综述

血管内皮生长因子抑制剂在胆管细胞癌治疗中的应用进展

  • 张建芳 ,
  • 孙雪琴 ,
  • 崔叶谦 ,
  • 陈洋 ,
  • 王绍波
展开
  • 1.昆明理工大学附属医院/云南省第一人民医院核医学科 (云南 昆明 650500 )
    2.昆明理工大学医学部 ;(云南 昆明 650500 )

收稿日期: 2024-08-26

  网络出版日期: 2024-12-23

基金资助

国家自然科学基金项目(B146-82260355);云南省科技厅科技计划项目(202403AC100018)

Effects of VEGF inhibitors for treating cholangiocarcinoma: A review of literature

  • Jianfang ZHANG ,
  • Xueqin SUN ,
  • Yeqian CUI ,
  • Yang CHEN ,
  • Shaobo. WANG
Expand
  • *.Nuclear Medicine Department,the First People's Hospital of Yunnan Province,the Affiliated Hospital of Kunming University of Science and Technology,Kunming 650500,Yunnan,China
    *.Medical school,Kunmin University of Science and Technology,Kunming 650500,Yunnan,China

Received date: 2024-08-26

  Online published: 2024-12-23

摘要

胆管细胞癌(cholangiocarcinoma, CCA)是一种起源于胆管上皮细胞的恶性肿瘤,侵袭性高、预后较差。手术为首选治疗,但因多数患者确诊晚,手术效果不佳,通常需依赖化疗等综合治疗,然而中位生存期依然很短,迫切需要新策略。血管内皮生长因子(vascular endothelial growth factor, VEGF)作为血管生成的重要因素,常在CCA患者肿瘤细胞中高表达。近年研究表明,VEGF促进血管生成,加剧CCA的侵袭和转移。VEGF抑制剂作为治疗CCA的新兴手段,为实现精准医疗打开了新的窗口。采用VEGF抑制剂靶向治疗联合免疫治疗、化疗等方法可有效延长患者的生存期,为改善患者的生活质量带来了新的希望。本文综述了VEGF在CCA中的表达情况和肿瘤发展中的作用机制,以及VEGF抑制剂在CCA治疗中的应用进展。

本文引用格式

张建芳 , 孙雪琴 , 崔叶谦 , 陈洋 , 王绍波 . 血管内皮生长因子抑制剂在胆管细胞癌治疗中的应用进展[J]. 实用医学杂志, 2024 , 40(24) : 3554 -3560 . DOI: 10.3969/j.issn.1006-5725.2024.24.019

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignant tumor originating from bile duct epithelial cells, characterized by a poor prognosis. Surgery is the primary treatment, but late diagnosis often leads to poor surgical outcomes. Consequently, patients typically rely on comprehensive treatment such as chemotherapy. However, the median survival remains short, highlighting the urgent need for new strategies. Vascular endothelial growth factor (VEGF), a crucial factor in angiogenesis, is frequently overexpressed in tumor cells of CCA patients. Recent studies have shown that VEGF not only promotes angiogenesis but also exacerbates the invasion and metastasis of CCA. Therefore, targeting VEGF-mediated angiogenesis provides a new strategy for treating CCA. VEGF inhibitors represent a new frontier in CCA treatment, offering opportunities for precision therapy. By integrating VEGF inhibitors with immunotherapy and chemotherapy, it is possible to not only effectively prolong the survival of CCA patients but also to offer new hope for improving their quality of life. This review examines the expression of VEGF in CCA, its role in tumorigenesis, and the clinical application of VEGF inhibitors in treating CCA.

参考文献

1 RIZVI S, GORES G J. Pathogenesis, diagnosis, and management of cholangiocarcinoma [J]. Gastroenterology, 2013, 145(6): 1215-1229. doi:10.1053/j.gastro.2013.10.013
2 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. doi:10.3322/caac.21834
3 CLEMENTS O, ELIAHOO J, KIM J U, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis [J]. J Hepatol, 2020, 72(1): 95-103. doi:10.1016/j.jhep.2019.09.007
4 KHAN S A, TAVOLARI S, BRANDI G. Cholangiocarcinoma: Epidemiology and risk factors [J]. Liver International, 2019, 39(S1): 19-31. doi:10.1111/liv.14095
5 S?REIDE K, DOPAZO C, BERREVOET F, et al. Biliary tract cancer [J]. Eur J Surg Oncol, 2024: 108489. doi:10.1016/j.ejso.2024.108489
6 SPOLVERATO G, VITALE A, CUCCHETTI A, et al. Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma? [J]. Cancer, 2015, 121(22): 3998-4006. doi:10.1002/cncr.29619
7 RUZZENENTE A, CONCI S, VALDEGAMBERI A, et al. Role of surgery in the treatment of intrahepatic cholangiocarcinoma [J]. Eur Rev Med Pharmacol Sci, 2015, 19(15): 2892-900.
8 AISHIMA S, ODA Y. Pathogenesis and classification of intrahepatic cholangiocarcinoma: Different characters of perihilar large duct type versus peripheral small duct type [J]. J Hepatobiliary Pancreat Sci, 2015, 22(2): 94-100. doi:10.1002/jhbp.154
9 UENISHI T, YAMAMOTO T, TAKEMURA S, et al. Surgical treatment for intrahepatic cholangiocarcinoma [J]. Clin J Gastroenterol, 2014, 7(2): 87-93. doi:10.1007/s12328-014-0460-z
10 BANALES J M, CARDINALE V, MACIAS R I R, et al. Cholangiocarcinoma: State-of-the-art knowledge and challenges [J]. Liver Int, 2019, 39(): 5-6. doi:10.1111/liv.14101
11 DIERKS J, GASPERSZ M P, BELKOUZ A, et al. Translating the ABC-02 trial into daily practice: Outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin [J]. Acta Oncol, 2018, 57(6): 807-812. doi:10.1080/0284186x.2017.1418532
12 ZHANG Y, YAN H J, WU J. The Tumor Immune Microenvironment plays a Key Role in Driving the Progression of CholangioCarcinoma [J]. Current Cancer Drug Targets, 2024, 24(7): 681-700. doi:10.2174/0115680096267791231115101107
13 李斌, 纪元. 中国抗癌协会胆道恶性肿瘤靶向及免疫治疗指南(2022)(简要版) [J]. 中国实用外科杂志, 2023, 43(5): 481-491.
14 NTANASIS-STATHOPOULOS I, TSILIMIGRAS D I, GAVRIATOPOULOU M, et al. Cholangiocarcinoma: Investigations into pathway-targeted therapies [J]. Expert Rev Anticancer Ther, 2020, 20(9): 765-773. doi:10.1080/14737140.2020.1807333
15 JIANG Z, ZHOU J, LI L, et al. Pericytes in the tumor microenvironment [J]. Cancer Lett, 2023, 556: 216074. doi:10.1016/j.canlet.2023.216074
16 SIVEEN K S, PRABHU K, KRISHNANKUTTY R, et al. Vascular Endothelial Growth Factor (VEGF) Signaling in Tumour Vascularization: Potential and Challenges [J]. Curr Vasc Pharmacol, 2017, 15(4): 339-351. doi:10.2174/1570161115666170105124038
17 SHAW P, DWIVEDI S K D, BHATTACHARYA R, et al. VEGF signaling: Role in angiogenesis and beyond [J]. Biochim Biophys Acta Rev Cancer, 2024, 1879(2): 189079. doi:10.1016/j.bbcan.2024.189079
18 CAI C, WANG X, FU Q, et al. The VEGF expression associated with prognosis in patients with intrahepatic cholangiocarcinoma: A systematic review and meta-analysis [J]. World J Surg Oncol, 2022, 20(1): 40. doi:10.1186/s12957-022-02511-7
19 BOKHARI S M Z, HAMAR P. Vascular Endothelial Growth Factor-D (VEGF-D): An Angiogenesis Bypass in Malignant Tumors [J]. Int J Mol Sci, 2023, 24(17): 13317. doi:10.3390/ijms241713317
20 WHITE A L, BIX G J. VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases [J]. Biomolecules, 2023, 13(4): 702. doi:10.3390/biom13040702
21 LEE C, CHEN R, SUN G, et al. VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway [J]. Signal Transduct Target Ther, 2023, 8(1): 305. doi:10.1038/s41392-023-01539-9
22 CADAMURO M, BRIVIO S, MERTENS J, et al. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma [J]. J Hepatol, 2019, 70(4): 700-709. doi:10.1016/j.jhep.2018.12.004
23 TANG D, NAGANO H, YAMAMOTO H, et al. Angiogenesis in cholangiocellular carcinoma: expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance [J]. Oncol Rep, 2006, 15(3): 525-532.
24 CALASTRI M C J, FERREIRA R F, TENANI G D, et al. Investigating VEGF. miR-145-3p, and miR-101-3p Expression in Patients with Cholangiocarcinoma [J]. Asian Pac J Cancer Prev, 2022, 23(7): 2233-2341. doi:10.31557/apjcp.2022.23.7.2233
25 MAO J, TAN L, TIAN C, et al. Research progress on rodent models and its mechanisms of liver injury [J]. Life Sci, 2024, 337: 122343. doi:10.1016/j.lfs.2023.122343
26 ABHINAND C S, RAJU R, SOUMYA S J, et al. VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis [J]. J Cell Commun Signal, 2016, 10(4): 347-354. doi:10.1007/s12079-016-0352-8
27 RIMINI M, CASADEI-GARDINI A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential [J]. Expert Opin Investig Drugs, 2021, 30(4): 411-418. doi:10.1080/13543784.2021.1881479
28 MARIOTTI V, FIOROTTO R, CADAMURO M, et al. New insights on the role of vascular endothelial growth factor in biliary pathophysiology [J]. JHEP Rep, 2021, 3(3): 100251. doi:10.1016/j.jhepr.2021.100251
29 成芳芳, 陈庆会, 李嫣, 等. VEGF基因多态性与手足口病脑炎易患性关系研究 [J]. 国际儿科学杂志, 2020, 47(10): 746-748.
30 车雅丹, 李丽霞. 小分子抗血管生成药物在晚期乳腺癌中的研究进展 [J]. 实用医学杂志, 2023, 39(22): 2866-2871.
31 PEREZ-GUTIERREZ L, FERRARA N. Biology and therapeutic targeting of vascular endothelial growth factor A [J]. Nat Rev Mol Cell Biol, 2023, 24(11): 816-834. doi:10.1038/s41580-023-00631-w
32 LIU Z L, CHEN H H, ZHENG L L, et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer [J]. Signal Transduct Target Ther, 2023, 8(1): 198. doi:10.1038/s41392-023-01460-1
33 PARMAR D, APTE M. Angiopoietin inhibitors: A review on targeting tumor angiogenesis [J]. Eur J Pharmacol, 2021, 899: 174021. doi:10.1016/j.ejphar.2021.174021
34 APTE R S, CHEN D S, FERRARA N. VEGF in Signaling and Disease: Beyond Discovery and Development [J]. Cell, 2019, 176(6): 1248-1264. doi:10.1016/j.cell.2019.01.021
35 HSU J Y, WAKELEE H A. Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy [J]. BioDrugs, 2009, 23(5): 289-304. doi:10.2165/11317600-000000000-00000
36 MAURIZ J L, GONZALEZ-GALLEGO J. Antiangiogenic drugs: current knowledge and new approaches to cancer therapy [J]. J Pharm Sci, 2008, 97(10): 4129-4154. doi:10.1002/jps.21286
37 GIGANTE E, BOUATTOUR M, BEDOYA J U, et al. Atezolizumab and bevacizumab for non-resectable or metastatic combined hepatocellular-cholangiocarcinoma: A multicentric retrospective study [J]. United European Gastroenterol J, 2024, 12(4): 429-439. doi:10.1002/ueg2.12503
38 GARCIA J, HURWITZ H I, SANDLER A B, et al. Bevacizumab (Avastin(R)) in cancer treatment: A review of 15 years of clinical experience and future outlook [J]. Cancer Treat Rev, 2020, 86: 102017. doi:10.1016/j.ctrv.2020.102017
39 LEE S, SHROFF R T, MAKAWITA S, et al. Phase II Study of Ramucirumab in Advanced Biliary Tract Cancer Previously Treated By Gemcitabine-Based Chemotherapy [J]. Clin Cancer Res, 2022, 28(11): 2229-2236. doi:10.1158/1078-0432.ccr-21-3548
40 WANG Y, CHEN T, LI K, et al. Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer [J]. Front Oncol, 2021, 11: 777617. doi:10.3389/fonc.2021.777617
41 LIU Y, LI Y, WANG Y, et al. Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy [J]. J Hematol Oncol, 2022, 15(1): 89. doi:10.1186/s13045-022-01310-7
42 HSU J Y, WAKELEE H A. Monoclonal antibodies targeting vascular endothelial growth factor: Current status and future challenges in cancer therapy [J]. BioDrugs, 2009, 23(5):289-304. doi:10.2165/11317600-000000000-00000
43 ABDELGALIL A A, ALKAHTANI H M, AL-JENOOBI F I. Sorafenib [J]. Profiles Drug Subst Excip Relat Methodol, 2019, 44: 239-266. doi:10.1016/bs.podrm.2018.11.003
44 GRIMALDI A M, GUIDA T, D'ATTINO R, et al. Sunitinib: bridging present and future cancer treatment [J]. Ann Oncol, 2007, 18 : vi31-4. doi:10.1093/annonc/mdm221
45 HUANG M, HUANG B, LI G, et al. Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell [J]. BMC Gastroenterol, 2018, 18(1): 169. doi:10.1186/s12876-018-0870-3
46 LI H, KUANG X, LIANG L, et al. The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD-L1 [J]. Adv Sci (Weinh), 2021, 8(2): 2001596. doi:10.1002/advs.202001596
47 DREYER C, SABLIN M P, BOUATTOUR M, et al. Disease control with sunitinib in advanced intrahepatic cholangiocarcinoma resistant to gemcitabine-oxaliplatin chemotherapy [J]. World J Hepatol, 2015, 7(6): 910-915. doi:10.4254/wjh.v7.i6.910
48 EL-KHOUEIRY A B, RANKIN C J, BEN-JOSEF E, et al. SWOG 0514: A phase Ⅱ study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma [J]. Invest New Drugs, 2012, 30(4): 1646-1651. doi:10.1007/s10637-011-9719-0
49 SONG F, HU B, CHENG J W, et al. Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma [J]. Cell Death Dis, 2020, 11(7): 573. doi:10.1038/s41419-020-02749-7
50 SHEN G, ZHENG F, REN D, et al. Anlotinib: A novel multi-targeting tyrosine kinase inhibitor in clinical development [J]. J Hematol Oncol, 2018, 11(1): 120. doi:10.1186/s13045-018-0664-7
51 XU J, BAI Y, SUN H, et al. A single-arm, multicenter, open-label phase 2 trial of surufatinib in patients with unresectable or metastatic biliary tract cancer [J]. Cancer, 2021, 127(21): 3975-3984. doi:10.1002/cncr.33803
52 杨婷婷, 李鹏运, 郑志兵. VEGFR小分子抑制剂研究的新进展 [J]. 军事医学, 2021, 45(5): 390-396.
53 ROSSI J J, ROSSI D J. siRNA Drugs: Here to Stay [J]. Mol Ther, 2021, 29(2): 431-432. doi:10.1016/j.ymthe.2021.01.015
54 CORYDON I J, FABIAN-JESSING B K, JAKOBSEN T S, et al. 25 years of maturation: A systematic review of RNAi in the clinic [J]. Mol Ther Nucleic Acids, 2023, 33: 469-482. doi:10.1016/j.omtn.2023.07.018
55 ZHANG C, ZHAO Y, ZHANG E, et al. Co-delivery of paclitaxel and anti-VEGF siRNA by tripeptide lipid nanoparticle to enhance the anti-tumor activity for lung cancer therapy [J]. Drug Deliv, 2020, 27(1): 1397-1411. doi:10.1080/10717544.2020.1827085
56 LIU Y C, MA W H, GE Y L, et al. RNAi-mediated gene silencing of vascular endothelial growth factor C suppresses growth and induces apoptosis in mouse breast cancer in vitro and in vivo [J]. Oncol Lett, 2016, 12(5): 3896-3904. doi:10.3892/ol.2016.5158
57 KALATHINGAL M, RHEE Y M. Molecular mechanism of binding between a therapeutic RNA aptamer and its protein target VEGF: A molecular dynamics study [J]. J Comput Chem, 2023, 44(11): 1129-1137. doi:10.1002/jcc.27070
58 HOBEL S, KOBURGER I, JOHN M, et al. Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab [J]. J Gene Med, 2010, 12(3): 287-300. doi:10.1002/jgm.1431
59 LU S, LI J. Treatment of cholangiocarcinoma by pGCsiRNA-vascular endothelial growth factor in vivo [J]. Asian Biomed (Res Rev News), 2024, 18(2): 61-68. doi:10.2478/abm-2024-0009
60 WANG Y, WEI Y, CHEN L, et al. Research progress of siVEGF complex and their application in antiangiogenic therapy [J]. Int J Pharm, 2023, 643: 123251. doi:10.1016/j.ijpharm.2023.123251
61 LEONG A, KIM M. The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer [J]. Int J Mol Sci, 2020, 21(22):8689. doi:10.3390/ijms21228689
62 吴克林, 吴天英, 许海. 卡瑞利珠单抗联合化疗对老年非小细胞肺癌患者血清细胞角蛋白19片段抗原21-1、基质金属蛋白酶9表达及肿瘤生长转移的影响 [J]. 实用医学杂志, 2020, 36(20): 2830-2833.
63 MA Z, LI H, LIU L. Combining PD-1 Inhibitor with VEGF/VEGFR2 Inhibitor in Chemotherapy: Report of a Patient with End-Stage Cholangiocarcinoma and Review of Literature [J]. Recent Pat Anticancer Drug Discov, 2021, 16(1): 101-107. doi:10.2174/1574892815999201231215311
64 ZHOU M, JIN Y, ZHU S, et al. A phase II study to evaluate the safety and efficacy of anlotinib combined with toripalimab for advanced biliary tract cancer [J]. Clin Trans Immunol, 2024, 13(1):e1483. doi:10.1002/cti2.1483
65 SHI G M, HUANG X Y, WU D, et al. Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: A single-center, single-arm, phase 2 study [J]. Signal Transduct Target Ther, 2023, 8(1): 106. doi:10.1038/s41392-023-01317-7
66 DONG Z, SUI C, LU J, et al. Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative option for advanced unresectable intrahepatic cholangiocarcinoma: A retrospective real-world study [J]. Front Immunol, 2024, 15: 1463574. doi:10.3389/fimmu.2024.1463574
67 LIU J, CAO J, WANG G, et al. Abstract 944: Analysis of efficacy of receptor tyrosine kinase and immune checkpoint inhibitors and insights to potential combinatorial treatment strategies in cholangiocarcinomas [J]. Cancer Res, 2021, 81(): 944. doi:10.1158/1538-7445.am2021-944
68 LUO J, ZHENG J, YAO H, et al. Radioactive (125)I Seed Inhibits Cell Migration and Invasion and Promotes Apoptosis by Inactivating the VEGFR2 Signaling Pathway in Cholangiocarcinoma [J]. Dose Response, 2023, 21(3): 15593258231187348. doi:10.1177/15593258231187348
69 VALLE J W, VOGEL A, DENLINGER C S, et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: A randomised, double-blind, multicentre, phase 2 study [J]. Lancet Oncol, 2021, 22(10): 1468-1482. doi:10.1016/s1470-2045(21)00409-5
70 ARKENAU H T, MARTIN-LIBERAL J, CALVO E, et al. Ramucirumab Plus Pembrolizumab in Patients with Previously Treated Advanced or Metastatic Biliary Tract Cancer: Nonrandomized, Open-Label, Phase I Trial (JVDF) [J]. Oncologist, 2018, 23(12): 1407-e136. doi:10.1634/theoncologist.2018-0044
文章导航

/