Role of FGFR1 signaling in distinct cell lineages in prostate cancer progresssion

FGFR1 信号在不同细胞谱系中在前列腺癌进展中的作用

• 批准号: 8334481
• 负责人: Michael M Ittmann
• 金额: $ 67.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-09 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334481
• 关键词: Affect; Animal Model; Biological; Biological Markers; Biology; Carcinoma; Cell Lineage; Cells; Clinical; Drug Delivery Systems; Ectopic Expression; Epithelial; Epithelium; Evaluation; Fibroblast Growth Factor Receptor 1; Genetic Recombination; Genetically Engineered Mouse; Glean; Human; Knock-out; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Modeling; Molecular; Neoplasm Metastasis; Outcome; Patients; Primary Neoplasm; Principal Investigator; Property; Prostate; Reagent; Relative (related person); Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Stem cells; Testing; Tissue Microarray; Tissue Model; Transgenic Model; Work; base; cancer initiation; design; experience; human tissue; improved; in vivo; knowledge base; mouse model; novel; programs; tumor growth; tumor progression

DESCRIPTION (provided by applicant): This application focuses on understanding the fundamental biology induced by ectopic expression and activation of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. Our previous studies utilizing genetically engineered mouse models (GEMMs) demonstrated that ectopic FGFR1 signaling in prostate epithelium results in an epithelial-mesenchymal transition (EMT)-associated carcinoma, and conditional knockout of FGFR1 results in decreased primary tumor growth. These studies also showed that ectopic FGFR1 is linked to metastasis. It is now clear that FGFR1 is ectopically present in human PCa, as well, and this has been suggested to mediate EMT, invasion and metastasis. We will now probe several interrelated key questions in order to further define FGFR1's role in cancer initiation, promotion of an inductive microenvironment, and progression to metastases. Our proposed study involves novel transgenic models, cell recombination models, and evaluation of human tissue specimens. This integrative approach, by design, takes advantages of our combined strengths and experiences in building novel transgenic models, probing signaling pathways, and evaluating extensive human tissue sets relative to clinical outcomes. Completion of the proposed study will allow us to understand whether FGFR1activation in epithelial progenitor cells produces cancer with different properties relative to activation in more differentiated, prostate luminal cells, and how these putatively distinct lesions respond to different drugs targeting the FGFR1 signaling axis. The role of FGFR1 signaling in inducing EMT and cell invasion and metastasis will be probed. Moreover, how key FGFR1-activated signaling pathways program a "reactive stroma" microenvironment, and how this biology affects tumor progression will be assessed. To place this work into a clinical perspective, new biological discoveries gleaned from in vivo mouse models will be validated using human tissue arrays, comprising a large set of patient samples. This will help determine the correlation between ectopic FGFR1 expression with cancer grade and clinical outcome. It is anticipated that this study will provide a deeper, molecular understanding of PCa, characterize key animal and tissue models and build a broad knowledge base from which to build improved strategic approaches to targeting the FGFR1 signaling axis therapeutically.

描述（由申请人提供）：本申请的重点是理解前列腺癌（PCA）进展中成纤维细胞生长因子受体1（FGFR1）引起的基本生物学。我们先前利用基因工程小鼠模型（GEMM）的研究表明，前列腺上皮中的异位FGFR1信号传导导致上皮 - 间质转变（EMT）相关癌，而有条件的FGFR1敲除fGFR1导致原发性肿瘤生长减少的结果。这些研究还表明，异位FGFR1与转移有关。现在很明显，FGFR1在人类PCA中也存在于异位中，并且有人建议介导EMT，入侵和转移。现在，我们将探究几个相互关联的关键问题，以进一步定义FGFR1在癌症启动中的作用，促进电感微环境以及向转移的发展。我们提出的研究涉及新颖的转基因模型，细胞重组模型以及人类组织标本的评估。通过设计，这种综合方法在构建新型的转基因模型，探测信号通路以及评估相对于临床结果的广泛人体组织集时，利用了我们的联合优势和经验。拟议研究的完成将使我们能够了解上皮祖细胞中的FGFR1活化是否会产生具有不同特性的癌症，而相对于更分化的前列腺腔细胞中的激活，以及这些推定的不同病变对靶向FGFR1信号轴的不同药物的反应。 FGFR1信号在诱导EMT和细胞侵袭和转移中的作用将被探测。此外，将如何评估关键FGFR1激活的信号通路计划“反应性基质”微环境，以及该生物学如何影响肿瘤进展。为了将这项工作置于临床角度，使用人体组织阵列验证了从体内小鼠模型收集的新生物学发现，包括大量的患者样品。这将有助于确定异位FGFR1表达与癌级和临床结果之间的相关性。可以预料，这项研究将提供对PCA的更深入，分子的理解，表征关键动物和组织模型，并建立广泛的知识基础，从中建立了改进的战略方法，以治疗FGFR1信号轴。