肿瘤抗血管生成治疗耐药机制

doi:10.16288/j.yczz.24-110

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

肿瘤抗血管生成治疗耐药机制

闫旭¹^,²(), 郭影¹^,², 孙冬琳¹^,², 吴楠¹^,²(), 金焰¹^,²()

1.中国遗传资源保护与疾病防控教育部重点实验室(哈尔滨医科大学)，哈尔滨 150081
2.哈尔滨医科大学医学遗传学研究室，哈尔滨 150081

收稿日期:2024-04-24 修回日期:2024-08-20 出版日期:2024-11-20 发布日期:2024-08-27
通讯作者: 吴楠，博士，副教授，研究方向：肿瘤遗传与进化。E-mail: wunan@hrbmu.edu.cn;
金焰，博士，教授，研究方向：肿瘤标记物筛选验证与智慧医疗。E-mail: jinyan@hrbmu.edu.cn
作者简介:闫旭，硕士研究生，专业方向：基础医学。E-mail: 15774511409@163.com
基金资助:
国家自然科学基金面上项目(82172353);黑龙江省省属科研院所科研业务费项目(CZKYF2021-2-B012);中国博士后科学基金特别资助(2020T130159);黑龙江省博士后特别资助(LBH-TZ2020);黑龙江省自然科学基金项目(YQ2022H004);黑龙江省头雁创新团队项目资助

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 Published:2024-11-20 Online:2024-08-27
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

摘要/Abstract

摘要：

血管生成指的是通过内皮细胞的迁移、增殖和分化，从现有血管网络中形成新的血管网络的过程。这一过程对于实体肿瘤的生长和扩散至关重要，尤其是在肿瘤体积超过2 mm³之后，新生的血管网络为肿瘤提供了至关重要的氧气、营养及生长因子。抗血管生成已经成为临床常用靶向治疗肿瘤的方案之一。首个抗血管生成药物贝伐单抗已广泛应用于多种实体肿瘤治疗，但由于获得性耐药现象，疗效仅能维持1~2年。即使血管内皮细胞的基因组相对稳定，不易产生耐药性，但临床实践中仍观察到多种类型的耐药现象，这表明抗血管生成治疗的耐药问题仍然是一个具有挑战性的研究领域。本文主要综述了肿瘤抗血管生成治疗耐药机制的最新进展，并探讨了抗肿瘤血管生成治疗的新前景，以期为临床实践提供有力的理论支持和指导。

关键词: 肿瘤耐药, 抗血管生成, 血管共选择, 血管拟态, 血管套叠

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

闫旭, 郭影, 孙冬琳, 吴楠, 金焰. 肿瘤抗血管生成治疗耐药机制[J]. 遗传, 2024, 46(11): 911-919.

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.

图/表 2

图1

表1

VEGF治疗耐药的旁路途径"

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]

表1

参考文献 45

[1]	Naito H, Iba T, Takakura N. Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells. Int Immunol, 2020, 32(5): 295-305. doi: 10.1093/intimm/dxaa008 pmid: 31996897
[2]	Lopes-Coelho F, Martins F, Pereirs SA, Serpa J. Anti-angiogenic therapy: current challenges and future perspectives. Int J Mol Sci, 2021, 22(7): 3765.
[3]	Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971, 285(21): 1182-1186.
[4]	Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, Chinot OL. Bevacizumab (Avastin^®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev, 2020, 86: 102017.
[5]	Teuwen LA, De Rooij LPMH, Cuypers A, Rohlenova K, Dumas SJ, García-Caballero M, Meta E, Amersfoort J, Taverna F, Becker LM, Veiga N, Cantelmo AR, Geldhof V, Conchinha NV, Kalucka J, Treps L, Conradi LC, Khan S, Karakach TK, Soenen S, Vinckier S, Schoonjans L, Eelen G, Van Laere S, Dewerchin M, Dirix L, Mazzone M, Luo YL, Vermeulen P, Carmeliet P. Tumor vessel co-option probed by single-cell analysis. Cell Rep, 2021, 35(11): 109253.
[6]	Lazaris A, Amri A, Petrillo SK, Zoroquiain P, Ibrahim N, Salman A, Gao ZH, Vermaulen PB, Metrakos P. Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti-angiogenic therapies. J Pathol Clin Res, 2018, 4(3): 184-192.
[7]	Pezzella F, Ribatti D. Vascular co-option and vasculogenic mimicry mediate resistance to antiangiogenic strategies. Cancer Rep (Hoboken), 2022, 5(12): e1318.
[8]	Ribatti D, Annese T, Tamma R. Vascular co-option in resistance to anti-angiogenic therapy. Front Oncol, 2023, 13: 1323350.
[9]	Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol, 1999, 155(3): 739-752. doi: 10.1016/S0002-9440(10)65173-5 pmid: 10487832
[10]	He M, Yang H, Shi HC, Hu YX, Chang CS, Liu SF, Yeh SY. Sunitinib increases the cancer stem cells and vasculogenic mimicry formation via modulating the lncRNA-ECVSR/ERβ/Hif2-α signaling. Cancer Lett, 2022, 524: 15-28.
[11]	Wei Z, Lei M, Wang YH, Xie YZ, Xie XY, Lan DW, Jia YB, Liu JY, Ma YF, Cheng B, Gerecht S, Xu F. Hydrogels with tunable mechanical plasticity regulate endothelial cell outgrowth in vasculogenesis and angiogenesis. Nat Commun, 2023, 14(1): 8307. doi: 10.1038/s41467-023-43768-0 pmid: 38097553
[12]	Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci, 2020, 77(9): 1745-1770. doi: 10.1007/s00018-019-03351-7 pmid: 31690961
[13]	Saravanan S, Vimalraj S, Pavani K, Nikarika R, Sumantran VN. Intussusceptive angiogenesis as a key therapeutic target for cancer therapy. Life Sci, 2020, 252: 117670.
[14]	Ayala-Domínguez L, Olmedo-Nieva L, Muñoz-Bello JO, Contreras-Paredes A, Manzo-Merino J, Martínez-Ramírez I, Lizano M. Mechanisms of vasculogenic mimicry in ovarian cancer. Front Oncol, 2019, 9: 998. doi: 10.3389/fonc.2019.00998 pmid: 31612116
[15]	Akwii RG, Mikelis CM. Targeting the angiopoietin/tie pathway: prospects for treatment of retinal and respiratory disorders. Drugs, 2021, 81(15): 1731-1749. doi: 10.1007/s40265-021-01605-y pmid: 34586603
[16]	Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol, 2018, 15(5): 325-340. doi: 10.1038/nrclinonc.2018.29 pmid: 29508855
[17]	Hosaka K, Yang YL, Seki T, Du QQ, Jing X, He XK, Wu JY, Zhang Y, Morikawa H, Nakamura M, Scherzer M, Sun XT, Xu YF, Cheng T, Li XR, Liu XL, Li Q, Liu YZ, Hong A, Chen YG, Cao YH. Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors. Nat Commun, 2020, 11(1): 3704. doi: 10.1038/s41467-020-17525-6 pmid: 32709869
[18]	Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther, 2023, 8(1): 198.
[19]	Kalra VK, Zhang SX, Malik P, Tahara SM. Placenta growth factor mediated gene regulation in sickle cell disease. Blood Rev, 2018, 32(1): 61-70. doi: S0268-960X(17)30072-3 pmid: 28823762
[20]	Arai H, Battaglin F, Wang JY, Lo JH, Soni S, Zhang W, Lenz HJ. Molecular insight of regorafenib treatment for colorectal cancer. Cancer Treat Rev, 2019, 81: 101912.
[21]	Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int J Mol Sci, 2018, 19(4): 1232.
[22]	Cheng Y, Li SJ, Hou YY, Wan WJ, Wang K, Fu SH, Yuan Y, Yang KD, Ye XF. Glioma-derived small extracellular vesicles induce pericyte-phenotype transition of glioma stem cells under hypoxic conditions. Cell Signal, 2023, 109: 110754.
[23]	Pineda E, Salud A, Vila-Navarro E, Safont MJ, Llorente B, Aparicio J, Vera R, Escudero P, Casado E, Bosch C, Bohn U, Pérez-Carrión R, Carmona A, Ayuso JR, Ripollés T, Bouzas R, Gironella M, García-Albéniz X, Feliu J, Maurel J. Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: a prospective translational study in the BECOX (GEMCAD 09-01) trial. Tumour Biol, 2017, 39(6): 1010428317705509.
[24]	Jung K, Heishi T, Incio J, Huang YH, Beech EY, Pinter M, Ho WW, Kawaguchi K, Rahbari NN, Chung E, Kim JK, Clark JW, Willett CG, Yun SH, Luster AD, Padera TP, Jain RK, Fukumura D. Targeting CXCR4-dependent immunosuppressive Ly6C(low) monocytes improves antiangiogenic therapy in colorectal cancer. Proc Natl Acad Sci USA, 2017, 114(39): 10455-10460.
[25]	Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: progress, opportunities, and challenges. Annu Rev Physiol, 2019, 81: 505-534. doi: 10.1146/annurev-physiol-020518-114700 pmid: 30742782
[26]	Chen WZ, Jiang JX, Yu XY, Xia WJ, Yu PX, Wang K, Zhao ZY, Chen ZG. Endothelial cells in colorectal cancer. World J Gastrointest Oncol, 2019, 11(11): 946-956.
[27]	Eikesdal HP, Kalluri R. Drug resistance associated with antiangiogenesis therapy. Semin Cancer Biol, 2009, 19(5): 310-317. doi: 10.1016/j.semcancer.2009.05.006 pmid: 19524042
[28]	Patel SA, Nilsson MB, Le XN, Cascone T, Jain RK, Heymach JV. Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy. Clin Cancer Res, 2023, 29(1): 30-39.
[29]	Goveia J, Rohlenova K, Taverna F, Treps L, Conradi LC, Pircher A, Geldhof V, De Rooij LPMH, Kalucka J, Sokol L, García-Caballero M, Zheng YF, Qian JB, Teuwen LA, Khan S, Boeckx B, Wauters E, Decaluwé H, De Leyn P, Vansteenkiste J, Weynand B, Sagaert X, Verbeken E, Wolthuis A, Topal B, Everaerts W, Bohnenberger H, Emmert A, Panovska D, De Smet F, Staal FJT, Mclaughlin RJ, Impens F, Lagani V, Vinckier S, Mazzone M, Schoonjans L, Dewerchin M, Eelen G, Karakach TK, Yang HM, Wang J, Bolund L, Lin L, Thienpont B, Li XR, Lambrechts D, Luo YL, Carmeliet P. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell, 2020, 37(1): 21-36.e13. doi: S1535-6108(19)30571-9 pmid: 31935371
[30]	Zhao Q, Eichten A, Parveen A, Adler C, Huang Y, Wang W, Ding YM, Adler A, Nevins T, Ni M, Wei Y, Thurston G. Single-cell transcriptome analyses reveal endothelial cell heterogeneity in tumors and changes following antiangiogenic treatment. Cancer Res, 2018, 78(9): 2370-2382. doi: 10.1158/0008-5472.CAN-17-2728 pmid: 29449267
[31]	Xiao Y, Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther, 2021, 221: 107753.
[32]	Song S, Zhang GH, Chen XT, Zheng J, Liu XD, Wang YQ, Chen ZJ, Wang YX, Song YL, Zhou Q. HIF-1α increases the osteogenic capacity of ADSCs by coupling angiogenesis and osteogenesis via the HIF-1α/VEGF/AKT/ mTOR signaling pathway. J Nanobiotechnology, 2023, 21(1): 257.
[33]	Qi SY, Deng SL, Lian ZX, Yu K. Novel drugs with high efficacy against tumor angiogenesis. Int J Mol Sci, 2022, 23(13): 6934.
[34]	Loizzi V, Del Vecchio V, Gargano G, De Liso M, Kardashi A, Naglieri E, Resta L, Cicinelli E, Cormio G. Biological pathways involved in tumor angiogenesis and Bevacizumab based anti-angiogenic therapy with special references to ovarian cancer. Int J Mol Sci, 2017, 18(9): 1967.
[35]	Huang CB, Li ZX, Li N, Li Y, Chang AT, Zhao TS, Wang XC, Wang HW, Gao S, Yang SY, Hao JH, Ren H. Interleukin 35 expression correlates with microvessel density in pancreatic ductal adenocarcinoma, recruits monocytes, and promotes growth and angiogenesis of xenograft tumors in mice. Gastroenterology, 2018, 154(3): 675-688.
[36]	Castro B A, Flanigan P, Jahangiri A, Hoffman D, Chen W, Kuang R, De Lay M, Yagnik G, Wagner JR, Mascharak S, Sidorov M, Shrivastav S, Kohanbash G, Okada H, Aghi MK. Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy. Oncogene, 2017, 36(26): 3749-3759. doi: 10.1038/onc.2017.1 pmid: 28218903
[37]	Goto H, Nishioka Y. Fibrocytes: a novel stromal cells to regulate resistance to anti-angiogenic therapy and cancer progression. Int J Mol Sci, 2017, 19(1): 98.
[38]	Cheng J, Wei JW, Tong T, Sheng WQ, Zhang YL, Han YQ, Gu DS, Hong N, Ye YJ, Tian J, Wang Y. Prediction of histopathologic growth patterns of colorectal liver metastases with a noninvasive imaging method. Ann Surg Oncol, 2019, 26(13): 4587-4598. doi: 10.1245/s10434-019-07910-x pmid: 31605342
[39]	Thiel KW, Devor EJ, Filiaci VL, Mutch D, Moxley K, Alvarez Secord A, Tewari KS, McDonald ME, Mathews C, Cosgrove C, Dewdney S, Aghajanian C, Samuelson MI, Lankes HA, Soslow RA, Leslie KK. TP53 sequencing and p53 immunohistochemistry predict outcomes when Bevacizumab is added to frontline chemotherapy in endometrial cancer: an NRG oncology/gynecologic oncology group study. J Clin Oncol, 2022, 40(28): 3289-3300.
[40]	Brenner A, Zuniga R, Sun JD, Floyd J, Hart CP, Kroll S, Fichtel L, Cavazos D, Caflisch L, Gruslova A, Huang S, Liu YC, Lodi A, Tiziani S. Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study. Neuro Oncol, 2018, 20(9): 1231-1239.
[41]	Shiraishi Y, Kishimoto J, Sugawara S, Mizutani H, Daga H, Azuma K, Matsumoto H, Hataji O, Nishino K, Mori M, Shukuya T, Saito H, Tachihara M, Hayashi H, Tsuya A, Wakuda K, Yanagitani N, Sakamoto T, Miura S, Hata A, Okada M, Kozuki T, Sato Y, Harada T, Takayama K, Yamamoto N, Nakagawa K, Okamoto I. Atezolizumab and platinum plus pemetrexed with or without Bevacizumab for metastatic nonsquamous non-small cell lung cancer: a phase 3 Randomized clinical trial. JAMA Oncol, 2024, 10(3): 315-324.
[42]	Kienast Y, Klein C, Scheuer W, Raemsch R, Lorenzon E, Bernicke D, Herting F, Yu S, The HH, Martarello L, Gassner C, Stubenrauch KG, Munro K, Augustin HG, Thomas M. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res, 2013, 19(24): 6730-6740. doi: 10.1158/1078-0432.CCR-13-0081 pmid: 24097868
[43]	Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae DS, Oaknin A, Ray-Coquard I, Provencher DM, Karlan BY, Lhommé C, Richardson G, Rincón DG, Coleman RL, Herzog TJ, Marth C, Brize A, Fabbro M, Redondo A, Bamias A, Tassoudji M, Navale L, Warner DJ, Oza AM. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol, 2014, 15(8): 799-808. doi: 10.1016/S1470-2045(14)70244-X pmid: 24950985
[44]	Belotti D, Pinessi D, Taraboletti G. Alternative vascularization mechanisms in tumor resistance to therapy. Cancers (Basel), 2021, 13(8): 1912.
[45]	Klemke L, De Oliveira T, Witt D, Winkler N, Bohnenberger H, Bucala R, Conradi LC, Schulz-Heddergott R. Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer. Cell Death Dis, 2021, 12(2): 155. doi: 10.1038/s41419-021-03426-z pmid: 33542244

编辑推荐

Metrics

www.chinagene.cn
备案号：京ICP备09063187号-4
总访问:,今日访问:,当前在线:

肿瘤抗血管生成治疗耐药机制

Drug resistance mechanism of anti-angiogenesis therapy in tumor

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 2

参考文献 45

相关文章 1

编辑推荐

Metrics