GENETIC MODULATION OF THE TUMOR MICROENVIRONMENT IN THE APCMIN/+ MOUSE

APCMIN/小鼠肿瘤微环境的基因调控

• 批准号: 8360354
• 负责人: MARIA Marjorette PENA
• 金额: $ 14.15万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360354
• 关键词: Adenomatous Polyps; Bone Marrow Transplantation; Cell Death; Cells; Clinical Management; Colon; Colon Carcinoma; Development; Down-Regulation; Endothelial Cells; Ensure; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Extracellular Matrix; Fibroblasts; Funding; Genetic; Grant; Growth Factor; Hormones; Lymphocyte; Malignant Neoplasms; Mediator of activation protein; Molecular Genetics; Mus; National Center for Research Resources; Pharmaceutical Preparations; Play; Population Heterogeneity; Principal Investigator; Research; Research Infrastructure; Resources; Role; Small Intestines; Source; Stromal Cells; Testing; Thymidylate Synthase; Thymidylate Synthase Inhibitor; United States National Institutes of Health; anticancer research; cancer cell; cancer therapy; clinical efficacy; cost; cytokine; improved; macrophage; neoplastic cell; novel strategies; response; treatment strategy; tumor; tumor growth; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Anti-cancer therapy has typically been targeted on neoplastic cells. Inhibitors of the enzyme thymidylate synthase (TS) have been used for many years in the clinical management of a variety of cancers. In spite of the extensive research on the genetic and molecular factors governing tumor response to TS inhibitors, its clinical efficacy remains limited. In this project, we propose a novel approach to increase tumor response to these agents. Tumors are infiltrated with a heterogeneous population of non-neoplastic cells. These include host-derived cells such as fibroblasts, macrophages, lymphocytes, endothelial cells, etc. Together with extracellular matrix, they make up the tumor stroma or microenvironment. By secreting an array of cytokines, growth factors, hormones, etc., they play a critical role in tumor growth and progression, and response to therapy. We will test the hypothesis that tumor response to TS inhibitors is governed by the chemosensitivity of infiltrating stromal cells. We utilized the ApcMin/+ mice which spontaneously develop adenomatous polyps in the small intestine and the colon. By bone marrow transplantation we generated chimeric mice wherein the chemosensitivity of stromal cells is distinct from that of the tumor and predicted that tumors in these mice will show a drug response that reflects the chemosensitivity of stromal cells. The specific aims are: 1) to determine the impact of TS inhibitors on cells in the stromal compartment and identify mediators of response to TS inhibitors; 2) to examine the effect of TS down regulation in stromal cells on tumor response to TS inhibitors; and 3) to direct sensitization to TS inhibitors specifically to tumor associated stromal cells. The hypothesis being tested will pave the way for development of new treatment strategies using stromal cells to improve therapies targeted at tumor cells to ensure drug induced cancer cell death.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 抗癌疗法通常靶向肿瘤细胞。 胸苷酸合成酶（TS）的抑制剂已在多种癌症的临床管理中使用多年。 尽管对控制肿瘤对TS抑制剂反应的遗传和分子因素进行了广泛的研究，但其临床疗效仍然有限。在这个项目中，我们提出了一种新的方法来增加肿瘤对这些药物的反应。肿瘤被非肿瘤细胞的异质群体浸润。这些细胞包括宿主来源的细胞，如成纤维细胞、巨噬细胞、淋巴细胞、内皮细胞等。它们与细胞外基质一起构成肿瘤基质或微环境。通过分泌一系列细胞因子，生长因子，激素等，它们在肿瘤生长和进展以及对治疗的反应中起关键作用。 我们将检验肿瘤对TS抑制剂的反应是由浸润基质细胞的化学敏感性决定的假设。我们利用ApcMin/+小鼠，其在小肠和结肠中自发地发展腺瘤性息肉。 通过骨髓移植，我们产生了嵌合小鼠，其中基质细胞的化学敏感性与肿瘤的化学敏感性不同，并预测这些小鼠中的肿瘤将显示反映基质细胞的化学敏感性的药物反应。 具体目标是：1）确定TS抑制剂对基质隔室中的细胞的影响并鉴定对TS抑制剂的应答的介质; 2）检查基质细胞中TS下调对肿瘤对TS抑制剂的应答的影响;和3）将TS抑制剂特异性地直接致敏于肿瘤相关基质细胞。 正在测试的假设将为开发新的治疗策略铺平道路，使用基质细胞来改善靶向肿瘤细胞的治疗，以确保药物诱导的癌细胞死亡。