Advances in molecular oncology (E-Journal) / Успехи молекулярной онкологии
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ЭКЗОСОМЫ И ПЕРЕДАЧА (ЭПИ)ГЕНЕТИЧЕСКОЙ ИНФОРМАЦИИ ОПУХОЛЕВЫМИ КЛЕТКАМИ
Get PDFIn 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
Альтернативные убиквитин-конъюгирующие ферменты Е2 регулируют эндоцитоз рецептора интерферона-1
Get PDFUbiquitination of signaling receptors triggers their endocytosis to restrict the extent of cell signaling. Type 1 interferon (IFN1) eliminates its receptor from cell surface via stimulating the ubiquitination of its IFNAR1 chain. While it was suggested that this ubiquitination aids IFNAR1 internalization via relieving a steric hindrance of a linear motif within IFNAR1 from the endocytic machinery, the mechanisms involved remain poorly understood. Here we describe a specific role for two disparate ubiquitin acceptor sites within this receptor. These sites, Lys501 and Lys525 / 526, exhibit a preference for polyubiquitination via either Lys63- or Lys48‑linked chains (K63‑Ub and K48‑Ub, respectively). Whereas the SCFβTrcp E3 ubiquitin ligase controls either type of ubiquitination-dependent IFNAR1 endocytosis, the specificity of these processes is determined by two different E2 ubiquitin conjugating enzymes, Ubc13 and Cdc34. These enzymes can be directly used by SCFβTrcp E3 ubiquitin ligase to generate either K63‑Ub or K48‑Ub in vitro. Ubc13 is involved in IFNAR1 endocytosis driven by the K63‑Ub modification of Lys501, whereas the K48‑Ub-specific Cdc34 affects receptor endocytosis via ubiquitin conjugation that occurs onLys525 / 526. Both types of linkages combine to maximize IFNAR1 endocytosis otherwise suppressed by unfavorable conformation dependent on the presence of a conserved Pro470 within the intracellular domain of IFNAR1. We propose a model where alternate utilization of both E2s to assemble diverse polyubiquitin linkages cooperates to achieve IFNAR1 intracellular domain conformations and spatial arrangements that favor a maximal rate of receptor endocytosis
Наследственный рак молочной железы: генетическая и клиническая гетерогенность, молекулярная диагностика, хирургическая профилактика в группах риска
Get PDF5–10 % of breast cancer cases are hereditary, 30 % of them are caused by BRCA1 and BRCA2 mutations (breast / ovarian cancer syndrome). Average cumulative risks of breast and ovarian cancer in BRCA1 mutation carriers run up to 87 % and 44 %, correspondingly. The risk for contralateral breast cancer is also high: after 25 years, 62.9 % of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer develop contralateral breast cancer. The role of single nucleotide polymorphisms in BRCA1 and BRCA2 genes modifying breast and gynaecological cancer risks is actively studied. Genetic testing is performed as a part of genetic counselling. The main inclusion criteria are multiple affected family members with breast / ovarian cancer, breast cancer at young age (under 35–50 years), ovarian cancer at any age, male breast cancer, morphological features of breast cancer (triple-negative, medullar tumors), ethnicity (Jewish ancestry). High-risk individuals carrying BRCA mutations undergo specific surveillance, chemoprophylaxis and surgery protocols. Prophylactic bilateral mastectomy reduces breast cancer risk by 90–94 %
ИССЛЕДОВАНИЕ ВЗАИМОСВЯЗИ МЕЖДУ ЦИРКАДНЫМ РИТМОМ И ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТЬЮ НА ПРИМЕРЕ КЛЕТОЧНЫХ ЛИНИЙ РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ
Get PDF10 % 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
Трабектедин – лиганд узкой бороздки ДНК
Get PDFTrabectedin (ET-743, Yondelis) is an alkaloid that was originally isolated from the Caribbean Sea squirt, Ecteinascidia turbinata and is now produced synthetically. Its chemical structure consists in three fused tetrahydroisoquinoline rings. Two of them, A and B, binds covalently to guanine residues in the minor groove of the DNA double helix to bend the molecule toward the major groove and the third ring C protrudes from the DNA duplex, apparently allowing interactions with several nuclear proteins. Binding to the minor groove of DNA, trabectedin trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways in particular nucleotide excision repair. It acts both as a DNA-alkylating drug and topoisomerase poison. Trabectedin-DNA adduct traps the nucleotide excision repair proteins repairing the DNA damage in transcribing genes and induces DNA strand breaks. Cells deficient in homologous recombination pathway which repairs these double-strand breaks show increased sensitivity to trabectedin. The most sensitive of them were myxoid liposarcomas. Trabectedin is also effective in chemotherapy-experienced patients with advanced, recurrent liposarcoma or leiomyosarcoma as well as in women with ovarian cancer and breast cancer with BRCAness phenotype. Besides of tumor cells Trabectedin inhibits inflammatory cells by affecting directly monocytes and tumorassociated macrophages and indirectly by inhibiting production of inflammatory mediators, the cytokines and chemokines. It inhibits also the MDR-1 gene, which is responsible for the resistance of cancer cells to chemotherapeutic agents and strikes tumor angiogenesis
Некоторые новые аспекты исследований множественной лекарственной устойчивости опухолевых клеток
Get PDFMultidrug resistance (MDR) of tumor cells is the resistance to a broad spectrum of structurally unrelated cytotoxic drugs with different mechanisms of action. One of the main causes of MDR phenotype is the activity of ATP-binding cassette transporters (ABC transporters). ABC transporters efflux toxic compounds from the cells. All living cells contain ABC transporters. This review is dedicated to the studies of three-dimensional structure of ABC transporters, to the data concerning MDR evolution in tumor cell populations. Some information about molecular mechanisms of MDR evolution is also presented.Множественная лекарственная устойчивость (МЛУ) опухолевых клеток – резистентность клетки одновременно к большому количеству веществ, разных по химическому строению и механизму действия. Одним из важнейших и наиболее исследованных механизмов МЛУ является активность транспортных белков семейства АВС (АВС-транспортеры). АВС-транспортеры, выводящие токсические соединения из клеток, и гены, кодирующие АВС-транспортеры, содержатся во всех живых клетках. В обзоре рассматриваются работы, посвященные исследованию трехмерной структуры АВС-транспортеров; результаты, полученные при изучении эволюции МЛУ, определяемой АВС-транспортерами, а также некоторые молекулярные механизмы, которые могут определять эволюцию МЛУ
Амниокар – пролиферативная среда для мезенхимальных клеток
Get PDFObjectives. To develop the Amniocar nutrient medium that contains fetal calf serum (FCS) and growth factors cocktail for mass cultivation of human fibroblasts. To study proliferative activity of the medium on cultures of HUVEC cells of mesenchymal origin and mesenchymal stromal cells, as well as on cell culture of human amniotic fluid.Materials and methods. Determination of the rate of accumulation of the cellular mass and cell morphology in the course of cultivation of cells of various histogenesis in the Amniocar medium and nutrient medium that contains 10 % of FCS.Results. It has been demonstrated that the Amniocar medium is prevalent as compared to the standard DMEM medium with 10 % of FCS by 2 to 5 times for cultivation of skin fibroblasts, HUVEC, and mesenchymal stem cells. The Amniocar medium increased the quantity of endothelial cells that enter mitosis and maintained the culture of HUVEC cells with prolonged passaging in vitro. Clonal cultivation of human amniotic fluid cells in the Amniocar medium secured development of colonies of both fibroblast and epithelial type.Conclusions. Proliferative Amniocar medium is efficient for mass cultivation of various cells of mesenchymal origin and can be used for diagnostic purposes in medical genetics, oncology, etc
Роль Е-кадхерина в неопластической эволюции эпителиальных клеток
Get PDFInteraction of the extracellular domains of the transmembrane proteins cadherins provides cell-cell adhesion. For many years epithelial E- cadherin was regarded as a tumor suppressor and was used as a prognostic marker in cancer. Suppression of E-cadherin expression was observed in many carcinomas. During recent years, the tumor suppressor function of E-cadherin is being reconsidered. It has been shown that ductal breast carcinomas, colorectal carcinomas, oral cavity carcinomas, and squamous cell carcinomas of the head and neck can retain E-cadherin expression. Immunohistochemical staining with a panel of monoclonal antibodies revealed membrane localization of E-cadherin in many tumors. It was shown that transformed epithelial cells in vitro form dynamic adherens junctions that are essential for the effective collective migration of these cells.Трансмембранные белки кадхерины обеспечивают межклеточную адгезию через взаимодействие внеклеточных доменов. На протяжении многих лет эпителиальный Е-кадхерин считался опухолевым супрессором и рассматривался в качестве прогностического маркера у онкологических больных. Угнетение экспрессии Е-кадхерина наблюдали во многих карциномах. В последние несколько лет пересматриваются представления о супрессирующей оли Е-кадхерина. Показано, что протоковые карциномы молочной железы, карциномы толстой кишки, карциномы полости рта, плоскоклеточные карциномы головы и шеи могут сохранять экспрессию Е-кадхерина. При иммуногистохимическом окрашивании с использованием панели моноклональных антител во многих опухолях была выявлена мембранная локализация Е-кадхерина. В трансформированных эпителиоцитах in vitro были обнаружены динамичные межклеточные адгезионные контакты, образованные Е-кадхерином, которые важны для эффективной коллективной миграции клеток