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Interactions of the WNT and RANKL/OPG pathways in osteomimicry of prostate cancer

WNT 和 RANKL/OPG 通路在前列腺癌拟骨学中的相互作用

基本信息

批准号：
197527952
负责人：
Professor Dr. Lorenz C. Hofbauer
金额：
--
依托单位：
Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/197527952?language=en
关键词：
Interactions WNT RANKL OPG pathways

项目摘要

In the process of skeletal metastasis it remains unclear how prostate cancer cells acquire an osteoblast-like phenotype (osteomimicry) and modulate osteogenesis. We will test the hypothesis whether WNT proteins, in particular WNT5A, promote tumor development and tumor cell osteomimicry and modulate osteoclast biology through receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). Based on studies on RANKL/OPG and our recent findings that WNT proteins and RANKL are highly expressed in advanced prostate cancer, we will address three specific aims. (I) Define the WNT and RANKL/OPG profile of osteotropic prostate cancer cell lines and tissues during skeletal metastasis. (II) Analyze interactions between WNT and RANKL/OPG and the involved signaling pathways in the bone-tumor dialogue. We will employ co-culture models and assess specific factors from aim I by using knock-down and over-expression techniques. (III) To investigate the role of the WNT pathway in skeletal metastases, we will employ animal models. Osteoblastic and osteolytic tumor cell lines with defined WNT profiles will be fluorescent-labeled and injected into Col1α1-IFP-transgenic mice. Skeletal tumor progression and altered osteoblastic function will be monitored in vivo using molecular imaging and analyzed by histology and gene expression analysis. These studies may identify key signals of skeletal metastasis which could be targeted for diagnosis and therapy.

在骨转移过程中，前列腺癌细胞如何获得成骨细胞样表型（拟骨）并调节骨生成仍不清楚。我们将检验WNT蛋白（特别是WNT 5A）是否通过NF-κB配体（RANKL）和骨保护素（OPG）受体激活剂促进肿瘤发展和肿瘤细胞骨模拟并调节破骨细胞生物学。基于对RANKL/OPG的研究以及我们最近的发现，即WNT蛋白和RANKL在晚期前列腺癌中高度表达，我们将解决三个具体目标。(I)确定骨转移过程中骨转移性前列腺癌细胞系和组织的WNT和RANKL/OPG谱。(II)分析WNT和RANKL/OPG之间的相互作用以及骨肿瘤对话中涉及的信号通路。我们将采用共培养模型，并通过敲低和过表达技术评估目标I的特定因素。(III)为了研究WNT通路在骨转移中的作用，我们将采用动物模型。将具有确定WNT特征的成骨细胞和溶骨性肿瘤细胞系进行荧光标记，并注射至Col 1 α1-IFP转基因小鼠中。将使用分子成像在体内监测骨肿瘤进展和改变的成骨细胞功能，并通过组织学和基因表达分析进行分析。这些研究可以识别骨转移的关键信号，这些信号可以作为诊断和治疗的靶点。