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51.
Irene Ischenko Jizu Zhi Ute M. Moll Alice Nemajerova Oleksi Petrenko 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(10):3937-3942
Genetically or epigenetically defined reprogramming is a hallmark of cancer cells. However, a causal association between genome reprogramming and cancer has not yet been conclusively established. In particular, little is known about the mechanisms that underlie metastasis of cancer, and even less is known about the identity of metastasizing cancer cells. In this study, we used a model of conditional expression of oncogenic KrasG12D allele in primary mouse cells to show that reprogramming and dedifferentiation is a fundamental early step in malignant transformation and cancer initiation. Our data indicate that stable expression of activated KrasG12D confers on cells a large degree of phenotypic plasticity that predisposes them to neoplastic transformation and acquisition of stem cell characteristics. We have developed a genetically tractable model system to investigate the origins and evolution of metastatic pancreatic cancer cells. We show that metastatic conversion of KrasG12D-expressing cells that exhibit different degrees of differentiation and malignancy can be reconstructed in cell culture, and that the proto-oncogene c-Myc controls the generation of self-renewing metastatic cancer cells. Collectively, our results support a model wherein non-stem cancer cells have the potential to dedifferentiate and acquire stem cell properties as a direct consequence of oncogene-induced plasticity. Moreover, the disturbance in the normally existing dynamic equilibrium between cancer stem cells and non-stem cancer cells allows the formation of cancer stem cells with high metastatic capacity at any time during cancer progression.Activating Ras mutations are the most frequent oncogenic alterations in human cancers. The three related genes, Hras, Kras, and Nras, are all widely expressed, engage overlapping signaling pathways, and can each exhibit oncogenic activity. The frequency of Kras mutations is higher compared with other Ras isoforms, as they are present in 90% of pancreatic cancers, 50% of colon and thyroid carcinomas, 30% of non–small-cell lung cancers, and 25% of ovarian cancers (1). The consequence of oncogenic activation of different Ras isoforms has been extensively explored in various in vitro studies and, more recently, by using genetic mouse models with targeted mutations of the respective genes (2–7). An important observation from these studies is that individual Ras proteins induce tumors in a cell context-dependent fashion. The functional specificity of Ras isoforms can be determined by the amount of transgene expression (8), by the specific regulatory networks controlled by each isoform (4–7), and by their differential abilities to render cells permissive to oncogene-driven proliferation (9, 10). The unifying theme underlying these studies is that there exists a permissive cellular context for each particular genetic lesion, and that only certain types of cells are capable of cancer initiation. However, defining the causes of preferential occurrence of cell type-specific and tissue-specific cancerous mutations remains one of the unanswered fundamental questions.Data derived from mouse models of lung and colon cancer indicate that oncogenic Kras accelerates tumor progression by imposing on cells an immature stem-like state in which differentiation is inhibited (11–13). Compelling evidence also exists for Kras-induced reprogramming of pancreatic acinar cells into ductal intraepithelial neoplasia, a histologically well-defined precursor to pancreatic ductal adenocarcinoma (PDAC) (14–17). Although these findings provide evidence of pathological plasticity associated with the early stages of malignant transformation, it is unclear whether Kras-dependent reprogramming is unique to pancreatic tumors or whether it takes place in a broad range of neoplasms. Moreover, the concept of plasticity itself has been challenged, as it remains unclear why only some, but not all, cells in the adult lung, pancreas, and colon have the capacity to give rise to Kras-driven tumors (10, 12, 18, 19). In this study, we sought to address this question and to determine the role of cellular plasticity in the origin of Kras-mediated transformation. To ascertain that genuine reprogramming occurred, we set benchmark criteria and based our assessments on the accepted definition of reprogramming kinetics of somatic cells (20, 21), i.e., a long latency in the appearance of transformed cells in culture, stochastic nature of the process, direct phenotypic conversion occurring in many cells at once, all in the absence of new discernible mutations. 相似文献
52.
ÖZGE GÜNDÜZ M.D. SIBEL ERSOY‐EVANS M.D. AYŞEN KARADUMAN M.D. 《Pediatric dermatology》2009,26(6):750-751
Abstract: Pityriasis rosea (PR) is an acute, self‐limiting papulosquamous disorder of unknown etiology. Published studies of childhood PR are scarce and most are reviews. The aim of this study was to determine the demographic and clinical features of childhood PR. 相似文献
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A. I. Matyushin Yu. M. Petrenko E. V. Popova 《Bulletin of experimental biology and medicine》1995,119(1):45-47
It is demonstrated that a water-soluble form of estradiol (disodium salt of estradiol diphosphate), apart from having an estrogenic
influence on the uterus, is effective against severe blood loss and has a cardiotropic actiity.
Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N
o
1, pp. 51–53, January, 1995
Presented by P. V. Sergeev, Member of the Russian Academy of Medical Sciences 相似文献
56.
6-(αα-二苯基乙酰哌嗪基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮对兔血小板聚集及TXB2,cAMP的影响 总被引:4,自引:0,他引:4
6-(αα-二苯基乙酰哌嗪基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮(简称DMDP)是我院新合成的哒嗪酮的衍生物。DMDP可以显著抑制由花生四烯酸(AA(?),ADP和血小板活化因子(PAF)诱导的免血小板聚集,其IC50分别为1.12±0.1.4.19±0.5和2.97±0.1μmol/L。实验还表明DMDP在1~500 μmol/L浓度范围内呈剂量依赖性地抑制兔血小板内血栓素B2含量,但升高兔血小板内环腺苷酸水平,这可能是其抑制血小板聚集的作用机理之一。 相似文献
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