骨转移瘤发病的细胞生物学机制与细胞分子靶向治疗

Cell biological mechanism of bone metastasis and cellular molecular targeted treatment

骨骼是实体肿瘤转移最常见的部位。骨转移瘤目前不可治愈,发病率高,可以导致一系列骨相关事件,显著降低患者的生活质量,加重患者家庭的经济负担。肿瘤细胞转移至骨骼的生物学机制正处于研究之中,这些机制包括成骨细胞"双重"调节与骨保护素-核因子-κB受体活化因子配体-核因子-κB受体活化因子系统、肿瘤细胞和骨骼微环境中细胞产生的各种细胞因子激活破骨细胞以及相关分子的作用,例如甲状旁腺激素相关蛋白(PTHr P)介导"恶性循环"。一些具有吸引力的分子或者通路已经成为治疗骨转移瘤的新潜在性靶点,例如核因子-κB受体活化因子配体(RANKL)、组织蛋白酶K、PTHr P以及Wnt信号通路等。本综述主要阐述正常骨骼生物学、骨转移瘤骨骼生物学机制以及细胞分子靶向治疗的临床进展。这些治疗制剂包括二磷酸盐、迪诺塞麦(RANKL抑制剂)和奥当卡替(组织蛋白酶K抑制剂)。更好地理解骨转移瘤发病的生物学机制和发展更有效的靶向制剂,将有希望延长患者的生存期以及提高患者的生活质量。

Bone is the most common site of metastases in patients with solid tumor. Currently,bone metastases are virtually incurable and have high incidence. They can lead to a series of skeletal-related events,thus negatively impacting on the patients’ quality of life and burdening patients’ family financial problems. Biological mechanisms leading to metastases of tumor cells to bone are being studied. Among these are the osteoblast double regulation and osteoprotegerin-receptor activator of nuclear factor-κB ligandreceptor activator of nuclear factor-κB system,osteoclast activation via cytokines which produced by tumor cell and cells in the bone microenvironment as well as the roles of some molecules,such as parathyroid hormone related protein( PTHr P)-mediated vicious cycle. Several attractive molecules or pathways have been identified as new potential therapeutic targets for bone metastases,such as receptor activator of nuclear factor-κB ligand( RANKL),Cathepsin K,PTHr P and Wnt signaling. This review mainly present normal bone biology,metastatic tumor bone biology and the recent clinical advances in cell and molecular targeted therapeutic agents for bone metastases, including bisphosphonates, denosumab-RANKL inhibitor and odanacatib-cathepsin K inhibitor. Hopefully,with better understanding of the biology of the disease and the development of more robust targeted therapeutic drugs,the survival and quality of life of the affected individuals could be significantly improved.