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Collagen-based three-dimensional culture microenvironment promotes epithelial to mesenchymal transition and drug resistance of human ovarian cancer in vitro

机译:基于胶原的三维培养微环境促进了体外卵巢癌的间充质转变和耐药性的上皮

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摘要

Ovarian cancer (OvCa) is a leading cause of mortality from gynecologic malignancy due to its disseminated peritoneal metastasis. The tumor microenvironment dominates epithelial-mesenchymal transition (EMT) development and impacts cancer metastasis as well as mediates drug resistance. Tumour cell interaction with the collagen I matrix is critical in OvCa development. To better understand the role of the collagen matrix and the underlying mechanisms in the early stage of OvCa invasion, we developed a three-dimensional (3D) culture model in vitro by embedding OvCa cells within collagen I to recreate the architecture of a solid tumour. Our results showed that tumour spheroids formed in the 3D collagen model displayed good viability and decreased growth rates, which partly recapitulated the growth behavior of in vivo tumour cells. Collagen I enhanced the OvCa cell motility/invasion capability by up-regulating the expression of MMPs and 51 integrin. Moreover, highly invasive OvCa cells in collagen showed the overexpression of mesenchymal markers (N-cadherin, vimentin and fibronectin) and transcriptional factors (Snail and Slug). EMT-associated TGF-1/Smad4 and Wnt5b/-catenin signaling pathways were significantly up-regulated accordingly. Additionally, a remarkably enhanced drug resistance to chemotherapeutics was also detected in the 3D cultures. Collectively, the bioengineered 3D collagen models could recapitulate the in vivo tumour-like microenvironment and reflect some biological characteristics of human OvCa more accurately. The collagen I matrix promoted local invasion via EMT and enhanced the multidrug resistance in OvCa. This system might serve as a comprehensive in vitro model to better understand the manifold mechanisms of OvCa metastasis and also provide a robust tool for screening new anti-ovarian cancer therapeutics.
机译:卵巢癌(OVCA)是由于其传播的腹膜转移,妇科恶性肿瘤死亡的主要原因。肿瘤微环境占据上皮 - 间充质转换(EMT)发育,并影响癌症转移以及介质耐药性。与胶原蛋白I基质的肿瘤细胞相互作用在OVCA发育中至关重要。为了更好地了解胶原蛋白矩阵的作用和ovca侵袭早期的潜在机制,我们通过将胶原I内的OVCA细胞嵌入胶原I内的卵巢细胞来开发了一种三维(3D)培养模型,以重建实体瘤的结构。我们的研究结果表明,3D胶原模型中形成的肿瘤球状体形成良好的活力并降低生长速率,其部分重新覆盖了体内肿瘤细胞的生长行为。胶原蛋白通过Up-Cnoicating的MMP和51整联蛋白的表达增强了OVCA细胞运动/侵袭能力。此外,胶原蛋白的高度侵袭性OVCA细胞显示间充质标记物的过度表达(N-Cadherin,Vimentin和纤连蛋白)和转录因子(蜗牛和粘连)。 EMT相关的TGF-1 / smad4和Wnt5b / -catenin信号传导途径相应地显着调节。另外,在3D培养物中也检测到对化学治疗剂的显着增强的耐药性。集体,生物工程3D胶原蛋白模型可以重新制备体内肿瘤样的微环境,更准确地反映人OVCA的一些生物学特性。胶原蛋白I基质通过EMT促进局部入侵,增强了OVCA中的多药抗性。该系统可以作为全面的体外模型,以更好地了解OVCA转移的歧管机制,并提供一种用于筛选新的抗卵巢癌治疗的鲁棒工具。

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  • 来源
    《RSC Advances》 |2018年第16期|共10页
  • 作者单位

    Dalian Med Univ Coll Basic Med Sci Dept Cell Biol Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Dept Human Histol &

    Embryol Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Dept Human Histol &

    Embryol Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Lab Med Funct Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Dept Human Histol &

    Embryol Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Dept Human Histol &

    Embryol Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Dept Human Histol &

    Embryol Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Morphol Lab Dalian 116044 Peoples R China;

    Dalian Med Univ Coll Basic Med Sci Dept Human Histol &

    Embryol Dalian 116044 Peoples R China;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 化学;
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