In this review, we will introduce the current knowledge about exosomes – vesicles that are generated in the cells and released into the extracellular space. Exosomes are forming in the cell plasma membrane and represent the spherical shapes restricted by their membrane and contained the various biomolecules including nucleic acids, proteins, lipids etc. The intent interest to exosomes is based on their ability to horizontal transfer between the cells, to permeate into vascular system reaching the different tissues and to incorporate into the recipient cells. It was shown that exosome incorporation into the cells lead to remarkable changes in the recipient cells both in genomic level (via the integration of exosomal DNA into the host DNA) and in epigenomic level (via the modulation of the content and/or activity of the signaling proteins, microRNA etc.). Undoubtedly, one of the most interesting and perspective achievements in the exosome study is the demonstration of exosome ability to provide the horizontal transfer of the genetic information from cell to cell – the fact supported in the different studies with the various cell models. Here, we will discuss the recent data regarding the main characteristics and properties of exosomes, the role of exosomes in the tumorigenesis including neoplastic transformation, metastasis, multi-drug resistance. The final part of the review involves the most growing area in the exosome study – the possible usage of exosomes in the cancer treatment, in particular – as the specific drug delivery system.

One of the differences between normal and tumor cells is more intensive acidification of the extracellular area in tumor cells compare with intracellular area. Low pH in extracellular region stimulates invasion and metastatic process. This effect of low pH is not fully understood. There are some mechanisms of maintenance of low pH in extracellular region of tumor. In tumor some cells exist in hypoxic state. It is accepted that invasion and metastatic process occur at hypoxic area of tumor. During hypoxia due to activation of transcription factor HIF-1α the tumor cells turn to glycolysis and the end point of glucose oxidation is lactate. The formation of lactate from pyruvate is catalyzed by HIF-1α-dependent lactate dehydrogenase isoform. Accumulation lactate with pK 3.9 is dangerous for cells and monocarboxilate transporters which transport lactate and proton from cytosol are activated. The other mechanism of extracellular protonation is realized by functioning of HIF-1α-dependent carbonic anhydrase (СА IX). СА IX catalyzed the proton formation by interaction of carbonate dioxide with water. СА IX is situated in cell membrane in such manner, that active centre is directed in extracellular matrix. The function of other transmembrane proton pomp is not associated with hypoxia. The activation of Na+/H+ exchanger occur by stress, like osmotic chock or proliferation stimuli. In would be reviewed here the mechanisms of activation of proton pumps. It is shown the results of experiments devoted the effects of different types of inhibitors on tumor growth in cell culture and in vivo. It is suggest that proton pump inhibitors could be in complex with “classical” antineoplastic compounds perspective in cancer treatment.

Notch transmembrane receptors family in humans consists of 4 proteins (Notch1–4) which are activated upon direct contact of cells, carrying appropriate ligands of Jagged or Dll families. This interaction leads to certain proteolytic events resulting in Notch intracellular domain translocation to the nucleus, where it activates various signaling pathways regulating the balance between cellular proliferation, apoptosis or differentiation.
Proteins of the Notch family influence intraand intercellular pathways and communications of the majority of cell types. These receptors regulate both embryogenesis and adult organs and tissues homeostasis sustenance. Dysregulation of Notch signaling result in various diseases, and carcinogenesis as well. These Notch alterations are better studied in various hemoblastoses but it ,s involvement in solid tumors car- cinogenesis has recently been shown. Notch proor antioncogenic action depends not only on the type of transformed cells but also on their microenvironment.
This review is dedicated to canonical Notch signaling, as well as to non-canonical actions, epigenetic regulation and current proand antioncogenic functions in human malignancies. Special attention is drawn to interaction between Notch and other signaling pathways controlling epithelia-to-mesenchyma transition of cells, stem cells formation, sustention of specific niches, cellular differentiation, angiogenesis both during embryogenesis and in pathological conditions. Pharmacological regulation of Notch activation could be a promising way of anticancer therapy.

Syndecan-1 (CD138) is one of the main cell markers used in flow cytometric analysis of multiple myeloma (MM) cells. CD138 and several other markers – CD19, CD45, CD56 – which are often used in order to characterize MM and give the possibility to differentiate MM cells from the normal plasmocytes are described. Only CD138-expressing MM plasma cells are usually taken into account in MM analysis. The current literature data point out that CD138-negative MM plasma cells could be important for MM prognosis, as well. This cell population demonstrates certain properties that are typical to the cancer stem cells. CD138-negative cell population is characterized by higher proliferation, clonogenicity, engraftment in immunodeficient mice as compared to CD138 expressing plasma cells. Besides that, CD138-negative cells were more resistant than CD138-positive cells to the drugs that are used in MM chemotherapy. CD138-negative plasma cells are able to produce CD138 expressing cells upon a long-term culture in vitro and thus to reproduce the heterogenic in CD138 expression population of MM plasma cells. The results of these investigations, as well as statistical data indicating the worse overall survival of CD138 low expressing MM patients point out that CD138-negative population of MM plasma cells should be taken into consideration in MM analysis. Thus, it could be important to find the new markers distinguishing the plasma cell population differing in CD138 expression. Vascular endothelial growth factor receptor VEGFR3 was found to be a new marker with such properties.

RANK/RANKL/OPG ligand-receptor system is a key player in bone homeostasis regulation directly regulating osteoclast differentiation and osteolysis. Disbalance of bone homeostasis associated with malfunctioning of RANK/RANKL/OPG system underlies such oncological processes as the destruction of bone, metastasis development, tumor progression. Involvement of RANK/RANKL/OPG system in the development of metastasis from various tumors is practically confirmed, but its influence on the development and progression of primary bone tumors still needs thorough evaluation. , In this paper experimental and clinical-laboratory data on the role of RANK/RANKL/OPG system in primary bone tumors pathogenesis available in modern literature are summarized with special attention,paid to giant-cell bone tumor (GCBT) that is already treated with RANK/RANKL interaction inhibitor denosumab. Results of authors study of the levels of RANK/RANKL/OPG system,s components in blood serum of 101 malignant bone tumor (37 – osteosarcoma, 41 – chondrosarcoma, 12 – chordoma, 7 – Ewing sarcoma, 2 – pleomorhic undifferentiated sarcoma, 2 – fibrosarcoma), 32 borderline GCBT, and 30 benign bone tumor patients are also presented. The disturbances in the balance of osteolysis activators and inhibitors in patients with primary bone tumor depending both on the character of neoplasm (malignant, borderline or benign), and histological structure of malignant tumors were demonstrated. The most striking changes in RANK/ RANKL/OPG system manifesting itself in an increase of serum concentrations of all its components and strengthening of association between the levels of soluble receptor and its natural inhibitor OPG were revealed in giant-cell bone tumor patients.
The study of the role of RANK/RANKL/OPG system in primary bone neoplasms is a topical goal for clinical investigations; it is also a promising tool for development of new diagnostic methods and for targeted application of specific drugs inhibiting its activity.

10 % of genome mRNA expression is rhythmic and these 24-hrs rhythms are under control of the circadian clock. Epidemiologic studies have revealed a clear link between the disruption of circadian rhythms and cancer development in humans. Growing evidence shows that circadian disruption is associated with development of malignant tumors, including breast cancer. Aim of this study was to investigate: the expression of circadian clock genes in human mammary epithelial cell line MCF10A and breast cancer cell lines MCF-7, ZR-75-1, BT-474 and if the multidrug resistance phenotype of cancer cells is associated with changes in circadian clock genes expression. We have found that Per1 expression significantly reduced in cancer cells. No correlation was detected between the expression of circadian clock genes and cancer breast cell lines drug resistance. Interestingly, the expression of Bmal1, Per1 and Cry1 were increased in multi-drug resistant MCF-7_D cells compare with the parent cells MCF-7 cells, however, if these changes in the expression contribute to the drug-resistance or not is not clear. These results argue for further study.