动物模型在Eph家族蛋白功能研究中的应用

doi:10.12300/j.issn.1674-5817.2022.010

实验动物与比较医学 ›› 2022, Vol. 42 ›› Issue (4): 351-357.DOI: 10.12300/j.issn.1674-5817.2022.010

动物模型在Eph家族蛋白功能研究中的应用

胡耀华¹^,²(), 赵菊梅¹()(), 师长宏²()()

^1.延安大学医学院, 延安 716000
^2.空军军医大学实验动物中心, 西安 710032

收稿日期:2022-01-25 修回日期:2022-04-01 出版日期:2022-08-25 发布日期:2022-08-25
通讯作者: 师长宏（1973—），男，博士研究生导师，教授，研究方向：肿瘤模型的制备与评价。E-mail：changhong@fmmu.edu.cn。ORCID： 0000-0001-7490-3593
赵菊梅(1970—）1970—），女，硕士研究生导师，教授，研究方向：肿瘤分子病理与药物。E-mail：jmz2003.stu@163.com。ORCID：0000-0002-7813-8224
作者简介:胡耀华（1997—），女，硕士研究生，研究方向：肿瘤分子病理与药物研究。E-mail：457495004@qq.com
基金资助:
国家自然科学基金资助项目“基于临床肿瘤标本的胃癌个体化转移模型的建立及评估”(31772546)

Application of Animal Models in the Functional Studies of Eph Family Proteins

Yaohua HU¹^,²(), Jumei ZHAO¹()(), Changhong SHI²()()

^1.Medical College of Yan 'an University, Yan'an 716000, China
^2.Laboratory Animal Center, the Air Force Medical University, Xi'an 710032, China

Received:2022-01-25 Revised:2022-04-01 Published:2022-08-25 Online:2022-08-25
Correspondence to: SHI Changhong (ORCID: 0000-0001-7490-3593), E-mail: changhong@fmmu.edu.cn
ZHAO Jumei(ORCID: 0000-0002-7813-8224), E-mail: jmz2003.stu@163.com

摘要/Abstract

摘要：

促红细胞生成素产生肝细胞激酶（erythropoietin-producing hepatocyte kinase，Eph）作为家族成员最多的受体酪氨酸激酶，与恶性肿瘤的发生、发展密切相关，具有广泛的临床应用价值。动物模型在探索Eph家族分子的生物学功能、分子机制以及筛选治疗靶点等方面发挥了重要作用。本文总结归纳了异种移植瘤模型、肿瘤免疫治疗模型以及基因修饰模型在Eph家族功能研究中的应用及最新研究进展，总结了各类模型的优缺点，以期为研究者开展Eph相关研究时选择合适的动物模型提供参考。

关键词: 促红细胞生成素产生肝细胞激酶, 动物模型, 应用, 优缺点

Abstract:

As a receptor tyrosine kinase with the most family members, erythropoietin-producing hepatocyte kinase (Eph) is closely related to the occurrence and development of malignant tumors and displays a wide range of clinical application value. Animal models have played an important role in exploring the biological functions, molecular mechanisms and screening therapeutic targets of Eph family molecules. In this paper, we reviewed the application and latest research progress of xenotransplantation model, immune-related model, and gene modification model in the study of Eph family's functional research, and summarized the advantages and disadvantages of various models, in order to provide a reference for researchers to select appropriate animal models for Eph related research.

Key words: Erythropoietin-producing hepatocyte kinase, Animal models, Application, Advantages and disadvantages

中图分类号:

R-332

胡耀华,赵菊梅,师长宏. 动物模型在Eph家族蛋白功能研究中的应用[J]. 实验动物与比较医学, 2022, 42(4): 351-357. DOI: 10.12300/j.issn.1674-5817.2022.010.

Yaohua HU,Jumei ZHAO,Changhong SHI. Application of Animal Models in the Functional Studies of Eph Family Proteins[J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 351-357. DOI: 10.12300/j.issn.1674-5817.2022.010.

参考文献 49

1	RUDNO-RUDZIŃSKA J, KIELAN W, FREJLICH E, et al. A review on Eph/ephrin, angiogenesis and lymphangiogenesis in gastric, colorectal and pancreatic cancers[J]. Chin J Cancer Res, 2017, 29(4):303-312. DOI:10.21147/j.issn.1000-9604.2017.04.03 .
2	O'LEARY D D, WILKINSON D G. Eph receptors and ephrins in neural development[J]. Curr Opin Neurobiol, 1999, 9(1):65-73. DOI:10.1016/s0959-4388(99)80008-7 .
3	ORICCHIO E, NANJANGUD G, WOLFE A L, et al. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma[J]. Cell, 2011, 147(3):554-564. DOI:10.1016/j.cell.2011.09.035 .
4	KUNG A L. Practices and pitfalls of mouse cancer models in drug discovery[J]. Adv Cancer Res, 2006, 96:191-212. DOI:10.1016/S0065-230X(06)96007-2 .
5	STERNER R M, SAKEMURA R, COX M J, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts[J]. Blood, 2019, 133(7):697-709. DOI:10.1182/blood-2018-10-881722 .
6	KOPETZ S, LEMOS R, POWIS G. The promise of patient-derived xenografts: the best laid plans of mice and men[J]. Clin Cancer Res, 2012, 18(19):5160-5162. DOI:10.1158/1078-0432.CCR-12-2408 .
7	LIN J H, ZENG C T, ZHANG J K, et al. EFNA4 promotes cell proliferation and tumor metastasis in hepatocellular carcinoma through a PIK3R2/GSK3β/β-catenin positive feedback loop[J]. Mol Ther Nucleic Acids, 2021, 25:328-341. DOI:10.1016/j.omtn.2021.06.002 .
8	DOPESO H, MATEO-LOZANO S, MAZZOLINI R, et al. The receptor tyrosine kinase EPHB₄ has tumor suppressor activities in intestinal tumorigenesis[J]. Cancer Res, 2009, 69(18):7430-7438. DOI:10.1158/0008-5472.CAN-09-0706 .
9	ASTIN J W, BATSON J, KADIR S, et al. Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells[J]. Nat Cell Biol, 2010, 12(12):1194-1204. DOI:10.1038/ncb2122 .
10	MIAO H, LI D Q, MUKHERJEE A, et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt[J]. Cancer Cell, 2009, 16(1):9-20. DOI:10.1016/j.ccr.2009.04.009 .
11	QAZI M A, VORA P, VENUGOPAL C, et al. Cotargeting ephrin receptor tyrosine kinases A2 and A3 in cancer stem cells reduces growth of recurrent glioblastoma[J]. Cancer Res, 2018, 78(17):5023-5037. DOI:10.1158/0008-5472.CAN-18-0267 .
12	王洁. 基于肿瘤标本异种移植模型的胃癌转移相关基因研究[D]. 延安: 延安大学, 2020. DOI:10.27438/d.cnki.gyadu.2020.000548 .
	WANG J. Research of metastasis-related genes derived from gastric cancer patient-derived xenograft models[D].Yan'an :Yan'an University, 2020. DOI:10.27438/d.cnki.gyadu.2020.000548 .
13	LV J H, XIA Q Y, WANG J J, et al. EphB4 promotes the proliferation, invasion, and angiogenesis of human colorectal cancer[J].Exp Mol Pathol, 2016, 100(3):402-408. DOI:10.1016/j.yexmp.2016.03.011 .
14	SATO S, VASAIKAR S, ESKAROS A, et al. EPHB₂ carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling[J]. JCI Insight, 2019, 4(23): e132447. DOI:10.1172/jci.insight.132447 .
15	LI S, MA Y, XIE C, et al. EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression[J]. Oncotarget, 2015, 6(26): 22587-97. DOI:10.18632/oncotarget.4088 .
16	NEUBER C, BELTER B, MEISTER S, et al. Overexpression of receptor tyrosine kinase EphB4 triggers tumor growth and hypoxia in A375 melanoma xenografts: Insights from multitracer small animal imaging experiments[J]. Molecules, 2018, 23(2). DOI:10.3390/molecules23020444 .
17	FESTUCCIA C, GRAVINA G L, GIORGIO C, et al. UniPR1331, a small molecule targeting Eph/ephrin interaction, prolongs survival in glioblastoma and potentiates the effect of antiangiogenic therapy in mice[J]. Oncotarget, 2018, 9(36):24347-24363. DOI:10.18632/oncotarget.25272 .
18	MIAO B C, JI Z Y, TAN L, et al. EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma[J]. Cancer Discov, 2015, 5(3):274-287. DOI:10.1158/2159-8290.CD-14-0295 .
19	YANG X K, YANG Y D, TANG S Q, et al. EphB4 inhibitor overcome the acquired resistance to cisplatin in melanomas xenograft model[J]. J Pharmacol Sci, 2015, 129(1):65-71. DOI:10.1016/j.jphs.2015.08.009 .
20	LEUNG H W, LEUNG C O N, LAU E Y, et al. EPHB₂ activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma[J]. Cancer Res, 2021, 81(12):3229-3240. DOI:10.1158/0008-5472.can-21-0184 .
21	TOOSI B M, ZAWILY A EL, TRUITT L, et al. EPHB₆ augments both development and drug sensitivity of triple-negative breast cancer tumours[J]. Oncogene, 2018, 37(30):4073-4093. DOI:10.1038/s41388-018-0228-x .
22	ZHANG J L, DU Z Q, PAN S, et al. Overcoming multidrug resistance by codelivery of MDR1-targeting siRNA and doxorubicin using EphA10-mediated pH-sensitive lipoplexes: in vitro and in vivo evaluation[J]. ACS Appl Mater Interfaces, 2018, 10(25):21590-21600. DOI:10.1021/acsami.8b01806 .
23	ZHANG J L, YANG C R, PAN S, et al. Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine-docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo [J]. Drug Deliv, 2018, 25(1):723-737. DOI:10.1080/10717544.2018.1446475 .
24	MORILLON Y M 2nd, SABZEVARI A, SCHLOM J, et al. The development of next-generation PBMC humanized mice for preclinical investigation of cancer immunotherapeutic agents[J]. Anticancer Res, 2020, 40(10):5329-5341. DOI:10.21873/anticanres.14540 .
25	ZUMWALDE N A, GUMPERZ J E. Modeling human antitumor responses in vivo using umbilical cord blood-engrafted mice[J]. Front Immunol, 2018, 9:54. DOI:10.3389/fimmu.2018.00054 .
26	SANMAMED M F, RODRIGUEZ I, SCHALPER K A, et al. Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice[J]. Cancer Res, 2015, 75(17):3466-3478. DOI:10.1158/0008-5472.CAN-14-3510 .
27	PREVOST N, WOULFE D, TANAKA T, et al. Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred[J]. Proc Natl Acad Sci USA, 2002, 99(14):9219-9224. DOI:10.1073/pnas.142053899 .
28	BERROU E, SOUKASEUM C, FAVIER R, et al. A mutation of the human EPHB2 gene leads to a major platelet functional defect[J]. Blood, 2018, 132(19):2067-2077. DOI:10.1182/blood-2018-04-845644 .
29	BRAUN J, HOFFMANN S C, FELDNER A, et al. Endothelial cell ephrinB2-dependent activation of monocytes in arteriosclerosis[J]. Arterioscler Thromb Vasc Biol, 2011, 31(2):297-305. DOI:10.1161/ATVBAHA.110.217646 .
30	ZHOU Q, FACCIPONTE J, JIN M, et al. Humanized NOD-SCID IL2rg^–/– mice as a preclinical model for cancer research and its potential use for individualized cancer therapies[J]. Cancer Lett, 2014, 344(1):13-19. DOI: 10.1016/j.canlet. 2013.10.015 .
31	ZHANG L, MEISSNER E, CHEN J, et al. Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis[J]. Sci China Life Sci, 2010, 53(2): 195-203.
32	CHIARI R, HAMES G, STROOBANT V, et al. Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class Ⅱ molecules[J]. Cancer Res, 2000, 60(17):4855-4863.
33	TATSUMI T, HERREM C J, OLSON W C, et al. Disease stage variation in CD4⁺ and CD8⁺ T-cell reactivity to the receptor tyrosine kinase EphA2 in patients with renal cell carcinoma[J]. Cancer Res, 2003, 63(15):4481-4489.
34	ALVES P M S, FAURE O, GRAFF-DUBOIS S, et al. EphA2 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes[J]. Cancer Res, 2003, 63(23):8476-8480.
35	HART D N. Dendritic cells: unique leukocyte populations which control the primary immune response[J]. Blood, 1997, 90(9):3245-3287.
36	YAMAGUCHI S, TATSUMI T, TAKEHARA T, et al. Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell vaccines[J]. Cancer, 2007, 110(7):1469-1477. DOI:10.1002/cncr.22958 .
37	YAMAGUCHI S, TATSUMI T, TAKEHARA T, et al. Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity[J]. Cancer Immunol Immunother, 2008, 57(12):1861-1869. DOI:10.1007/s00262-008-0514-5 .
38	DOTTI G, GOTTSCHALK S, SAVOLDO B, et al. Design and development of therapies using chimeric antigen receptor-expressing T cells[J]. Immunol Rev, 2014, 257(1):107-126. DOI:10.1111/imr.12131 .
39	CHOW K K H, NAIK S, KAKARLA S, et al. T cells redirected to EphA2 for the immunotherapy of glioblastoma[J]. Mol Ther, 2013, 21(3):629-637. DOI:10.1038/mt.2012.210 .
40	LI N, LIU S H, SUN M J, et al. Chimeric antigen receptor-modified T cells redirected to EphA2 for the immunotherapy of non-small cell lung cancer[J]. Transl Oncol, 2018, 11(1):11-17. DOI:10.1016/j.tranon.2017.10.009 .
41	SHI H, YU F, MAO Y T, et al. EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma[J]. J Thorac Dis, 2018, 10(5):2779-2788. DOI:10.21037/jtd.2018.04.91 .
42	WANG E N, CESANO A, BUTTERFIELD L H, et al. Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy[J]. J Immunother Cancer, 2020, 8(2): e001619. DOI:10.1136/jitc-2020-001619 .
43	AN Z J, HU Y, BAI Y, et al. Antitumor activity of the third generation EphA2 CAR-T cells against glioblastoma is associated with interferon gamma induced PD-L1[J]. Oncoimmunology, 2021, 10(1):1960728. DOI:10.1080/2162402X. 2021.1960728 .
44	KAMOUN W S, DUGAST A S, SUCHY J J, et al. Synergy between EphA2-ILs-DTXp, a novel EphA2-targeted nanoliposomal taxane, and PD-1 inhibitors in preclinical tumor models[J]. Mol Cancer Ther, 2020, 19(1):270-281. DOI:10.1158/1535-7163.MCT-19-0414 .
45	YANG W H, CHA J H, XIA W Y, et al. Juxtacrine signaling inhibits antitumor immunity by upregulating PD-L1 expression[J]. Cancer Res, 2018, 78(14):3761-3768. DOI:10.1158/0008-5472.CAN-18-0040 .
46	FAWAL M A, JUNGAS T, DAVY A. Inhibition of DHFR targets the self-renewing potential of brain tumor initiating cells[J]. Cancer Lett, 2021, 503:129-137. DOI:10.1016/j.canlet.2021.01.026 .
47	MATEO-LOZANO S, BAZZOCCO S, RODRIGUES P, et al. Loss of the EPH receptor B6 contributes to colorectal cancer metastasis[J]. Sci Rep, 2017, 7:43702. DOI:10.1038/srep43702 .
48	BHATIA S, HIRSCH K, BAIG N A, et al. Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model[J]. J Hematol Oncol, 2015, 8:105. DOI:10.1186/s13045-015-0202-9 .
49	MOHD-ZIN S W, ABDULLAH N L, ABDULLAH A, et al. Identification of the genomic mutation in Epha4(rb-2J/rb-2J) mice[J]. Genome, 2016, 59(7):439-448. DOI:10.1139/gen-2015-0142 .

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动物模型在Eph家族蛋白功能研究中的应用

Application of Animal Models in the Functional Studies of Eph Family Proteins

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