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Investigating the cellular origin of pancreatic ductal adenocarcinoma in mice.

机译：研究小鼠胰腺导管腺癌的细胞起源。

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摘要

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a grave prognosis. Identification of single genetic mutations, such as mutant Kras, involved in the initiation and progression of this cancer has facilitated a greater understanding of its basic biology. However, fundamental questions about the cell of origin remain unanswered. Using the Ela-Kras mouse previously developed in the laboratory, I have shown that targeting mutant Kras to pancreatic acinar cells results in preinvasive ductal lesions with morphology similar to human pancreatic intraepithelial neoplasms (PanINs). Additional loss of the tumor suppressor genes p16 or p53 results in metastatic pancreatic ductal adenocarcinoma or acinar cell carcinomas. Both tumor types display similar biologic behavior as the human disease, including similar activation of signaling pathways implicated in human PDAC pathogenesis. Genetic analyses further distinguished the ductal or acinar cell tumors based on areas of chromosomal copy number gains/losses.The development of preinvasive ductal lesions and invasive metastatic PDAC makes Ela-Kras p16+/- mice a good model in which to test therapies. These mice were used in a chemotherapy trial to test the efficacy of 5-Fluorouracil on tumor growth based on monitoring of tumor volumes acquired by high resolution MRI. No effect of 5-FU on the primary tumor growth or metastatic potential was noted in these mice, but this study demonstrated the feasibility of clinical trials in these mice.To specifically address the potential of ductal epithelial cells as tumor-initiating cells in PDAC, I developed mouse models in which oncogene expression is restricted to pancreatic ductal epithelial cells. Mutant Kras or overexpressed ErbB2 was targeted to ductal epithelial cells using a novel cre/lox recombination scheme, restricting oncogene expression to CK19 positive cells in the pancreas. There was no evidence of ductal dysplasia/preneoplasia noted in the Kras mice. The ErbB2 mice are being evaluated.
机译：胰腺导管腺癌（PDAC）是一种具有严重预后的侵袭性癌症。鉴定与这种癌症的发生和发展有关的单个基因突变，例如突变体Kras，已经促进了对其基本生物学的深入了解。但是，关于起源细胞的基本问题仍未得到解答。使用先前在实验室中开发的Ela-Kras小鼠，我已经证明将突变体Kras靶向胰腺腺泡细胞会导致浸润前导管病变，其形态类似于人胰上皮内肿瘤（PanINs）。肿瘤抑制基因p16或p53的额外丧失导致转移性胰腺导管腺癌或腺泡细胞癌。两种肿瘤类型均显示出与人类疾病相似的生物学行为，包括人类PDAC发病机制中涉及的信号通路类似激活。遗传分析进一步根据染色体拷贝数增加/减少的区域来区分导管或腺泡细胞瘤。侵袭性导管损伤和侵袭性转移性PDAC的发展使Ela-Kras p16 +/-小鼠成为测试疗法的良好模型。这些小鼠用于化学疗法试验中，通过监测高分辨率MRI采集的肿瘤体积来测试5-氟尿嘧啶对肿瘤生长的功效。在这些小鼠中未观察到5-FU对原发性肿瘤生长或转移潜能的影响，但这项研究证明了在这些小鼠中进行临床试验的可行性。要专门研究导管上皮细胞作为PDAC中肿瘤引发细胞的潜能，我开发了其中癌基因表达仅限于胰导管上皮细胞的小鼠模型。使用新颖的cre / lox重组方案，将突变的Kras或过表达的ErbB2靶向导管上皮细胞，从而将癌基因表达限制在胰腺中的CK19阳性细胞上。在Kras小鼠中没有发现导管异常增生/ neopoplasia的迹象。正在对ErbB2小鼠进行评估。

著录项

  • 作者

    Schutten, Melissa M.;

  • 作者单位

    The University of Wisconsin - Madison.;

  • 授予单位 The University of Wisconsin - Madison.;
  • 学科 Health Sciences Pathology.Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 142 p.
  • 总页数 142
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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