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北京大学学报（医学版） ›› 2026, Vol. 58 ›› Issue (2): 251-256. doi: 10.19723/j.issn.1671-167X.2026.02.005

• 工作综述 • 上一篇    下一篇

靶向血管治疗在乳腺癌精准治疗中的分子机制与临床应用

王海, 江一舟*()   

  1. 复旦大学附属肿瘤医院乳腺外科，复旦大学上海医学院肿瘤学系，上海 200032
  • 收稿日期:2025-12-25 出版日期:2026-04-18 发布日期:2026-02-06
  • 通讯作者: 江一舟
  • 基金资助:
    国家自然科学基金(82403845); 全国博士后管理委员会博士后创新人才计划(A类)(BX20230092); 全国博士后管理委员会博士后面上项目(2025M772257); 上海市白玉兰浦江人才计划(24PJD019); 上海市自然科学项目(24ZR1413100)

Molecular mechanisms and clinical applications of anti-angiogenic therapy in precision treatment of breast cancer

Hai WANG, Yizhou JIANG*()   

  1. Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
  • Received:2025-12-25 Online:2026-04-18 Published:2026-02-06
  • Contact: Yizhou JIANG
  • Supported by:
    the National Natural Science Foundation of China(82403845); Postdoctoral Innovative Talents Support Program (Class A), National Postdoctoral Management Committee(BX20230092); General Program of China Postdoctoral Science Foundation, National Postdoctoral Management Committee(2025M772257); Shanghai Magnolia Pujiang Talent Program(24PJD019); Shanghai Natural Science Foundation Program(24ZR1413100)

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摘要：

肿瘤血管形成是乳腺癌进展与治疗应答的重要决定因素，本文首先回溯了肿瘤血管形成理论的提出与演变历程，系统梳理了其多样化的发生模式，包括出芽性血管生成、血管内生性分裂、血管拟态与血管共选等，深入剖析了不同模式的异质性特征及其在肿瘤进展各阶段的生物学意义。在分子调控机制层面，重点总结了缺氧诱导因子-1轴、血管内皮生长因子/血管内皮生长因子受体、血小板衍生生长因子/血小板衍生生长因子受体、血管生成素/血管生成素受体及Delta样配体4/Notch受体信号通路等核心调控网络的作用机制。此外，本文还全面回顾了抗血管生成治疗在乳腺癌中的临床探索历程，同时探讨了该治疗策略面临的疗效不稳定、耐药、缺乏精准分层标志物及治疗相关毒性等现实挑战。最后，本文提出了面向精准治疗的未来研究方向，包括优化血管正常化窗口、基于多维标志物的患者分层策略，以及利用空间组学解析肿瘤血管异质性等，为乳腺癌抗血管生成治疗的优化与创新提供了理论参考。

关键词: 肿瘤血管形成, 乳腺癌, 抗血管生成治疗, 精准治疗

Abstract:

Tumor angiogenesis is a crucial determinant of breast cancer progression and therapeutic response. This review first traces the proposal and evolutionary course of the tumor angiogenesis theory, and systematically collates its diverse occurrence patterns, including sprouting angiogenesis, intussusceptive angiogenesis, vascular mimicry and vascular co-option, while conducting an in-depth analysis of the heterogeneous characteristics of different patterns and their biological significance at various stages of tumor progression. At the molecular regulatory mechanism level, this paper focuses on summarizing the mechanisms of core regulatory networks, such as the hypoxia-inducible factor-1 axis, vascular endothelial growth factor/vascular endothelial growth factor receptor, platelet-derived growth factor/platelet-derived growth factor receptor, angiopoietin/angiopoietin receptor, and Delta-like ligand 4/Notch receptor signaling pathway. In addition, this paper comprehensively reviews the clinical exploration of anti-angiogenic therapy for breast cancer, and discusses the practical challenges faced by this therapeutic strategy, including unstable efficacy, drug resistance, the lack of precise stratification biomarkers and treatment-related toxicities. Finally, this paper proposes future research directions oriented toward precision therapy, including optimizing the vascular normalization window, developing patient stratification strategies based on multidimensional biomarkers, and deciphering tumor vascular heterogeneity by using spatial omics. These findings provide a theoretical reference for the optimization and innovation of anti-angiogenic therapy for breast cancer.

Key words: Tumor angiogenesis, Breast cancer, Anti-angiogenic therapy, Precision medicine

中图分类号: 

  • R737.9
1
Folkman J . Tumor angiogenesis: Therapeutic implications[J]. N Engl J Med, 1971, 285 (21): 1182- 1186.

doi: 10.1056/NEJM197111182852108
2
Gimbrone MA Jr , Cotran RS , Leapman SB , et al. Tumor growth and neovascularization: An experimental model using the rabbit cornea[J]. J Natl Cancer Inst, 1974, 52 (2): 413- 427.

doi: 10.1093/jnci/52.2.413
3
Brem H , Folkman J . Inhibition of tumor angiogenesis mediated by cartilage[J]. J Exp Med, 1975, 141 (2): 427- 439.

doi: 10.1084/jem.141.2.427
4
Folkman J . Tumor angiogenesis: A possible control point in tumor growth[J]. Ann Intern Med, 1975, 82 (1): 96- 100.

doi: 10.7326/0003-4819-82-1-96
5
Bergers G , Hanahan D . Modes of resistance to anti-angiogenic therapy[J]. Nat Rev Cancer, 2008, 8 (8): 592- 603.

doi: 10.1038/nrc2442
6
Carmeliet P , Jain RK . Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases[J]. Nat Rev Drug Discov, 2011, 10 (6): 417- 427.

doi: 10.1038/nrd3455
7
Gerhardt H , Golding M , Fruttiger M , et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia[J]. J Cell Biol, 2003, 161 (6): 1163- 1177.

doi: 10.1083/jcb.200302047
8
Jain RK . Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy[J]. Science, 2005, 307 (5706): 58- 62.

doi: 10.1126/science.1104819
9
Burri PH , Hlushchuk R , Djonov V . Intussusceptive angiogenesis: Its emergence, its characteristics, and its significance[J]. Dev Dyn, 2004, 231 (3): 474- 488.

doi: 10.1002/dvdy.20184
10
Maniotis AJ , Folberg R , Hess A , et al. Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry[J]. Am J Pathol, 1999, 155 (3): 739- 752.

doi: 10.1016/S0002-9440(10)65173-5
11
Ruf W , Seftor EA , Petrovan RJ , et al. Differential role of tissue factor pathway inhibitors 1 and 2 in melanoma vasculogenic mimi-cry[J]. Cancer Res, 2003, 63 (17): 5381- 5389.
12
Seftor REB , Hess AR , Seftor EA , et al. Tumor cell vasculogenic mimicry: From controversy to therapeutic promise[J]. Am J Pathol, 2012, 181 (4): 1115- 1125.

doi: 10.1016/j.ajpath.2012.07.013
13
Pezzella F , Pastorino U , Tagliabue E , et al. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis[J]. Am J Pathol, 1997, 151 (5): 1417- 1423.
14
Kuczynski EA , Vermeulen PB , Pezzella F , et al. Vessel co-option in cancer[J]. Nat Rev Clin Oncol, 2019, 16 (8): 469- 493.

doi: 10.1038/s41571-019-0181-9
15
Carmeliet P , Jain RK . Angiogenesis in cancer and other diseases[J]. Nature, 2000, 407 (6801): 249- 257.

doi: 10.1038/35025220
16
Semenza GL . Targeting HIF-1 for cancer therapy[J]. Nat Rev Cancer, 2003, 3 (10): 721- 732.

doi: 10.1038/nrc1187
17
Semenza GL . Hypoxia-inducible factors in physiology and medicine[J]. Cell, 2012, 148 (3): 399- 408.

doi: 10.1016/j.cell.2012.01.021
18
Ferrara N , Henzel WJ . Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells[J]. Biochem Biophys Res Commun, 1989, 161 (2): 851- 858.

doi: 10.1016/0006-291X(89)92678-8
19
Ferrara N , Gerber HP , LeCouter J . The biology of VEGF and its receptors[J]. Nat Med, 2003, 9 (6): 669- 676.

doi: 10.1038/nm0603-669
20
Shen C , Lin C , Qu F , et al. Genomic spectra of lymphovascular invasion in breast cancer[J]. Chin J Cancer Res, 2025, 37 (2): 138- 153.

doi: 10.21147/j.issn.1000-9604.2025.02.02
21
Hellström M , Phng LK , Hofmann JJ , et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis[J]. Nature, 2007, 445 (7129): 776- 780.

doi: 10.1038/nature05571
22
Ferrara N . VEGF and the quest for tumour angiogenesis factors[J]. Nat Rev Cancer, 2002, 2 (10): 795- 803.

doi: 10.1038/nrc909
23
Miller K , Wang M , Gralow J , et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer[J]. N Engl J Med, 2007, 357 (26): 2666- 2676.

doi: 10.1056/NEJMoa072113
24
Miles DW , Chan A , Dirix LY , et al. Phase Ⅲ study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer[J]. J Clin Oncol, 2010, 28 (20): 3239- 3247.

doi: 10.1200/JCO.2008.21.6457
25
Robert NJ , Diéras V , Glaspy J , et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase Ⅲ trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer[J]. J Clin Oncol, 2011, 29 (10): 1252- 1260.

doi: 10.1200/JCO.2010.28.0982
26
Ferrara N , Hillan KJ , Gerber HP , et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer[J]. Nat Rev Drug Discov, 2004, 3 (5): 391- 400.

doi: 10.1038/nrd1381
27
Baselga J , Segalla JGM , Roché H , et al. Sorafenib in combination with capecitabine: An oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer[J]. J Clin Oncol, 2012, 30 (13): 1484- 1491.

doi: 10.1200/JCO.2011.36.7771
28
Fukumura D , Kloepper J , Amoozgar Z , et al. Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges[J]. Nat Rev Clin Oncol, 2018, 15 (5): 325- 340.

doi: 10.1038/nrclinonc.2018.29
29
Fan L , Wang ZH , Ma LX , et al. Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): A multi-cohort, randomised, phase 2 trial[J]. Lancet Oncol, 2024, 25 (2): 184- 197.

doi: 10.1016/S1470-2045(23)00579-X
30
Wang Y , Xu B . Recent advances in systematic therapy of breast cancer: Chinese contribution for international progress[J]. Chin J Cancer Res, 2024, 36 (6): 587- 591.

doi: 10.21147/j.issn.1000-9604.2024.06.01
31
Ellis LM , Hicklin DJ . Pathways mediating resistance to vascular endothelial growth factor-targeted therapy[J]. Clin Cancer Res, 2008, 14 (20): 6371- 6375.

doi: 10.1158/1078-0432.CCR-07-5287
32
Kerbel RS . Tumor angiogenesis[J]. N Engl J Med, 2008, 358 (19): 2039- 2049.

doi: 10.1056/NEJMra0706596
33
Goel S , Dan GD , Lei X , et al. Normalization of the vasculature for treatment of cancer and other diseases[J]. Physiol Rev, 2011, 91 (3): 1071- 1121.

doi: 10.1152/physrev.00038.2010
34
Hurwitz H , Fehrenbacher L , Novotny W , et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[J]. N Engl J Med, 2004, 350 (23): 2335- 2342.

doi: 10.1056/NEJMoa032691
35
Ranpura V , Pulipati B , Chu D , et al. Increased risk of high-grade hypertension with bevacizumab in cancer patients: A meta-analysis[J]. Am J Hypertens, 2010, 23 (5): 460- 468.

doi: 10.1038/ajh.2010.25
36
De Palma M , Biziato D , Petrova TV . Microenvironmental regulation of tumour angiogenesis[J]. Nat Rev Cancer, 2017, 17 (8): 457- 474.

doi: 10.1038/nrc.2017.51
37
Wu SZ , Al-Eryani G , Roden DL , et al. A single-cell and spatially resolved atlas of human breast cancers[J]. Nat Genet, 2021, 53 (9): 1334- 1347.

doi: 10.1038/s41588-021-00911-1
38
Batchelor TT , Sorensen AG , di Tomaso E , et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients[J]. Cancer Cell, 2007, 11 (1): 83- 95.

doi: 10.1016/j.ccr.2006.11.021
39
Jubb AM , Oates AJ , Holden S , et al. Predicting benefit from anti-angiogenic agents in malignancy[J]. Nat Rev Cancer, 2006, 6 (8): 626- 635.

doi: 10.1038/nrc1946
40
Tian L , Goldstein A , Wang H , et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming[J]. Nature, 2017, 544 (7649): 250- 254.

doi: 10.1038/nature21724
41
Kalucka J , de Rooij LPMH , Goveia J , et al. Single-cell transcriptome atlas of murine endothelial cells[J]. Cell, 2020, 180 (4): 764- 779.

doi: 10.1016/j.cell.2020.01.015
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ISSN 1671-167X
CN 11-4691/R
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