Neville-Webbe H L, Cross N A, Eaton C L, Nyambo R, Evans C A, Coleman R E, Holen I
Clinical Oncology, Division of Genomic Medicine, School of Medicine and Biological Sciences, University of Sheffield, UK Sheffield Bone Oncology Group, UK.
Breast Cancer Res Treat. 2004 Aug;86(3):269-79. doi: 10.1023/b:brea.0000036900.48763.b3.
Advanced breast cancer is often associated with metastatic bone disease, causing a number of serious complications for the patients such as hypercalceamia, pain, nerve compression and fractures. The formation of bone metastases depends on complex interactions between tumour cells and the cells of the bone microenvironment, but the precise molecular mechanisms involved in the development of tumour-induced bone disease have not been identified. We have investigated the ability of bone marrow stromal cells (BMSC) isolated from breast cancer patients to generate osteoprotegerin (OPG), a molecule involved both in bone turnover and cell survival. The potential survival effects of OPG are mediated through binding to a member of the TNF super family, TNF-related Apoptosis Inducing Ligand (TRAIL), preventing association between TRAIL and its death-inducing receptors present on a number of tumour cell types. In the present report we show that bone marrow stromal cells isolated from breast cancer patients produce OPG when grown in culture. The levels of OPG present in BMSC conditioned medium is sufficient to protect breast cancer cells from undergoing TRAIL induced apoptosis. Our data suggest that bone-derived OPG may increase survival of breast cancer cells that reach the bone microenvironment as part of the metastatic process.
晚期乳腺癌常与转移性骨病相关，给患者带来许多严重并发症，如高钙血症、疼痛、神经压迫和骨折。骨转移的形成取决于肿瘤细胞与骨微环境细胞之间的复杂相互作用，但肿瘤诱导性骨病发生发展所涉及的精确分子机制尚未明确。我们研究了从乳腺癌患者分离出的骨髓基质细胞（BMSC）产生骨保护素（OPG）的能力，OPG是一种参与骨转换和细胞存活的分子。OPG的潜在存活效应是通过与肿瘤坏死因子超家族成员肿瘤坏死因子相关凋亡诱导配体（TRAIL）结合来介导的，从而阻止TRAIL与其在多种肿瘤细胞类型上存在的死亡诱导受体之间的结合。在本报告中，我们表明从乳腺癌患者分离出的骨髓基质细胞在培养时会产生OPG。BMSC条件培养基中存在的OPG水平足以保护乳腺癌细胞免受TRAIL诱导的凋亡。我们的数据表明，作为转移过程的一部分，骨源性OPG可能会增加到达骨微环境的乳腺癌细胞的存活率。
