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首页> 外文学位 >In Vitro Model of Inflammatory Signaling and Cancer Stem Cell Signaling in Pancreatic Cancer using 3D Hetero-Cellular Spheroids and MicroRNA Delivery using Hyaluronic Acid-Based Nanoparticles.
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In Vitro Model of Inflammatory Signaling and Cancer Stem Cell Signaling in Pancreatic Cancer using 3D Hetero-Cellular Spheroids and MicroRNA Delivery using Hyaluronic Acid-Based Nanoparticles.

机译：使用3D异质细胞球体和使用透明质酸基纳米颗粒进行MicroRNA递送的胰腺癌炎症信号和癌症干细胞信号传导体外模型。

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摘要

Pancreatic cancer is one of the most aggressive cancers worldwide with an extremely poor prognosis. There is a largely unmet clinical need for the development of effective therapies for its treatment. Most incidences of pancreatic cancer in patients are a direct result of chronic pancreatitis. This chronic inflammatory state is strongly implicated in bringing about a mutation of healthy cells into tumor cells. Also, the cross-talk between tumor cells and their in-vivo stromal microenvironment, containing macrophages, fibroblasts and other tumor-associated cells through various cytokines results in the development of a more aggressive and malignant phenotype.;Additionally, the three dimensional environment of a tumor contains an outer proliferative zone, with a healthy supply of blood vessels and thereby, oxygen and other necessary nutrients that are required for cell growth. However, the inner core of a tumor is necrotic and hypoxic due to diminished blood supply. This oxygen gradient contributes towards the development of a stem cell like phenotype among the tumor cells, which is more metastatic and aggressive.;These inflammatory and cancer stem cell signaling pathways are regulated by a number of small non-coding micro-RNAs (miRNAs) that are present endogenously. Exogenous delivery of miRNA or miRNA mimics to induce silencing of pro-oncogenic genes and to increase expression of tumor-suppressive genes is emerging as an efficacious platform to modulate the phenotype of tumor cells as these are highly selective to their targets compared to small molecule therapies.;However, most anti-cancer therapies use cell monolayers as a model to test efficacy. These models do not recapitulate the complex signaling pathways that occur in vivo in tumors. Therefore, therapies that show promise in these monolayer platforms do not necessarily have translatable efficacies in vivo. Thus, the establishment of a hetero-cellular, three-dimensional in-vitro tumor model is essential to mimic in vivo hypoxic microenvironments and the dynamic interplay between tumor cells, macrophages and fibroblasts.;This MS dissertation project will focuses on the establishment of such an in vitro spheroid model, an analysis of the inflammatory and cancer stem cell-like phenotype and the evaluation of a nano-scale, hyaluronic acid (HA) based miRNA delivery system to modulate the phenotype of the tumor cells. The delivery system will be evaluated for uptake, transfection within spheroid models. Finally downstream effects of the tumor suppressive microRNA will be evaluated through cytotoxicity studies.
机译：胰腺癌是世界上最具侵略性的癌症之一，预后极差。开发有效的治疗方法的临床需求在很大程度上尚未得到满足。患者胰腺癌的大多数发生是慢性胰腺炎的直接结果。这种慢性炎症状态与健康细胞突变成肿瘤细胞密切相关。同样，肿瘤细胞与其体内基质细胞（包含巨噬细胞，成纤维细胞和其他与肿瘤相关的细胞）之间通过各种细胞因子的相互作用也导致了更具攻击性和恶性的表型的发展。肿瘤包含外部增生区，具有健康的血管供应，因此，氧气和细胞生长所需的其他必需营养素也是如此。然而，由于血液供应的减少，肿瘤的内核坏死和缺氧。该氧梯度有助于肿瘤细胞之间的干细胞表型的发展，这更具转移性和侵略性;这些炎症和癌症干细胞的信号传导途径受到许多小的非编码微RNA（miRNA）的调节。内生存在的miRNA或miRNA模拟物的外源传递可诱导致癌基因沉默并增加肿瘤抑制基因的表达，是调节肿瘤细胞表型的有效平台，因为与小分子疗法相比，它们对靶标的选择性高。;但是，大多数抗癌疗法都使用细胞单层作为测试功效的模型。这些模型没有概括体内发生在肿瘤中的复杂信号通路。因此，在这些单层平台上显示出希望的疗法不一定在体内具有可翻译的功效。因此，建立异质性三维体外肿瘤模型对于模拟体内缺氧的微环境以及肿瘤细胞，巨噬细胞和成纤维细胞之间的动态相互作用是必不可少的。该硕士论文的重点是建立这种模型。体外球体模型，炎症和癌症干细胞样表型的分析以及基于纳米级透明质酸（HA）的miRNA传递系统的评估，以调节肿瘤细胞的表型。将评估球状模型中的摄取系统，转染系统。最后，将通过细胞毒性研究评估肿瘤抑制性microRNA的下游作用。

著录项

  • 作者

    Suresh, Megha.;

  • 作者单位

    Northeastern University.;

  • 授予单位 Northeastern University.;
  • 学科 Nanoscience.;Oncology.;Molecular biology.
  • 学位 M.S.
  • 年度 2016
  • 页码 121 p.
  • 总页数 121
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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