权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Dickkopf-1 as a critical determinant of malignant bone disease

Dickkopf-1 作为恶性骨疾病的关键决定因素

基本信息

批准号：
264899426
负责人：
Dr. Tilmann Rachner
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：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/264899426?language=en
关键词：
Dickkopf critical determinant malignant bone

项目摘要

Metastatic bone disease remains a clinically relevant complication of many malignancies including those of breast, prostate and skin. In addition to enhanced osteoclastic bone resorption, impaired osteoblast function may also contribute to metastatic lesions. Dickkopf-1 (DKK-1) is a Wnt inhibitor and associated with the development of bone lesions in multiple myeloma by inhibiting osteoblast function. We have previously shown that DKK-1 is highly expressed in breast cancer tissue and elevated in the serum of affected patients. As part of a physician-scientist (Gerok) project, we identified elevated DKK-1 expression in prostate cancer tissue and significantly better survival in patients with prostate cancer, who had low levels of DKK-1 at the time of diagnosis. In vitro, breast and prostate cancer cell lines with high levels of DKK-1 inhibit osteoblast differentiation, which can be reversed by blocking DKK-1. Based on these results, we hypothesize that DKK-1 is a critical determinant of the formation of skeletal metastases and is a suitable prognostic marker for breast cancer survival and a potential therapeutic target in osteotropic malignancies. Our specific aims for the second funding period are to: (I) assess the prognostic value of DKK-1 using a prognostic breast cancer tissue array (from the NCI) and serum analyses of a well-characterized cohort of breast cancer patients; (II) analyze the role of DKK-1 in the mutual interaction of cancer and bone cells (MSC, osteoclasts) in vitro by modulating DKK-1 using RNAi and overexpression constructs; (III) determine the therapeutic potential of DKK-1 in murine models of breast cancer (subcutaneous, intratibial and intracardiac tumor models) by stably over-expressing and inhibiting DKK-1 in breast cancer and melanoma cell lines, and by inhibiting DKK-1 using a monoclonal antibody; (IV) clarify the role of non-tumor derived DKK-1 in cancer progression using mice with a conditional global deletion of DKK-1 after skeletal development or a deletion of DKK-1 specifically in osteoblasts. Tumor growth and bone destruction will be determined using micro-CT, luminescence imaging, and histology. Furthermore the bone anabolic effects of DKK-1 inhibition will be comprehensively studied using bone histomorphometry, serum bone remodeling markers and imaging. These studies will help to clarify the molecular mechanisms and therapeutic potential of modifying DKK-1 signaling in bone metastasis.

转移性骨病仍然是许多恶性肿瘤包括乳腺、前列腺和皮肤的临床相关并发症。除了增强破骨细胞骨吸收外，成骨细胞功能受损也可能导致转移性病变。Dickkopf-1 （DKK-1）是一种Wnt抑制剂，通过抑制成骨细胞功能与多发性骨髓瘤骨病变的发展相关。我们之前的研究表明，DKK-1在乳腺癌组织中高度表达，在患者的血清中升高。作为Gerok项目的一部分，我们发现前列腺癌组织中DKK-1表达升高，在诊断时DKK-1水平较低的前列腺癌患者中生存率显著提高。在体外，高水平DKK-1的乳腺癌和前列腺癌细胞系抑制成骨细胞分化，可通过阻断DKK-1逆转。基于这些结果，我们假设DKK-1是骨骼转移形成的关键决定因素，是乳腺癌生存的合适预后标志物，也是嗜骨性恶性肿瘤的潜在治疗靶点。我们第二个资助期的具体目标是：(I)使用预后乳腺癌组织阵列（来自NCI）和对特征明确的乳腺癌患者队列的血清分析来评估DKK-1的预后价值；（II）通过RNAi和过表达构建体调控DKK-1，分析DKK-1在体外肿瘤与骨细胞（MSC、破骨细胞）相互作用中的作用；（III）通过在乳腺癌和黑色素瘤细胞系中稳定过表达和抑制DKK-1，以及使用单克隆抗体抑制DKK-1，确定DKK-1在小鼠乳腺癌模型（皮下、胫内和心内肿瘤模型）中的治疗潜力；（IV）阐明非肿瘤来源的DKK-1在癌症进展中的作用，使用在骨骼发育后条件性地缺失DKK-1或在成骨细胞中特异性地缺失DKK-1的小鼠。肿瘤生长和骨破坏将通过显微ct、发光成像和组织学来确定。此外，DKK-1抑制对骨合成代谢的影响将通过骨组织形态学、血清骨重塑标志物和影像学进行全面研究。这些研究将有助于阐明DKK-1信号在骨转移中的分子机制和治疗潜力。