Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis
Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis
复制标题
DOI：
10.1172/jci118947
复制
发表时间：
1996-10-01
影响因子：
15.9
通讯作者：
Mundy, GR
中科院分区：
文献类型：
--
作者：
Guise, TA;Yin, JJ;Mundy, GR
乳腺癌在晚期患者中几乎总是转移到骨转移并引起局部骨溶解，晚期乳腺癌的发病率很大程度上是这一过程的结果。尽管这一问题很重要，但对骨骼局部骨溶解的病理生理学或其预防和治疗知之甚少，但对骨转移患者的观察表明，骨中的乳腺癌细胞表达甲状旁腺激素相关蛋白(PTHrP)的频率高于转移部位的软组织或原发肿瘤。因此，利用人乳腺癌细胞系研究了PTHrP在乳腺癌骨转移中的作用。在已建立的8个人乳腺癌细胞系中有4个表达PTHrP，其中一个细胞系MDA-MB-231被用溶骨转移的体内模型进行了详细的研究，接种了MDA-MB-231细胞的小鼠出现了溶骨性骨转移，没有出现高钙血症或血浆PTHrP浓度升高，受溶骨性病变影响的股骨的骨髓血浆中的PTHrP浓度是相应血浆PTHrP浓度的2.5倍。在另一项单独的实验中，小鼠被针对PTHrP(1-34)的单抗、对照IgG、PTHrP抗体治疗组小鼠溶骨性病变总面积明显低于对照组或不治疗组。骨组织形态计量学分析显示，与对照组相比，PTHrP抗体治疗的荷瘤动物每毫米肿瘤/骨界面的破骨细胞数量减少，骨面积增加，肿瘤面积缩小。这些结果表明，即使在没有高钙血症或循环血浆PTHrP浓度升高的情况下，肿瘤产生的PTHrP也可以导致转移到骨的乳腺癌局部骨质破坏。因此，PTHrP可能在乳腺癌溶骨性骨病变的形成中起着重要的致病作用，中和PTHrP抗体可能减少破坏性骨病变的发生以及肿瘤细胞在骨中的生长。
Breast cancer almost invariably metastasizes to bone in patients with advanced disease and causes local osteolysis, Much of the morbidity of advanced breast cancer is a consequence of this process. Despite the importance of the problem, little is known of the pathophysiology of local osteolysis in the skeleton or its prevention and treatment, Observations in patients with bone metastases suggest that breast cancer cells in bone express parathyroid hormone-related protein (PTHrP) more frequently than in soft tissue sites of metastasis or in the primary tumor. Thus, the role of PTHrP in the causation of breast cancer metastases in bone was examined using human breast cancer cell lines. Four of eight established human breast cancer cell lines expressed PTHrP and one of these cell lines, MDA-MB-231, was studied in detail using an in vivo model of osteolytic metastases, Mice inoculated with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased plasma PTHrP concentrations, PTHrP concentrations in bone marrow plasma from femurs affected with osteolytic lesions were increased 2.5-fold over corresponding plasma PTHrP concentrations, In a separate experiment, mice were treated with either a monoclonal antibody directed against PTHrP(1-34), control IgG, or nothing before tumor inoculation with MDA-MB-231 and twice per week for 26 d. Total area of osteolytic lesions was significantly lower in mice treated with PTHrP antibodies compared with mice receiving control IgG or no treatment. Histomorphometric analysis of bone revealed decreased osteoclast number per millimeter of tumor/bone interface and increased bone area, as well as decreased tumor area, in tumor-bearing animals treated with PTHrP antibodies compared with respective controls. These results indicate that tumor-produced PTHrP can cause local bone destruction in breast cancer metastatic to bone, even in the absence of hypercalcemia or increased circulating plasma concentrations of PTHrP. Thus, PTHrP may have an important pathogenetic role in the establishment of osteolytic bone lesions in breast cancer, Neutralizing antibodies to PTHrP may reduce the development of destructive bone lesions as well as the growth of tumor cells in bone.