骨微环境介导乳腺癌骨转移耐药性的研究进展

doi:10.11904/j.issn.1002-3070.2025.05.014

摘要/Abstract

摘要： 与其他恶性肿瘤相比,原发性乳腺癌的诊断与治疗已相对成熟。然而,乳腺癌发生骨转移后的临床治疗主要依赖于药物,但该方法难以彻底清除肿瘤细胞,并伴随耐药性问题,导致溶骨性破坏和肿瘤侵袭性增殖,从而严重降低患者的生活质量和生存率。既往研究多集中于乳腺癌细胞本身,而较少关注其如何利用骨微环境的保护机制抵抗药物治疗。本研究回顾相关文献,探讨骨微环境在乳腺癌骨转移耐药性形成中的作用,以期为乳腺癌骨转移的治疗提供新的视角。

关键词: 骨转移, 耐药性, 临床前模型, 药物递送系统

Abstract: In comparison with other malignancies,the diagnosis and treatment of primary breast cancer are relatively mature.However,the clinical management of breast cancer bone metastasis primarily relies on drugs,but this approach struggles to completely eliminate tumor cells and is often accompanied by drug resistance,leading to osteolytic destruction and aggressive tumor proliferation,severely compromising patients'quality of life and survival.Previous studies have focused primarily on breast cancer cells themselves,with less attention paid to how they exploit the protective mechanisms of the bone microenvironment to resist drug therapy.The study reviews the relevant literature to explore the role of the bone microenvironment in the development of drug resistance in breast cancer bone metastasis,hoping to provide new insights into the treatment of breast cancer bone metastasis.

Key words: bone metastasis, drug resistance, preclinical model, drug delivery systems

中图分类号:

R737.9

吕睿, 甄林林. 骨微环境介导乳腺癌骨转移耐药性的研究进展[J]. 实用肿瘤学杂志, 2025, 39(5): 450-456.

LYU Rui, ZHEN Linlin. Research progress on bone microenvironment-mediated drug resistance in breast cancer bone metastasis[J]. Journal of Practical Oncology, 2025, 39(5): 450-456.

参考文献

1 Bray F,Laversanne M,Sung H,et al.Global cancer statistics 2022:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2024,74(3):229-263.
2 Zhang J,Cai D,Hong S.Prevalence and prognosis of bone metastases in common solid cancers at initial diagnosis:a population-based study[J].BMJ Open,2023,13(10):e069908.
3 Hardtstock F,Kocaata Z,Wilke T,et al.Healthcare resource utilization and associated cost of patients with bone metastases from solid tumors who are naïve to bone-targeting agents:a comparative analysis of patients with and without skeletal-related events[J].Eur J Health Econ,2021,22(2):243-254.
4 Ulas A,Bilici A,Durnali A,et al.Risk factors for skeletal-related events(SREs)and factors affecting SRE-free survival for nonsmall cell lung cancer patients with bone metastases[J].Tumour Biol,2016,37(1):1131-1140.
5 Sarnella A,Ferrara Y,Albanese S,et al.Inhibition of bone marrow-mesenchymal stem cell-induced carbonic anhydrase IX potentiates chemotherapy efficacy in triple-negative breast cancer cells[J].Cells,2023,12(2):298.
6 Alraouji NN,Colak D,Al-Mohanna FH,et al.Endogenous osteoprotegerin(OPG)represses ERα and promotes stemness and chemoresistance in breast cancer cells[J].Cell Death Discov,2024,10(1):377.
7 Wu Q,Tian P,He D,et al.SCUBE2 mediates bone metastasis of luminal breast cancer by modulating immune-suppressive osteoblastic niches[J].Cell Res,2023,33(6):464-478.
8 Özcan G.SCUBE2 as a marker of resistance to taxane-based neoadjuvant chemotherapy and a potential therapeutic target in breast cancer[J].Eur J Breast Health,2023,19(1):45-54.
9 Zheng H,Bae Y,Kasimir-Bauer S,et al.Therapeutic antibody targeting tumor-and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy[J].Cancer Cell,2017,32(6):731-747.e6.
10 Carlson P,Dasgupta A,Grzelak CA,et al.Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy[J].Nat Cell Biol,2019,21(2):238-250.
11 James JJ,Evans AJ,Pinder SE,et al.Bone metastases from breast carcinoma:histopathological-radiological correlations and prognostic features[J].Br J Cancer,2003,89(4):660-665.
12 Buschhaus JM,Rajendran S,Chen S,et al.Bone marrow mesenchymal stem cells induce metabolic plasticity in estrogen receptor-positive breast cancer[J].Mol Cancer Res,2023,21(5):458-471.
13 Buschhaus JM,Rajendran S,Humphries BA,et al.Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer[J].Oncogene,2022,41(29):3705-3718.
14 Tsoi H,Man EPS,Chau KM,et al.Targeting the IL-6/STAT3 signalling cascade to reverse tamoxifen resistance in estrogen receptor positive breast cancer[J].Cancers(Basel),2021,13(7):1511.
15 Lu Y,Zhang J,Dai J,et al.Osteoblasts induce prostate cancer proliferation and PSA expression through interleukin-6-mediated activation of the androgen receptor[J].Clin Exp Metastasis,2004,21(5):399-408.
16 Bado IL,Zhang W,Hu J,et al.The bone microenvironment increases phenotypic plasticity of ER(+)breast cancer cells[J].Dev Cell,2021,56(8):1100-1117.
17 Nakatsuji M,Fujimori K.Adipocyte-conditioned medium induces tamoxifen resistance by activating PI3K/Akt/mTOR pathway in estrogen receptor-positive breast cancer cells[J].Biochim Biophys Acta Mol Cell Res,2024,1871(7):119821.
18 Traina TA,Miller K,Yardley DA,et al.Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer[J].J Clin Oncol,2018,36(9):884-890.
19 孙红,侯佳林,蔡加琴,等.SUMO E3连接酶介导雄激素受体的转录促进乳腺癌他莫昔芬耐药[J].中国临床药理学与治疗学,2021,26(3):285-291.
20 Su S,Cao J,Meng X,et al.Enzalutamide-induced and PTH1R-mediated TGFBR2 degradation in osteoblasts confers resistance in prostate cancer bone metastases[J].Cancer Lett,2022,525:170-178.
21 Brauneck E,Leonhardt LG,Assemissen AM,et al.Expression of the TIGIT axis and the CD39/CD73 purinergic pathway in bone metastasis-derived immune cells[J].Cancer Immunol Immunother,2025,74(6):182.
22 Xu F,Sunderland A,Zhou Y,et al.Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions[J].Cancer Immunol Immunother,2017,66(10):1367-1375.
23 Fan H,Xu Z,Yao K,et al.Osteoclast cancer cell metabolic cross-talk confers PARP inhibitor resistance in bone metastatic breast cancer[J].Cancer Res,2024,84(3):449-467.
24 Cheung A,Chenoweth AM,Johansson A,et al.Anti-EGFR antibody-drug conjugate carrying an inhibitor targeting CDK restricts triple-negative breast cancer growth[J].Clin Cancer Res,2024,30(15):3298-3315.
25 Hsu DS,Hwang WL,Yuh CH,et al.Lymphotoxin-β interacts with methylated EGFR to mediate acquired resistance to cetuximab in head and neck cancer[J].Clin Cancer Res,2017,23(15):4388-4401.
26 Wang X,Zhang T,Zheng B,et al.Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth[J].Nat Cell Biol,2024,26(9):1597-1612.
27 Arellano DL,Juárez P,Verdugo-Meza A,et al.Bone microenvironment-suppressed T cells increase osteoclast formation and osteolytic bone metastases in mice[J].J Bone Miner Res,2022,37(8):1446-1463.
28 Monteran L,Ershaid N,Scharff Y,et al.Combining TIGIT blockade with MDSC inhibition hinders breast cancer bone metastasis by activating antitumor immunity[J].Cancer Discov,2024,14(7):1252-1275.
29 Park S,Choi S,Shimpi AA,et al.Collagen mineralization decreases NK cell-mediated cytotoxicity of breast cancer cells via increased glycocalyx thickness[J].Adv Mater,2024,36(43):e2311505.
30 Wang Y,Xu Z,Wu KL,et al.Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis[J].Proc Natl Acad Sci USA,2024,121(5):e2312929121.
31 Shi T,Liu W,Luo Y,et al.CHI3L3(+)immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases[J].Cancer Cell,2025,43(10):1937-1957.ell.
32 Cheng JN,Jin Z,Su C,et al.Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts[J].Cancer Cell,2025,43(6):1093-1107.
33 Glaser DE,Curtis MB,Sariano PA,et al.Organ-on-a-chip model of vascularized human bone marrow niches[J].Biomaterials,2022,280:121245.
34 Huang Z,Yu P,Tang J.Characterization of triple-negative breast cancer MDA-MB-231 cell spheroid model[J].Onco Targets Ther,2020,13:5395-5405.
35 Mohseni Garakani M,Cooke ME,Weber MH,et al.A 3D,compartmental tumor-stromal microenvironment model of patient-derived bone metastasis[J].Int J Mol Sci,2022,24(1):160.
36 Eyre R,Alférez DG,Santiago-Gómez A,et al.Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling[J].Nat Commun,2019,10(1):5016.
37 Jasuja H,Solaymani Mohammadi F,Kim J,et al.Patient-derived breast cancer bone metastasis in vitro model using bone-mimetic nanoclay scaffolds[J].J Tissue Eng Regen Med,2023,2023:5753666.
38 Farhoodi HP,Segaliny AI,Wagoner ZW,et al.Optimization of a syngeneic murine model of bone metastasis[J].J Bone Oncol,2020,23:100298.
39 Delaloge S,Pérol D,Courtinard C,et al.Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study[J].Ann Oncol,2016,27(9):1725-1732.
40 穆玉晶,冯雪,孔健达,等.CDK4/6抑制剂联合内分泌疗法治疗HR+/HER2-乳腺癌疗效和安全性的Meta分析[J].中国循证医学杂志,2024,24(3):280-287.
41 王帅,黎其庆,李瑞,等.纳米粒子在乳腺癌诊断和治疗中的应用进展[J].实用肿瘤学杂志,2025,39(02):151-156.
42 Mushtaq A,Li L,Grøndahl L,et al.Targeted nanoparticles based on alendronate polyethylene glycol conjugated chitosan for the delivery of siRNA and curcumin for bone metastasized breast cancer applications[J].Macromol Biosci,2024,24(2):e2300268.
43 Rocas P,Fernández Y,García-Aranda N,et al.Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανβ3-targeted polyurethane-polyurea nanoparticles[J].Nanomedicine,2018,14(2):257-267.
44 Chen C,Shen M,Liao H,et al.A paclitaxel and microRNA-124 coloaded stepped cleavable nanosystem against triple negative breast cancer[J].J Nanobiotechnology,2021,19(1):55.

[1]	吴小帆, 李琳. 卵巢癌中紫杉醇耐药性研究进展[J]. 实用肿瘤学杂志, 2025, 39(4): 343-347.
[2]	韩焱崧, 任明华. 前列腺癌骨转移机制和骨靶向药物研究进展[J]. 实用肿瘤学杂志, 2023, 37(3): 252-256.
[3]	冯诚天, 黄芙蓉, 姜永冬. 脂质代谢与乳腺癌曲妥珠单抗耐药性机制的相关性研究[J]. 实用肿瘤学杂志, 2023, 37(2): 155-159.
[4]	徐亭, 严斐斐, 张纯慧, 张艳桥. 胃癌骨转移患者临床病理与预后分析[J]. 实用肿瘤学杂志, 2019, 33(5): 436-441.
[5]	张莉, 方可薇, 岳茜, 王红, 杨汉丰, 徐晓雪. 冷冻消融治疗骨转移瘤的研究进展[J]. 实用肿瘤学杂志, 2018, 32(4): 353-356.
[6]	孟志英, 于松涛, 张晶晶, 金惠敏. 宫颈癌下颌骨转移1例报告并文献复习[J]. 实用肿瘤学杂志, 2018, 32(2): 122-124.
[7]	简立智，王天娇综述，吴瑾审校. 基质蛋白对恶性肿瘤骨转移作用的研究进展[J]. 实用肿瘤学杂志, 2017, 31(3): 285-288.
[8]	张锐，王智煜，王帅，赵晖. 重组人血管内皮抑素联合NP方案治疗初诊晚期非小细胞肺癌骨转移疗效及对血清VEGF表达的影响[J]. 实用肿瘤学杂志, 2016, 30(6): 527-522.
[9]	池淑琦综述, 汪宏波审校. 长链非编码RNA与肿瘤耐药性的研究进展[J]. 实用肿瘤学杂志, 2016, 30(2): 150-153.
[10]	潘夏综述, 江建平审校. Alectinib在非小细胞肺癌治疗中的研究进展[J]. 实用肿瘤学杂志, 2016, 30(1): 75-79.
[11]	曲文书,华海清. 原发性肝癌骨转移55例预后分析[J]. 实用肿瘤学杂志, 2015, 29(4): 327-332.
[12]	陈可心,李,琛,秦,誉,姚国栋,综述,耿敬姝,审校. 星形细胞上调基因1(AEG-1)介导肿瘤耐药的研究进展[J]. 实用肿瘤学杂志, 2014, 28(5): 447-450.
[13]	王萌,吕平欣. ⁸⁹Sr联合双膦酸盐在骨转移瘤姑息性治疗中的疗效观察[J]. 实用肿瘤学杂志, 2013, 27(5): 425-429.
[14]	张超, 杨春辉综述, 孟秀香审校. Bmi-1基因与肿瘤多药耐药性的关系[J]. 实用肿瘤学杂志, 2013, 27(4): 367-371.
[15]	胡章国综述, 蒋国兴审校. CXCR4与肝细胞肝癌转移的研究进展[J]. 实用肿瘤学杂志, 2013, 27(4): 381-384.