Secreted Wnt Inhibitors in the Biology of Osteosarcoma

骨肉瘤生物学中的分泌型 Wnt 抑制剂

• 批准号: 7102166
• 负责人: BANG H HOANG
• 金额: $ 12.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102166
• 关键词: Gastropoda; cadherins; cell line; human; lung; metastasis; neoplasm /cancer; osteosarcoma; receptor

DESCRIPTION (provided by applicant): Applicant: Dr. Hoang, the candidate, is currently a tenure-track Assistant Professor at the University of California, Irvine. As evident from his biography, the candidate has demonstrated a steadfast commitment to a career in academic medicine. To this end, he would like to continue his research training in a mentored environment with the goal of becoming an independent investigator in musculoskeletal oncology. Environment: The candidate is jointly mentored by several nationally and internationally recognized experts in Wnt signaling in human cancer and the genetics of osteosarcoma. The University of California, Irvine is a collegial environment with a tradition of nurturing career development of young clinician scientists. Research: Osteosarcoma (OS) remains a pediatric bone cancer with substantial mortality due to a high metastatic rate. Although Wnt signaling is activated in several human malignancies, its role in the pathobiology of OS progression is largely unknown. Our preliminary work suggested that secreted Wnt inhibitors modulate the following pro-invasive pathways in OS: (1) Transcriptional repressors Slug and Twist, (2) MMP-2 and 9, and (3) the hepatocyte growth factor receptor Met. Blocking receptor-mediated Wnt signaling by a dominant negative receptor or by the secreted inhibitor Dkk-3 dramatically decreases the invasive potential and motility of OS cells. These findings lead us to propose the following specific aims: 1) To examine whether secreted Wnt inhibitors can decrease invasive capacity of OS cells by suppressing E-cadherin transcriptional repressors; 2) To test the hypothesis that secreted Wnt inhibitors decrease OS invasiveness by suppressing MMP-2 and 9 or by regulating Met-dependent activity; 3) To determine whether overexpression of Wnt inhibitors will reduce lung metastasis in vivo in a tail-vein injection nude mouse model. These studies will bridge a gap in our knowledge on the role of secreted Wnt inhibitors in the biology of OS. Lessons learned from this investigation may be applicable to a wider range of human sarcomas and serves as a basis for future studies by the applicant as an independent investigator in musculoskeletal oncology.

描述（由申请人提供）： 申请人：Hoang 博士，候选人，目前是加州大学欧文分校的终身教授助理教授。从他的传记中可以看出，这位候选人表现出了对学术医学事业的坚定承诺。为此，他希望在指导环境中继续接受研究培训，目标是成为肌肉骨骼肿瘤学的独立研究者。 环境：候选人由多位国内和国际公认的人类癌症 Wnt 信号传导和骨肉瘤遗传学专家共同指导。加州大学欧文分校是一个具有培养年轻临床科学家职业发展传统的学院环境。 研究：骨肉瘤（OS）仍然是一种儿童骨癌，由于高转移率，死亡率很高。尽管 Wnt 信号在多种人类恶性肿瘤中被激活，但其在 OS 进展的病理生物学中的作用很大程度上未知。我们的初步工作表明，分泌型 Wnt 抑制剂在 OS 中调节以下促侵袭途径：(1) 转录抑制因子 Slug 和 Twist，(2) MMP-2 和 9，以及 (3) 肝细胞生长因子受体 Met。通过显性失活受体或分泌的抑制剂 Dkk-3 阻断受体介导的 Wnt 信号传导可显着降低 OS 细胞的侵袭潜力和运动性。这些发现使我们提出以下具体目标：1）检查分泌的Wnt抑制剂是否可以通过抑制E-钙粘蛋白转录抑制因子来降低OS细胞的侵袭能力； 2) 检验分泌型 Wnt 抑制剂通过抑制 MMP-2 和 9 或通过调节 Met 依赖性活性来降低 OS 侵袭性的假设； 3）在尾静脉注射裸鼠模型中确定Wnt抑制剂的过度表达是否会减少体内肺转移。这些研究将弥补我们关于分泌型 Wnt 抑制剂在 OS 生物学中的作用的知识空白。从这项调查中汲取的经验教训可能适用于更广泛的人类肉瘤，并作为申请人作为肌肉骨骼肿瘤学独立研究者进行未来研究的基础。