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Oncogene:大肠癌的新型治疗靶点

发布日期:2015-3-25 15:15:48 文章来源:生物谷 作者次数:908

     

    大肠癌是一种十分常见的胃肠道癌症,近些年来,大肠癌的死亡率在中国位于癌症致死率的第三位,而且其发病率呈现逐年上升趋势。目前,越来越多的证据证明,肿瘤起始细胞不仅仅存在于大脑,乳腺,前列腺及胰腺等实体瘤中,这些细胞也存在于大肠癌中。实体瘤中的细胞有一种复杂的等级制度,其中,肿瘤起始细胞是一小群具有正常干细胞特性的肿瘤细胞,这些细胞可以自我更新,具有分化多潜能性和强大的致癌性。最近,有报道称,肿瘤起始细胞在肿瘤转移,复发及药物抵抗中也起到了重要的作用。

    第一个大肠肿瘤起始细胞CD133+细胞,是由O'Brien 和 Ricci-Vitiani在2007年发现的。之后,一些靶向大肠癌的细胞表面分子被相继发现,例如,CD44, CD24,CD26,Lgr5等等,这些分子可以标记不同大肠肿瘤起始细胞的亚群。近日,来自浙江大学第二附属医院胃肠科的研究团队发现了一种新的大肠癌表面分子CD58,这个分子可以促进大肠癌肿瘤起始细胞的自我更新,此研究结果发表于3月19号的《Oncogene》杂志上

    在这项研究中,研究人员首先利用无血清-低粘附系统获得了大肠癌肿瘤起始细胞。接着,他们利用cDNA基因芯片发现,这些细胞的CD58,CD44及CD163L显著升高。由于CD163L是单细胞/巨噬细胞特异的分子标记,所以研究人员将注意力集中在了CD58和CD44上。CD58 和CD44高表达细胞群普遍存在于大肠癌细胞系及病人样本中,这些细胞具有高度的自我更新能力,上皮向间质转化的能力及致癌能力。之后,研究人员发现,CD58通过激活Wnt通路,促进了大肠癌起始细胞的自我更新。降低CD58的表达,可以显著抑制细胞球的形成及肿瘤的生长。利用免疫沉淀及免疫印迹技术,研究人员发现,CD58通过降解Dkk3,从而激活了Wnt通路。

    这项研究证实,CD58是一个新的大肠癌肿瘤起始细胞表面标记,它促进了这些细胞的自我更新,对肿瘤抑制药物有抵抗作用,例如,5-Fu和Oxaliplatin。CD58可以作为一个新的靶点来杀死及铲除大肠癌肿瘤起始细胞。



    PMC:

      PMID:

      CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer Colorectal tumor-initiating cells (CT-ICs) have self-renewal capabilities and have an important role in tumorigenesis, metastasis, recurrence and treatment resistance in colorectal cancer. Multiple cell-surface molecules targeting CT-ICs, possibly representing different CT-IC subpopulations, have been reported. However, whether new surface markers exist, as well as the mechanisms by which the markers regulate self-renewal, remain unclear. In this study, we enriched a CT-IC population through a serum-free low-adhesion system in vitro. Within this population, we found that CD58 and CD44 were upregulated using a cDNA GeneChip, and CD44highCD58high cancer cells, the common existence of which was demonstrated by flow cytometry in multiple colon cancer cell lines and primary specimens, exhibited enhanced self-renewal ability, epithelial-mesenchymal transition ability and tumorigenicity, both in vitro and in vivo. Furthermore, activated CD58 upregulated the Wnt/β-catenin pathway and thus promoted self-renewal of CT-ICs; conversely, knockdown of CD58 significantly impaired sphere formation and tumor growth. With immunoprecipitation and western blotting approaches, CD58 was found to upregulate the Wnt pathway by degradation of Dickkopf 3. These results indicate that CD58 is a novel cell-surfacemarker that functionally regulates self-renewal of CT-ICs, which may provide an intriguing therapeutic target for the efficient killing and elimination of CT-ICs.

    (作者:佚名)
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