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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Aberrant AKT activation drives well-differentiated liposarcoma
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Aberrant AKT activation drives well-differentiated liposarcoma

机译：异常AKT激活驱动高度分化的脂肪肉瘤

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摘要

Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebraf ish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in pS3 wild-type zebrafish, 6% in pS3 heterozygotes, and 29% in pS3-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS patho-genesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphoryla-tion in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.
机译：高分化脂肪肉瘤（WDLPS）是最常见的人类肉瘤之一，对放射线和化学疗法的反应较差，缺乏适用于实验分析的动物模型严重阻碍了其病理生物学功能的研究和有效靶向治疗的发展。在这里，我们显示在间充质祖细胞中表达组成性活性Akt2的斑马鱼发展出与人类疾病极为相似的WDLPS。 pS3野生型斑马鱼的肿瘤发生率为8％，pS3杂合子的肿瘤发生率为6％，pS3-纯合突变的斑马鱼的肿瘤发生率为29％（P = 0.013），这表明WDLPS发病机理中异常的Akt激活与p53突变协同作用。对WDLPS的主要临床标本以及密切相关的去分化脂肪肉瘤（DDLPS）亚型进行的分析显示，在27％的病例中有AKT活化的免疫组织化学证据。对来自WDLPS或DDLPS患者的一组细胞系的Western印迹分析显示，即使在无血清培养基中培养这些细胞，AKT磷酸化仍在所有受检细胞系中实现。此外，BEZ235是PI3K的小分子抑制剂，是雷帕霉素的哺乳动物靶标，可有效抑制这些细胞中AKT的活化，从而损害了纳摩尔浓度的生存能力。我们的发现在提供一种动物模型以破译WDLPS的分子发病机理，并暗示AKT作为该化学抗性肉瘤中以前未曾探索过的治疗靶标方面具有独特性。

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    Alejandro Gutierrez; Eric L. Snyder; Adrian Marino-Enriquez; Yi-Xiang Zhang; Stefano Sioletic; Elena Kozakewich; Ruta Grebliunaite; Wen-bin Ou; Ewa Sicinska; Chandrajit P. Raut; George D. Demetri; Antonio R. Perez-Atayde; Andrew J. Wagner; Jonathan A. Fletcher; Christopher D. M. Fletcher; A. Thomas Look;

  • 作者单位

    Department of Pediatric Oncology, The Dana-Farber Cancer Institute, MA 02215,Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115;

    rnDepartment of Pathology, Brigham and Women's Hospital, Boston, MA 02115 ,Departnient of Medical Oncology and Center for Molecular Oncologic Pathology, The Dana-Farber Cancer Institute, MA 02215,The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

    rn,The Ludwig Center at Dana-Farber/ Harvard Cancer Center, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    rnThe Ludwig Center at Dana-Farber/ Harvard Cancer Center, The Dana-Farber Cancer Institute, MA 02215,Center for Sarcoma and Bone Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnThe Ludwig Center at Dana-Farber/ Harvard Cancer Center, The Dana-Farber Cancer Institute, MA 02215,Center for Sarcoma and Bone Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pediatric Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pediatric Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    rnDepartnient of Medical Oncology and Center for Molecular Oncologic Pathology, The Dana-Farber Cancer Institute, MA 02215,The Ludwig Center at Dana-Farber/ Harvard Cancer Center, The Dana-Farber Cancer Institute, MA 02215;

    rnCenter for Sarcoma and Bone Oncology, The Dana-Farber Cancer Institute, MA 02215,Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115;

    rnThe Ludwig Center at Dana-Farber/ Harvard Cancer Center, The Dana-Farber Cancer Institute, MA 02215,Center for Sarcoma and Bone Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pathology, Children's Hospital, Boston, MA 02115;

    rnThe Ludwig Center at Dana-Farber/ Harvard Cancer Center, The Dana-Farber Cancer Institute, MA 02215,Center for Sarcoma and Bone Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pathology, Brigham and Women's Hospital, Boston, MA 02115 ,Center for Sarcoma and Bone Oncology, The Dana-Farber Cancer Institute, MA 02215;

    rnDepartment of Pathology, Brigham and Women's Hospital, Boston, MA 02115 rnDepartment of Pediatric Oncology, The Dana-Farber Cancer Institute, MA 02215,Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115;

  • 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);
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