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Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer 总被引:1,自引:0,他引:1
Yibing Hu Chang Yan Lei Mu Kaiyu Huang Xiaolan Li Deding Tao Yaqun Wu Jichao Qin 《PloS one》2015,10(5)
Chemotherapy resistance observed in patients with colorectal cancer (CRC) may be related to the presence of cancer stem cells (CSCs), but the underlying mechanism(s) remain unclear. Carcinoma-associated fibroblasts (CAFs) are intimately involved in tumor recurrence, and targeting them increases chemo-sensitivity. We investigated whether fibroblasts might increase CSCs thus mediating chemotherapy resistance. CSCs were isolated from either patient-derived xenografts or CRC cell lines based on expression of CD133. First, CSCs were found to be inherently resistant to cell death induced by chemotherapy. In addition, fibroblast-derived conditioned medium (CM) promoted percentage, clonogenicity and tumor growth of CSCs (i.e., CD133+ and TOP-GFP+) upon treatment with 5-fluorouracil (5-Fu) or oxaliplatin (OXA). Further investigations exhibited that exosomes, isolated from CM, similarly took the above effects. Inhibition of exosome secretion decreased the percentage, clonogenicity and tumor growth of CSCs. Altogether, our findings suggest that, besides targeting CSCs, new therapeutic strategies blocking CAFs secretion even before chemotherapy shall be developed to gain better clinical benefits in advanced CRCs. 相似文献
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Negative Feedback Loop of Wnt Signaling through Upregulation of Conductin/Axin2 in Colorectal and Liver Tumors 总被引:16,自引:0,他引:16 下载免费PDF全文
Barbara Lustig Boris Jerchow Martin Sachs Sigrid Weiler Torsten Pietsch Uwe Karsten Marc van de Wetering Hans Clevers Peter M. Schlag Walter Birchmeier Jürgen Behrens 《Molecular and cellular biology》2002,22(4):1184-1193
Activation of Wnt signaling through beta-catenin/TCF complexes is a key event in the development of various tumors, in particular colorectal and liver tumors. Wnt signaling is controlled by the negative regulator conductin/axin2/axil, which induces degradation of beta-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3beta. Here we show that conductin is upregulated in human tumors that are induced by beta-catenin/Wnt signaling, i.e., high levels of conductin protein and mRNA were found in colorectal and liver tumors but not in the corresponding normal tissues. In various other tumor types, conductin levels did not differ between tumor and normal tissue. Upregulation of conductin was also observed in the APC-deficient intestinal tumors of Min mice. Inhibition of Wnt signaling by a dominant-negative mutant of TCF downregulated conductin but not the related protein, axin, in DLD1 colorectal tumor cells. Conversely, activation of Wnt signaling by Wnt-1 or dishevelled increased conductin levels in MDA MB 231 and Neuro2A cells, respectively. In time course experiments, stabilization of beta-catenin preceded the upregulation of conductin by Wnt-1. These results demonstrate that conductin is a target of the Wnt signaling pathway. Upregulation of conductin may constitute a negative feedback loop that controls Wnt signaling activity. 相似文献
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Sumaiyah K. Rehman Jennifer Haynes Evelyne Collignon Kevin R. Brown Yadong Wang Allison M.L. Nixon Jeffrey P. Bruce Jeffrey A. Wintersinger Arvind Singh Mer Edwyn B.L. Lo Cherry Leung Evelyne Lima-Fernandes Nicholas M. Pedley Fraser Soares Sophie McGibbon Housheng Hansen He Aaron Pollet Trevor J. Pugh Catherine A. O’Brien 《Cell》2021,184(1):226-242.e21
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目的:探究缺氧调控结直肠癌细胞自噬的分子机制。方法:分别在常氧及缺氧(1%氧气浓度)条件下处理细胞,western blot检测细胞内沉默信息调节因子1(Silencing Information Regulator 1,SIRT1)及自噬相关标志分子的表达情况;慢病毒转染构建SIRT1稳定过表达或敲减细胞株,利用透射电镜观察细胞内自噬体形成的情况;使用m RFP-GFP-LC3双标腺病毒感染细胞,在激光扫描共聚焦显微镜下观察细胞自噬流的进展。结果:Western blot结果显示,缺氧条件下,HCT116及SW480细胞内SIRT1的表达水平随着缺氧时间的延长而降低,自噬特异性底物p62蛋白水平降低且LC3-I/II转换增加;与对照组相比,SIRT1过表达细胞内自噬特异性底物p62的表达水平升高而LC3-I/II转换受到抑制;相反在SIRT1敲减细胞内,p62的表达水平降低而LC3-I/II转换进一步促进。透射电镜结果发现SIRT1过表达后,细胞内自噬溶酶体形成减少、自噬体数量增多;激光共聚焦结果显示,SIRT1过表达细胞内绿色荧光淬灭减少、自噬体与自噬溶酶体的融合收到明显抑制,说明SIRT1通过抑制自噬溶酶体的形成,阻断自噬流的进展。结论:缺氧通过抑制SIRT1的表达促进结直肠癌的细胞自噬。 相似文献
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Leonie Harmse Nurit Dahan-Farkas Jenny-Lee Panayides Willem van Otterlo Clement Penny 《PloS one》2015,10(9)
Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues. 相似文献
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María López‐Lucendo Rubén A. Bartolomé Eva Calviño Rodrigo Barderas J. Ignacio Casal 《Proteomics》2017,17(19)
Colorectal cancer (CRC) is the second deadliest cancer worldwide. Here, we aimed to study metastasis mechanisms using spatial proteomics in the KM12 cell model. Cells were SILAC‐labeled and fractionated into five subcellular fractions corresponding to: cytoplasm, plasma, mitochondria and ER/golgi membranes, nuclear, chromatin‐bound and cytoskeletal proteins and analyzed with high resolution mass spectrometry. We provide localization data of 4863 quantified proteins in the different subcellular fractions. A total of 1318 proteins with at least 1.5‐fold change were deregulated in highly metastatic KM12SM cells respect to KM12C cells. The protein network organization, protein complexes and functional pathways associated to CRC metastasis was revealed with spatial resolution. Although 92% of the differentially expressed proteins showed the same deregulation in all subcellular compartments, a subset of 117 proteins (8%) showed opposite changes in different subcellular localizations. The chaperonin CCT, the Eif2 and Eif3 initiation of translation and the oxidative phosphorylation complexes together with an important number of guanine nucleotide‐binding proteins, were deregulated in abundance and localization within the metastatic cells. Particularly relevant was the relationship of deregulated protein complexes with exosome secretion. The knowledge of the spatial proteome alterations at subcellular level contributes to clarify the molecular mechanisms underlying colorectal cancer metastasis and to identify potential targets of therapeutic intervention. 相似文献
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目的:探讨E-钙粘蛋白基因(CDH1)启动子区域-347G→GA单核苷酸基因多态性(single nucleotide polymorphism,SNP)和中国地区散发大肠癌(colorectal cancer,CRC)人群遗传易感性的联系.方法:以中国地区大肠癌病人群为研究基础,同时建立无肿瘤家族史以及其它遗传性疾病史的正常对照组,进行病例对照研究,采用聚合酶链反应一限制性片段长度多态性技术(poly-merase chain reaction-restriction fragment length polymorphism,PCR-RFLP)行目的基因的多态性测定.结果:正常对照组和大肠癌组的目的基因型分布频率并无统计学差异(x2检验,P=0.246),而近端大肠癌患者中GA基因型(GA/GA杂合子和GA/GA纯合子)比例明显高于对照组(OR=1.773,95%CI=1.174-2.679,P=0.007),同时低分化大肠腺癌GA基因型比例也明显高于对照组(OR=2.623,95%CI=1.326-5.191,P=0.007).结论:CDHl启动子区域-347G→GA单核苷酸基因多态性中GA基因型可能增加近端大肠癌以及低分化腺癌的发病风险. 相似文献
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Dejuan Kong Sanjeev Banerjee Aamir Ahmad Yiwei Li Zhiwei Wang Seema Sethi Fazlul H. Sarkar 《PloS one》2010,5(8)
Background
Current management of patients diagnosed with prostate cancer (PCa) is very effective; however, tumor recurrence with Castrate Resistant Prostate Cancer (CRPC) and subsequent metastasis lead to poor survival outcome, suggesting that there is a dire need for novel mechanistic understanding of tumor recurrence, which would be critical for designing novel therapies. The recurrence and the metastasis of PCa are tightly linked with the biology of prostate cancer stem cells or cancer-initiating cells that is reminiscent of the acquisition of Epithelial to Mesenchymal Transition (EMT) phenotype. Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-like cells.Methodology/Principal Findings
In this study, we found that PCa cells with EMT phenotype displayed stem-like cell features characterized by increased expression of Sox2, Nanog, Oct4, Lin28B and/or Notch1, consistent with enhanced clonogenic and sphere (prostasphere)-forming ability and tumorigenecity in mice, which was associated with decreased expression of miR-200 and/or let-7 family. Reversal of EMT by re-expression of miR-200 inhibited prostasphere-forming ability of EMT-type cells and reduced the expression of Notch1 and Lin28B. Down-regulation of Lin28B increased let-7 expression, which was consistent with repressed self-renewal capability.Conclusions/Significance
These results suggest that miR-200 played a pivotal role in linking the characteristics of cancer stem-like cells with EMT-like cell signatures in PCa. Selective elimination of cancer stem-like cells by reversing the EMT phenotype to Mesenchymal-Epithelial Transition (MET) phenotype using novel agents would be useful for the prevention of tumor recurrence especially by eliminating those cells that are the “Root Cause” of tumor development and recurrence. 相似文献14.
Yvonne M?ller Martin Siegemund Sven Beyes Ricarda Herr Daniele Lecis Domenico Delia Roland Kontermann Tilman Brummer Klaus Pfizenmaier Monilola A. Olayioye 《PloS one》2014,9(9)
TRAIL is a death receptor ligand that induces cell death preferentially in tumor cells. Recombinant soluble TRAIL, however, performs poorly as an anti-cancer therapeutic because oligomerization is required for potent biological activity. We previously generated a diabody format of tumor-targeted TRAIL termed DbαEGFR-scTRAIL, comprising single-stranded TRAIL molecules (scTRAIL) and the variable domains of a humanized variant of the EGFR blocking antibody Cetuximab. Here we define the bioactivity of DbαEGFR-scTRAIL with regard to both EGFR inhibition and TRAIL receptor activation in 3D cultures of Caco-2 colorectal cancer cells, which express wild-type K-Ras. Compared with conventional 2D cultures, Caco-2 cells displayed strongly enhanced sensitivity toward DbαEGFR-scTRAIL in these 3D cultures. We show that the antibody moiety of DbαEGFR-scTRAIL not only efficiently competed with ligand-induced EGFR function, but also determined the apoptotic response by specifically directing DbαEGFR-scTRAIL to EGFR-positive cells. To address how aberrantly activated K-Ras, which leads to Cetuximab resistance, affects DbαEGFR-scTRAIL sensitivity, we generated stable Caco-2tet cells inducibly expressing oncogenic K-RasG12V. In the presence of doxycycline, these cells showed increased resistance to DbαEGFR-scTRAIL, associated with the elevated expression of the anti-apoptotic proteins cIAP2, Bcl-xL and FlipS. Co-treatment of cells with the Smac mimetic SM83 restored the DbαEGFR-scTRAIL-induced apoptotic response. Importantly, this synergy between DbαEGFR-scTRAIL and SM83 also translated to 3D cultures of oncogenic K-Ras expressing HCT-116 and LoVo colorectal cancer cells. Our findings thus support the notion that DbαEGFR-scTRAIL therapy in combination with apoptosis-sensitizing agents may be promising for the treatment of EGFR-positive colorectal cancers, independently of their KRAS status. 相似文献
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The miR-17-92 cluster of microRNAs is elevated in colorectal cancer, and has a causative role in cancer development. Of the six miR-17-92 cluster members, miR-19a and b in particular are key promoters of cancer development and cell proliferation, while preliminary evidence suggests that miR-18a may act in opposition to other cluster members to decrease cell proliferation. It was hypothesised that miR-18a may have a homeostatic function in helping to contain the oncogenic effect of the entire miR-17-92 cluster, and that elevated miR-17-92 cluster activity without a corresponding increase in miR-18a may promote colorectal tumour progression. In colorectal cancer samples and corresponding normal colorectal mucosa, miR-18a displayed lower overall expression than other miR-17-92 cluster members. miR-18a was shown to have an opposing role to other miR-17-92 cluster members, in particular the key oncogenic miRNAs, miR-19a and b. Transfection of HCT116 and LIM1215 colorectal cancer cell lines with miR-18a mimics decreased proliferation, while a miR-18a inhibitor increased proliferation. miR-18a was also responsible for decreasing cell migration, altering cell morphology, inducing G1/S phase cell cycle arrest, increasing apoptosis, and enhancing the action of a pro-apoptotic agent. CDC42, a mediator of the PI3K pathway, was identified as a novel miR-18a target. Overexpression of miR-18a reduced CDC42 expression, and a luciferase assay confirmed that miR-18a directly targets the 3′UTR of CDC42. miR-18a mimics had a similar effect on proliferation as a small molecule inhibitor of CDC42. Inhibition of CDC42 expression is likely to be a key mechanism by which miR-18a impairs cancer cell growth, with a target protector experiment revealing miR-18a influences proliferation via direct inhibition of CDC42. Inhibition of CCND1 by miR-18a may also assist in this growth-suppression effect. The homeostatic function of miR-18a within the miR-17-92 cluster in colorectal cancer cells may be achieved through suppression of CDC42 and the PI3K pathway. 相似文献
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Katsuhiko Nosho Natsumi Irahara Kaori Shima Shoko Kure Gregory J. Kirkner Eva S. Schernhammer Aditi Hazra David J. Hunter John Quackenbush Donna Spiegelman Edward L. Giovannucci Charles S. Fuchs Shuji Ogino 《PloS one》2008,3(11)