Characterization of the impact of bone-seeking tumors on the osteocyte network and the osteocyte-mediated regulation of bone turnover

骨寻找肿瘤对骨细胞网络的影响和骨细胞介导的骨转换调节的表征

• 批准号: 401077668
• 负责人: Professor Dr. Björn Busse
• 金额: --
• 依托单位: Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/401077668?language=en
• 关键词: Characterization; impact; bone; seeking; tumors

Osteocytes are the most frequent cell type in bone. Residing in lacunae, their protrusions span an area of about 1200 m². With this intricate network, osteocytes orchestrate skeletal adaptation to mechanical stimuli and regulate bone mineral homeostasis through intense communication with osteoblasts and osteoclasts. Recent studies indicate that the bone composition is altered by prostate cancer and that material stiffness is an important factor for the metastatic process. However, little is known about the characteristics of the osteocyte-lacunar network in bone of metastatic entities and how this affects tumor cell behavior. The central hypothesis is that the osteocyte network and functionality are affected by skeletal metastasis and these alterations contribute to pathological bone cell actions and the resulting bone fragility. To test this hypothesis, we will (I) characterize the osteocyte network, local mechanical properties, and bone ultrastructure using 2D/3D imaging/microanalysis during bone metastases formation, (II) determine the impact of osteocyte functionality on the bone metastatic process, (III) assess the bidirectional communication between osteocytes and tumor cells and the role of mechanosensation therein in vitro, and (IV) analyze the adhesion molecule profile of naïve osteocytes and tumor-primed osteocytes to identify targets to modulate osteocyte-tumor cell interactions. Key findings will be validated in bone metastases biopsies obtained from breast- and prostate cancer patients using the Hamburg bone registry. This project will provide novel and detailed insights into the interaction between osteocytes and tumor cells and may provide new therapeutic strategies to inhibit the formation of bone metastases via modulation of osteocyte/tumor cell cross-talks.

骨细胞是骨中最常见的细胞类型。居住在腔隙中，它们的突起跨越约1200平方米的面积。通过这个复杂的网络，骨细胞协调骨骼对机械刺激的适应，并通过与成骨细胞和破骨细胞的密切沟通来调节骨矿物质的稳态。最近的研究表明，前列腺癌会改变骨骼成分，并且材料硬度是转移过程的一个重要因素。然而，很少有人知道骨转移实体的骨细胞腔隙网络的特点，以及如何影响肿瘤细胞的行为。核心假设是骨细胞网络和功能受到骨转移的影响，这些改变导致病理性骨细胞作用和骨脆性。为了验证这一假设，我们将（I）在骨转移形成期间使用2D/3D成像/显微分析表征骨细胞网络、局部机械特性和骨超微结构，（II）确定骨细胞功能对骨转移过程的影响，（III）评估骨细胞和肿瘤细胞之间的双向通信以及体外机械感觉的作用，和（IV）分析幼稚骨细胞和肿瘤致敏骨细胞的粘附分子谱以鉴定调节骨细胞-肿瘤细胞相互作用的靶标。将使用汉堡骨登记处在乳腺癌和前列腺癌患者的骨转移活检中验证关键发现。该项目将为骨细胞和肿瘤细胞之间的相互作用提供新的和详细的见解，并可能提供新的治疗策略，通过调节骨细胞/肿瘤细胞的串扰来抑制骨转移的形成。