肿瘤抗血管生成治疗耐药机制

doi:10.16288/j.yczz.24-110

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Hereditas(Beijing) ›› 2024, Vol. 46 ›› Issue (11): 911-919.doi: 10.16288/j.yczz.24-110

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Drug resistance mechanism of anti-angiogenesis therapy in tumor

Xu Yan¹^,²(), Ying Guo¹^,², Donglin Sun¹^,², Nan Wu¹^,²(), Yan Jin¹^,²()

1. Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Harbin 150081, China
2. Ministry of Education and Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China

Received:2024-04-24 Revised:2024-08-20 Online:2024-11-20 Published:2024-08-27
Contact: Nan Wu, Yan Jin E-mail:15774511409@163.com;wunan@hrbmu.edu.cn;jinyan@hrbmu.edu.cn
Supported by:
National Natural Science Foundation of China(82172353);Research Business Funding Projects for Provincial Scientific Research Institutions in Heilongjiang Province(CZKYF2021-2-B012);China Postdoctoral Science Foundation(2020T130159);Heilongjiang Postdoctoral Financial Assistance(LBH-TZ2020);Natural Science Foundation of Heilongjiang Province of China(YQ2022H004);Heilongjiang Province Head Goose Innovation Team Project

Abstract

Abstract:

Angiogenesis refers to the process of forming a new network of blood vessels from existing ones through the migration, proliferation, and differentiation of endothelial cells. This process is crucial for the growth and spread of solid tumors, particularly once the tumor volume exceeds 2 mm³, as the newly formed vascular network provides essential oxygen, nutrients, and growth factors to the tumor. Anti-angiogenesis therapy has become one of the commonly used targeted treatments for cancer in clinical practice. Bevacizumab, the first anti-angiogenesis drug, has been widely applied in the treatment of various solid tumors. However, due to acquired resistance, its efficacy is typically sustained for only 1 to 2 years. Despite the relative genomic stability of endothelial cells, which makes resistance less likely, various types of resistance phenomena have been observed in clinical practice, indicating that resistance to anti-angiogenic therapy remains a challenging research area. This review focuses on the latest advances in the mechanisms of resistance to anti-angiogenic therapy in tumors and explores new prospects for anti-tumor angiogenesis treatment, in order to provide strong theoretical support and guidance for clinical practice.

Key words: tumor drug resistance, anti-angiogenic drugs, vessel co-option, vasculogenic mimicry, intussusceptive angiogenesis

Xu Yan, Ying Guo, Donglin Sun, Nan Wu, Yan Jin. Drug resistance mechanism of anti-angiogenesis therapy in tumor[J]. Hereditas(Beijing), 2024, 46(11): 911-919.

Figures/Tables 2

Fig. 1

Table 1

The alternative pathway of VEGF treatment resistance"

信号通路	生理作用	具体机制
血管生成素/Tie	调节血管的发育、重塑和血管通透性	血管生成素-1与VEGF同时表达可抑制VEGF诱导的新生血管形成^[15]；血管生成素-2与大量肿瘤的不良预后相关，包括用贝伐珠单抗治疗的结直肠癌患者^[16]
FGF/FGFR	激活细胞增殖、迁移、抗凋亡、分化与代谢	抗VEGF和抗PDGF耐药的肿瘤中发现FGF-2的上调，抑制PDGFRβ可以消融FGF-2募集的血管周围覆盖，暴露出抗VEGF的药物来抑制血管的萌发^[17]
PDGF/PDGFR	参与血管的成熟与外周细胞的募集	PDGF-BB可以促进周细胞向肿瘤周围的外周迁移，促进肿瘤血管生成和血管生成拟态的形成^[18]
PIGF	激活内皮细胞、巨噬细胞、骨髓祖细胞和肿瘤细胞的生长、生存和迁移	PIGF可通过激活内皮细胞和血管壁细胞的增殖来直接促进肿瘤的血管生成；也可以通过上调VEGF-A、FGF2、PDGFB和MMPs的表达来间接发挥促血管生成作用^[19]；PIGF选择性结合VEGFR1导致抗VEGF治疗获得性耐药^[20]
白细胞介素	诱导肿瘤细胞启动和血管生成和炎症的发生	白细胞介素-17A驱动 NF-kB信号来分泌G-CSF，后者可促进血管生成，并导致抗VEGF治疗逃逸^[21]
TGF-β	直接诱导血管生成，或通过活化成纤维细胞或刺激内皮细胞的血管形成	抗VEGF治疗耐药的肿瘤会表达高水平的TGF-β^[22]
可溶性血管内皮生长因子受体	可作为VEGF诱饵，导致加入的外源VEGF阻断剂无法发挥作用	在化疗联合贝伐珠单抗治疗期间，VEGF-A的减少和可溶性血管内皮生长因子受体的增加，通过降低VEGF的需求导致贝伐珠单抗的耐药^[23]
SDF1α/CXCR	促进血管新生、血管选定、纤维化、免疫细胞运输和肿瘤细胞的侵袭	阻断VEGF之后，利用普乐沙福阻断CXCR4可加强治疗效果^[24]；SDF1α的水平在VEGF治疗耐药的患者中增加，激活血管共选择，导致肿瘤可逃避VEGF的阻断^[25]

Table 1

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