Azim Hamdy A, Kamal Nermine S, Azim Hatem A
Department of Clinical Oncology, Cairo University Hospital, Cairo, Egypt.
J Egypt Natl Canc Inst. 2012 Sep;24(3):107-14. doi: 10.1016/j.jnci.2012.06.002. Epub 2012 Jul 10.
The primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases. In this review, we will focus on the unique patho-physiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach.
导致溶骨性骨转移的主要细胞机制是破骨细胞激活。临床前模型表明，乳腺癌细胞可产生甲状旁腺激素相关蛋白（PTHrP）及其他溶骨分子，这些分子会刺激过度的破骨细胞骨吸收并形成溶骨性病变。研究表明，PTHrP自身不能直接诱导破骨细胞激活，而是通过激活基质细胞和成骨细胞上的核因子κB受体活化因子配体（RANKL）基因来介导其作用。因此，在几乎所有癌症诱导的骨破坏情况下，RANKL上调都被视为一个先决条件。因此，靶向RANKL进行治疗似乎是治疗甚至预防骨转移过程的合理方法。在本综述中，我们将聚焦于与乳腺癌骨转移演变相关的独特病理生理方面，强调RANKL及其他一些关键分子在破骨细胞骨吸收中的关键作用。我们将讨论在骨转移患者中使用双膦酸盐和RANKL抑制剂的治疗干预措施以及这种新方法的效果。
