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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Modeling high-grade serous ovarian carcinogenesis from the fallopian tube
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Modeling high-grade serous ovarian carcinogenesis from the fallopian tube

机译：从输卵管模拟高级浆液性卵巢癌的发生

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摘要

High-grade serous ovarian carcinoma (HGSOC) is a lethal disease for which improved screening and treatment strategies are urgently needed. Progress in these areas is impeded by our poor understanding of HGSOC pathogenesis. Most ovarian cancer research is based on the hypothesis that HGSOC arises from ovarian surface epithelial cells. However, recent studies suggest that >50% of high-grade serous carcinomas involving the ovary likely arise from fallopian tube epithelium. Therefore, limiting HGSOC research to modeling based on ovarian surface epithelium alone is inadequate. To address the need for a fallopian tube-based model of HGSOC, we have developed a system for studying human fallopian tube secretory epithelial cell (FTSEC) transformation. Our model is based on (/) immortalization of FTSECs isolated from primary samples of normal, nondiseased human fallopian tubes, (ii) transformation of FTSECs with defined genetic elements, and (iii) xenograft-based tumorigenic assays. We use our model to show that FTSECs immortalized with human telomerase reverse transcriptase (hTERT) plus SV40 large T and small T antigens are transformed by either oncogenic Ras (H-Ras~(V12)) or c-Myc expression, leading to increased proliferation, clonogenicity, and anchorage-independent growth. Additionally, we demonstrate that FTSECs remain susceptible to c-Myc-mediated transformation in the absence of viral oncoproteins, by replacing SV40 large T and -small T antigens with sh-p53, mutant CDK4 (CDK4~(R24C)), and sh-PP2A-B56y. Importantly, all transformed FTSECs gave rise to high-grade Mullerian carcinomas that were grossly, histologically, im-munophenotypically, and genomically similar to human HGSOC. With this model, we will now be able to assess the transformative effects of specific genetic alterations on FTSECs in order to characterize their respective roles in HGSOC development.
机译：高度浆液性卵巢癌（HGSOC）是一种致死性疾病，迫切需要改进其筛查和治疗策略。由于我们对HGSOC发病机理的了解不足，阻碍了这些领域的进展。多数卵巢癌研究均基于以下假设：HGSOC来自卵巢表面上皮细胞。但是，最近的研究表明，> 50％的涉及卵巢的高级浆液性癌可能源自输卵管上皮。因此，将HGSOC研究局限于仅基于卵巢表面上皮的建模是不够的。为了满足基于HGSOC输卵管模型的需求，我们开发了一种用于研究人输卵管分泌上皮细胞（FTSEC）转化的系统。我们的模型基于（/）从正常，未患病的人类输卵管的原始样本中分离出的FTSEC永生化，（ii）具有确定的遗传成分的FTSEC转化以及（iii）基于异种移植的致瘤性检测。我们使用我们的模型显示，通过人类端粒酶逆转录酶（hTERT）和SV40大T和小T抗原永生的FTSEC被致癌Ras（H-Ras〜（V12））或c-Myc表达转化，从而导致增殖增加，克隆形成和不依赖锚定的增长。此外，我们证明了FTSEC在不存在病毒癌蛋白的情况下仍易受c-Myc介导的转化的影响，方法是用sh-p53，突变CDK4（CDK4〜（R24C））和sh- PP2A-B56y。重要的是，所有转化的FTSEC都引起了严重的穆勒氏癌，这些癌在组织学，免疫表型和基因组学上与人HGSOC大致相似。使用此模型，我们现在将能够评估特定基因改变对FTSEC的转化作用，以表征它们在HGSOC发展中的各自作用。

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  • 作者

    Alison M. Karst; Keren Levanon; Ronny Drapkin;

  • 作者单位

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115,Department of Pathology, Division ofWomen's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA 02215;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    fimbria; cell of origin; secretory cell; tp53;

    机译：菌毛;起源细胞;分泌细胞;tp53;

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