrations also has the ability to inhibit FGFR – sorafenib, vandetanib, motesanib, however, increasing the concentration of these drugs is associated with severe toxicity of treat- ment. In the recommended therapeutic concentrations, adequate blocking FGFR tyrosine kinase domain is doubtful. The review paid atten- tion to such drugs as pazopanib, nintedanib, cediranib, brivanib, dovitinib, ponatinib. We showed the results of treatment with inhibitors of FGFR in different cancers such as breast cancer, colon cancer, endometrial cancer, gastric cancer, thyroid cancer, lung cancer, ovarian cancer. Despite the fact that anti-FGFR therapy are at an early stage of clinical investigation, some difficulties in implementing this thera- peutic approach have been seen, such as high toxicity, not validated targets, the need for patient selection, depending on the activity of FGF– FGFR pathway, as well as mutations in genes of downstream molecular signaling pathways.

In summary in the article we reviewed relevant literature to identify current status, difficulties and future perspectives in development of anti- FGFR drugs. In this article, we review FGFR signaling and describe the therapeutic intervention in patients with solid tumors. 

Breast cancer (BC) is the most common cancer among women in Russia. One of the main treatment methods of BC is systemic chemotherapy. Multidrug resistance of tumor cells (MDR) is the important hindrance on the way to successful chemotherapy. The new data concerning molecular mechanisms of MDR will be presented in this review. The recent data concerning some new biological prognostic markers will be also discussed. There are data showing that transporters of ABC family (ABC transporters) influence tumor progression not only by MDR induction but also by the influence on the traits of malignancy in tumor cells. The results of the studies of ABC transporters, participation in the processes of accumulation of tumor stem cells under the influence of chemotherapy will be discussed. The problem of the participation of ABC transporters in the phenomenon of influence of PI3K/AKT/PTEN signal transduction pathway on the MDR regulation is discussed. The results of the studies of the role of microRNA deregulation in breast cancer drug resistance as well as studies of some epigenetic mechanisms of MDR regulation will be considered. Protein phosphatase 2A (PP2A, serine/threonine phosphatase), PTK7 (protein tyrosine kinase 7). fascin (an actin bundling cytoskeletal protein) multifunctional YB-1 protein will considered as new BC prognostic markers. The perspectives of MDR studies will be discussed as well.

This review deals with the analysis of up-to-date concepts of the human neuroendocrine tumors (NETs) of the digestive system, which are a heterogeneous group of epithelial neoplasms arising from the diffuse neuroendocrine system of the gastrointestinal tract and pancreas. The review summarizes the information about the specifics of the recent histological classifications and criteria of diagnosis the different types of neuroendocrine neoplasms accounting histological and immunohistochemical parameters. In the light of these criteria, current issues of the nomenclature, as well as systems of grading and staging are discussed. Well-differentiated NETs generally present characteristic histopathological features with nests, trabecular or gland-like formations, low mitotic activity and Ki-67 labeling indices and are mostly classified as either G1 or G2 NET. In contrast, poorly differentiated neuroendocrine carcinomas have diffuse growth pattern, high-grade nuclear atypia and cellular proliferation, necrosis. They are always classified as G3 and further subclassified into small-cell or large-cell types based on their histological features. Immunohistochemistry is a powerful tool in confirming neuroendocrine differentiation of tumor cells by the expression of chromogranin A and/or synaptophysin. The grade (G) is based on the proliferative activity of the tumor assessed by the mitotic rate or by Ki-67 immunohistochemistry. Several markers are useful in the identification of a primary organ of NETs in metastatic lesions are also discussed. NETs represent challenging neoplasms in terms of clinical management and prognosis assessment. Morphology alone and immunophenotypic features have no specific predictive implications. Ki-67 has been proven the only significant prognostic marker and can predict response to therapy. Additionally, data on key signaling pathways and potential predictive molecular markers involved in the development of neuroendocrine tumors of the gastrointestinal tract and pancreas are presented in this review. New molecular targeted therapies have become available in patients with NETs. Somatostatin receptors (SSTRs) are expressed by these tumors and show high affinity for somatostatin analogues. Immunohistochemical positive staining, especially of the subtype SSTR 2А, has been shown to be well associated with therapeutic response to somatostatin analogue therapy. Detecting the expression of SSTRs helps to predict not only the efficacy of treatment but also the prognosis in NETs. The PI3K/AKT/mTOR signaling pathway plays a crucial role in development of neuroendocrine neoplasms and is targeted by specific inhibitors. However, the exact cellular molecules, which may help predict response, their expression levels and prognostic values are still to be defined. Determining specific prognostic and predictive molecular markers in NETs can significantly improve biological and morphological characterization of individual neuroendocrine neoplasms and identification of patients that may benefit from targeted therapy.

Bone metastasis is one of the most frequent and dangerous complications of malignant tumors. The last years, achievements in the study of bone remodeling mechanisms promoted the search of sensitive and specific criteria reflecting the intensity of osteolysis and osteosynthesis in bone metastatic lesions. The most informative and clinically valid biochemical markers of bone formation and resorption are characterized in this review. The data on their possible implications in diagnostics, monitoring and prognosis of skeletal lesions by various malignant tumors are presented. The attention to biochemical markers of bone remodeling as noninvasive methods for oncologic patients examination is gradually increasing with adoption of modern laboratory technologies to clinical practice. The last years, publications suggest the possibility of their use both for monitoring, prognosis and early diagnostics of bone metastasis. We present the results of our own investigation of serum C-telopeptide of type I collagen (СТX) as bone resorption marker and bone-specific alkaline phosphatase (BAP) as formation marker in 238 breast cancer patients using ELISA methods. The elevation of studied biochemical parameters in breast cancer patients was significantly associated with the extent of skeletal metastases (р < 0.02–0.00001), pathological fractures (р < 0.005–0.0001) and the severity of pain (р < 0.01–0.00002). Elevated rate of bone turnover was associated with reduced overall survival of breast cancer patients. The significant difference of overall survival estimated on a base of cut-off values of CTX (0.74 ng/ml) and BAP (43.7 IU/L) was found both in the groups of breast cancer patients with and without bone metastases. Serum СТХ and BAP are of value in monitoring and predicting the status of breast cancer bone metastases.

Objective: to study the sensitivity of gastrointestinal stromal tumors (GISTs) to the topoisomerases type II inhibitors and ability of imatinib to enhance GISTs sensitivity to the chemotherapeutic drugs indicated above.

Subjects and Methods. We studied the sensitivity of gastrointestinal stromal tumors (GISTs) to the topoisomerases II inhibitors and ability of imatinib to enhance GISTs sensitivity to these chemotherapeutic agents. The expression of DNA damage and repair (DDR) markers was examined by western-blotting. Cleaved forms of poly (ADP-rybose) polymerase and caspase-3 were served as an apoptotic markers measured by western blotting. Amount of apoptotic cells was counted by flow cytometry analysis by using a propidium iodide DNA staining procedure and counting the numbers of hypodiploid cells.

Results. We observed the sensitivity of GISTs to topoisomerase II inhibitors – doxorubicine and etoposide inducing DNA double-strand breaks and apoptotic cell death. Imatinib enhances GISTs sensitivity to topoisomerase II inhibitors. This might be due to reduced ability of GISTs to repair DNA damage by homologous recombination. Imatinib-induced reduction of Rad51 recombinase might be due to increased proteasome-dependent degradation.

Conclusion. GIST cells are sensitive to topoisomerase II inhibitors (etoposide and doxorubicin) in vitro. Imatinib enhances GISTs sensitivity to the chemotherapeutic agents indicated above.

Methotrexate (Mtx) is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD) Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS), and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum.

246 children (boys – 125, girls – 121) aged 5 to 16 years with osteosarcoma (mean age 12.2 years) who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA). The technique of monitoring of homocysteine (Hcy) in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA) during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC), clearance of methotrexate (ClMtx), the elimination half-life (T1/2 ) and the total time of excretion (Ttotal). Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters: hourly concentration of Mtx, Ttotal, MtxAUC, Clmtx, T1/2 , is obtained statistically significant differences between normal and delayed Mtx excretion. Patients in group of delayed excretion of methotrexate were characterized by the development of hepatotoxicity, there were also observed 4 cases of the occurrence of acute renal failure.

Monitoring of biochemical parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) also revealed differences between the two groups – hepatotoxicity directly depended on MtxAUC, ClMtx and Ttotal, and the amplitude changes in activities of enzymes from course to course by increasing the number of course decreased.

Our developed methodology of monitoring of Hcy in serum during the course of HD Mtx revealed that Hcy metabolic interconnected with Mtx – the higher the concentration of Mtx, the greater the amount of Hcy released into the blood. Hcy has a close metabolic relationship with Mtx – it can serve as a marker of the efficiency of suppression of the transformation of folates. During slow excretion of Mtx Hcy significantly increased in the blood, which also suggests that it can serve as a marker of pharmacodynamic effects of HD Mtx.