骨转移瘤发病的细胞生物学机制与细胞分子靶向治疗

doi:10.3877/cma.j.issn.1673-9450.2015.02.013

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(PTHrP)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、PTHrP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。

关键词: 分子靶向治疗, 二磷酸盐类, 肿瘤, Wnt通路

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 ligand-receptor 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 (PTHrP)-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, PTHrP 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.

Key words: Molecular targeted therapy, Diphosphates, Neoplasms, Wnt pathway

图1 正常骨骼生物学

图2 骨转移瘤生物学与"恶性循环"

表1 食品药品监督管理局批准治疗骨转移瘤制剂的使用指南

制剂	癌症类型	剂量	方法	频率	不良反应
唑来磷酸	多发性骨髓瘤和实体肿瘤源性骨转移瘤	4 mg	静脉内给药，至少超过15 min	3～4周/次	肾毒性，下颌骨坏死，发热，恶心，便秘，贫血，呼吸困难，低钙血症
帕米磷酸	乳腺癌和多发性骨髓瘤溶骨型骨转移瘤	90 mg	静脉内给药，至少超过2 h	4周/次	肾毒性，下颌骨骨坏死，低钙血症
迪诺塞麦	预防实体肿瘤源性骨转移瘤SRE	120 mg	上臂、上臀或者腹部皮下注射	4周/次	低钙血症，泌尿道感染，上呼吸道感染，便秘，白内障，关节疼痛，下颌骨坏死

表1 食品药品监督管理局批准治疗骨转移瘤制剂的使用指南

制剂	癌症类型	剂量	方法	频率	不良反应
唑来磷酸	多发性骨髓瘤和实体肿瘤源性骨转移瘤	4 mg	静脉内给药，至少超过15 min	3～4周/次	肾毒性，下颌骨坏死，发热，恶心，便秘，贫血，呼吸困难，低钙血症
帕米磷酸	乳腺癌和多发性骨髓瘤溶骨型骨转移瘤	90 mg	静脉内给药，至少超过2 h	4周/次	肾毒性，下颌骨骨坏死，低钙血症
迪诺塞麦	预防实体肿瘤源性骨转移瘤SRE	120 mg	上臂、上臀或者腹部皮下注射	4周/次	低钙血症，泌尿道感染，上呼吸道感染，便秘，白内障，关节疼痛，下颌骨坏死

33	Le Gall C, Bellahcène A, Bonnelye E, et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden[J]. Cancer Res, 2007, 67(20): 9894-9902.
34	Jensen AB, Wynne C, Ramirez G, et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: Results of a 4-week, double-blind, randomized, controlled trial[J]. Clin Breast Cancer, 2010, 10(6): 452-458.
35	Ondoua A, Rodriquez J, Hanlon K, et al. Multivalent cathepsin inhibitor, VBY-825, attenuates breast-cancer induced bone remodeling and pain[J]. J Pain, 2012, 13(4): S43.
36	Gallwitz WE, Guise TA, Mundy GR. Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo[J]. J Clin Invest, 2002, 110(10): 1559-1572.
37	Leow PC, Tian Q, Ong ZY, et al. Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells[J]. Invest New Drugs, 2010, 28(6): 766-782.
38	Chen QY, Zheng Y, Jiao DM, et al. Curumin inhibits lung cancer cell migration and invasion through Rac1-dependent signaling pathway[J]. J Nutr Biochem, 2014, 25(2): 177-185.
1	Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity[J]. Clin Cancer Res, 2006, 12(20 Pt 2): 6243s-6249s.
2	Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial-The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group[J]. J Clin Oncol, 2003, 21(16): 3150-3157.
3	Delea TE, McKiernan J, Brandman J, et al. Impact of skeletal complications on total medical care costs among patients with bone metastases of lung cancer[J]. J Thorac Oncol, 2006, 1(6): 571-576.
4	Delea TE, McKiernan J, Brandman J, et al. Retrospective study of the effect of skeletal complications on total medical care costs in patients with bone metastases of breast cancer seen in typical clinical practice[J]. J Support Oncol, 2006, 4(7): 341-347.
5	Delank KS, Wendtner C, Eich HT, et al. The treatment of spinal metastases[J]. Dtsch Arzt Int, 2011, 108(5): 71-80.
6	Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand[J]. Proc Natl Acad Sci USA, 1999, 96(7): 3540-3545.
7	Roodman GD. Mechanisms of bone metastasis[J]. N Engl J Med, 2004, 350(16): 1655-1664.
8	Nguyen DX, Chiang AC, Zhang XH-F, et al. WNT/TCF signaling through LEF1 and HOXB 9 mediates lung adenocarcinoma metastasis[J]. Cell, 2009, 138(1): 51-62.
9	Bromme D, Okamoto K, Wang BB, et al. Human cathepsin O₂, a matrix protein-degrading cysteine protease expressed in osteoclasts. Functional expression of human cathepsin O₂ in Spodoptera frugiperda and characterization of the enzyme[J]. J Biol Chem, 1996, 271(4): 2126-2132.
10	Gamero P, Borel O, Byrjalsen I, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases[J]. J Biol Chem, 1998, 273(48): 32347-32352.
11	Wilson SR, Peters C, Saftig P, et al. Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption[J]. J Biol Chem, 2009, 284(4): 2584-2592.
12	Maeda T, Alexander CM, Friedl A. Induction of syndecan-1 expression in stromal fibroblasts promotes proliferation of human breast cancer cells[J]. Cancer Res, 2004, 64(2): 612-621.
13	Powle T, Paterson S, Kanis JA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer[J]. J Clin Oncol, 2002, 20(15): 3219-3224.
14	Bussard KM, Gay CV, Mastro AM. The bone microenvironment in metastasis; what is special about bone[J]. Cancer Metastasis Rev, 2008, 27(1): 41-55.
15	Thomas RJ, Guise TA, Yin JJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation[J]. Endocrinology, 1999, 140(10): 4451-4458.
16	Guise TA, Yin JJ, Taylor SD, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis[J]. J Clin Invest, 1996, 98(7): 1544-1549.
17	Yoneda T, Hiraga T. Crosstalk between cancer cells and bone microenvironment in bone metastasis[J]. Biochem Biophys Res Commun, 2005, 328(3): 679-687.
18	Fleisch H. Development of bisphosphonates[J]. Breast Cancer Res, 2002, 4(1): 30-34.
19	Green J, Clézardin P. The molecular basis of bisphosphonate activity: a preclinical perspective[J]. Semin Oncol, 2010, 37 Suppl 1: S3-S11.
20	Rosen L, Harland SJ, Osterlinck W. Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors[J]. Am J Clin Oncol, 2002, 25(6 Suppl 1): S19-S24.
21	Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer[J]. Cochrane Database Syst Rev, 2005, (3): CD003474.
22	Rosen LS, Gordon DH, Kaminski M, et al. Long-term ef？cacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter comparative trial[J]. Cancer, 2003, 98(8): 1735-1744.
23	Rosen LS, Gordon DH, Dugan W Jr, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion[J]. Cancer, 2004, 100(1): 36-43.
24	Filleul O, Crompot E, Saussez S. Bisphosphonate-induced osteonecrosis of the jaw: a review of 2, 400 patient cases[J]. J Cancer Res Clin Oncol, 2010, 136(8): 1117-1124.
25	Palaska PK, Cartsos V, Zavras AI. Bisphosphonates and time to osteonecrosis development[J]. Oncologist, 2009, 14(11): 1154-1166.
26	Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study[J]. Lancet, 2011, 377(9768): 813-822.
27	Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study[J]. J Clin Oncol, 2010, 28(35): 5132-5139.
28	Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma[J]. J Clin Oncol, 2011, 29(9): 1125-1132.
29	Lipton A, Fizazi K, Stopeck A. Effect of denosumab versus zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with metastatic bone disease: Subgroup analyses by baseline characteristics[J]. J of Clin Oncol, 2014, 32(15 suppl 1).
30	ScagliottiGV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study[J]. J Thorac Oncol, 2012, 7(12): 1823-1829.
39	Busch AM, Johnson KC, Stan RV, et al. Evidence for tankyrases as antineoplastic targets in lung cancer[J]. BMC Cancer, 2013, 13: 211.
40	Lau T, Chan E, Callow M, et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth[J]. Cancer Res, 2013, 73(10): 3132-3144.
31	Fizazi K, Coleman R, Klotz L, et al. Prevention of symptomatic skeletal events in patients with genitourinary (GU) tumors and bone metastases treated with denosumab or zoledronic acid[J]. Eur Urol Suppl, 2014, 13(1): e869.
32	Kawatani M, Osada H. Osteoclast-targeting small molecules for the treatment of neoplastic bone metastases[J]. Cancer Sci, 2009, 100(11): 1999-2005.

[1]	韩丹, 王婷, 肖欢, 朱丽容, 陈镜宇, 唐毅. 超声造影与增强CT对儿童肝脏良恶性病变诊断价值的对比分析[J]. 中华医学超声杂志（电子版）, 2023, 20(09): 939-944.
[2]	郏亚平, 曾书娥. 含鳞状细胞癌成分的乳腺化生性癌的超声与病理特征分析[J]. 中华医学超声杂志（电子版）, 2023, 20(08): 844-848.
[3]	姚宏伟, 魏鹏宇, 高加勒, 张忠涛. 不断提高腹腔镜右半结肠癌D3根治术的规范化[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 1-4.
[4]	杜晓辉, 崔建新. 腹腔镜右半结肠癌D3根治术淋巴结清扫范围与策略[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 5-8.
[5]	周岩冰, 刘晓东. 腹腔镜右半结肠癌D3根治术消化道吻合重建方式的选择[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 9-13.
[6]	唐旭, 韩冰, 刘威, 陈茹星. 结直肠癌根治术后隐匿性肝转移危险因素分析及预测模型构建[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 16-20.
[7]	张生军, 赵阿静, 李守博, 郝祥宏, 刘敏丽. 高糖通过HGF/c-met通路促进结直肠癌侵袭和迁移的实验研究[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 21-24.
[8]	张焱辉, 张蛟, 朱志贤. 留置肛管在中低位直肠癌新辅助放化疗后腹腔镜TME术中的临床研究[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 25-28.
[9]	李凤仪, 李若凡, 高旭, 张超凡. 目标导向液体干预对老年胃肠道肿瘤患者术后血流动力学、胃肠功能恢复的影响[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 29-32.
[10]	李建美, 邓静娟, 杨倩. 两种术式联合治疗肝癌合并肝硬化门静脉高压的安全性及随访评价[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 41-44.
[11]	燕速, 霍博文, 徐惠宁. 4K荧光腹腔镜扩大右半结肠CME+D3根治术及No.206、No.204组淋巴结清扫术[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 14-14.
[12]	钱龙, 陆晓峰, 王行舟, 杜峻峰, 沈晓菲, 管文贤. 神经系统调控胃肠道肿瘤免疫应答研究进展[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 86-89.
[13]	曹长青, 郭新艳, 高源, 张存, 唐海利, 樊东, 杨小军, 张松, 赵华栋. 肿瘤微环境参与介导HER2阳性乳腺癌曲妥珠单抗耐药的研究进展[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 90-95.
[14]	王军, 刘鲲鹏, 姚兰, 张华, 魏越, 索利斌, 陈骏, 苗成利, 罗成华. 腹膜后肿瘤切除术中大量输血患者的麻醉管理特点与分析[J]. 中华临床医师杂志(电子版), 2023, 17(08): 844-849.
[15]	徐军, 姬园园, 陈君平, 王健. 伴菊形团结构的脑膜瘤合并颅骨侵犯一例并文献复习[J]. 中华临床医师杂志(电子版), 2023, 17(08): 916-919.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Cell biological mechanism of bone metastasis and cellular molecular targeted treatment

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Cell biological mechanism of bone metastasis and cellular molecular targeted treatment