Research Progress on Delta-Like Ligand 4 in Gynecological Malignancies

doi:10.12280/gjfckx.20250776

Abstract

Abstract:

Cervical cancer, ovarian cancer and endometrial cancer are important causes of female mortality. Although standardized treatment can improve the condition of some patients, a considerable proportion of patients still have a poor prognosis and continuous disease progression. Early diagnosis and treatment are key strategies to improve the prognosis of patients with gynecological malignancies and reduce the disease burden. Therefore, exploring more effective therapeutic targets is of great significance. Delta-like ligand 4 (DLL4), as a key ligand of the Notch signaling pathway, plays an important role in tumor angiogenesis, tumor stem cell maintenance, and immune environment regulation. In recent years, studies have found that DLL4 is significantly highly expressed in various gynecological malignancies such as ovarian cancer, cervical cancer and endometrial cancer, and its expression level is closely related to tumor stage, metastasis and poor prognosis, showing the potential as a novel targeted therapeutic target. This article systematically elaborates on the biological functions of DLL4 and reviews the research progress on the correlation between DLL4 and the three major gynecological malignancies, aiming to provide new ideas for the precise treatment of gynecological malignancies.

Key words: Receptors, Notch, Genital neoplasms, female, Angiogenesis inhibitors, Antineoplastic combined chemotherapy protocols, Delta-like ligand 4

BAI Yao-jun, WANG Si-yao, LI Hong-li, LIU Chang. Research Progress on Delta-Like Ligand 4 in Gynecological Malignancies[J]. Journal of International Obstetrics and Gynecology, 2025, 52(6): 680-684.

References 30

[1]	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.
[2]	Polajžer S, Černe K. Precision Medicine in High-Grade Serous Ovarian Cancer: Targeted Therapies and the Challenge of Chemoresistance[J]. Int J Mol Sci, 2025, 26(6):2545. doi: 10.3390/ijms26062545.
[3]	Jin F, Guan P, Huang L, et al. DLL4/VEGF bispecific molecularly imprinted nanomissile for robust tumor therapy[J]. Biomaterials, 2025, 322:123412. doi: 10.1016/j.biomaterials.2025.123412.
[4]	Shi Z, Kuai M, Li B, et al. The role of VEGF in Cancer angiogenesis and tumorigenesis: Insights for anti-VEGF therapy[J]. Cytokine, 2025, 189:156908. doi: 10.1016/j.cyto.2025.156908.
[5]	宗如月, 罗新鹏, 路小超, 等. 血管生成在恶性肿瘤中作用及靶向治疗策略的研究进展[J]. 生命科学, 2022, 34(6):644-652. doi: 10.13376/j.cbls/2022074.
[6]	Afzalipour R, Abbasi-Dokht T, Sheikh M, et al. The Prediction of DLL4 as a Prognostic Biomarker in Patients with Gastric Cancer Using Anti-DLL4 Nanobody[J]. J Gastrointest Cancer, 2024, 55(3):1380-1387. doi: 10.1007/s12029-024-01093-9. pmid: 39046662
[7]	Sargis T, Youn SW, Thakkar K, et al. Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties[J]. Angiogenesis, 2023, 26(2):249-263. doi: 10.1007/s10456-022-09861-6.
[8]	甄千玮, 张友忠. 妇科肿瘤相关双特异性抗体药物[J]. 肿瘤药学, 2022, 12(4):433-440. doi: 10.3969/j.issn.2095-1264.2022.04.04.
[9]	Fasoulakis Z, Koutras A, Ntounis T, et al. The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development[J]. Cancers(Basel), 2022, 14(7):1649. doi: 10.3390/cancers14071649.
[10]	Chen D, Liu X, Wang H, et al. A model of Notch signalling control of angiogenesis: Evidence of a role for Notch ligand heterodimerization[J]. PLoS Comput Biol, 2025, 21(2):e1012825. doi: 10.1371/journal.pcbi.1012825.
[11]	Hu W, Lu C, Dong HH, et al. Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer[J]. Cancer Res, 2011, 71(18):6030-6039. doi: 10.1158/0008-5472.CAN-10-2719. pmid: 21795478
[12]	Khelil M, Griffin H, Bleeker M, et al. Delta-Like Ligand-Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis[J]. Cancer Res, 2021, 81(7):1909-1921. doi: 10.1158/0008-5472.CAN-20-1996.
[13]	Bocchicchio S, Tesone M, Irusta G. Convergence of Wnt and Notch signaling controls ovarian cancer cell survival[J]. J Cell Physiol, 2019, 234(12):22130-22143. doi: 10.1002/jcp.28775. pmid: 31087357
[14]	Chen B, Jiang K, Wang H, et al. NOTCH Pathway Genes in Ovarian Cancer: Clinical Significance and Associations with Immune Cell Infiltration[J]. Front Biosci(Landmark Ed), 2023, 28(9):220. doi: 10.31083/j.fbl2809220.
[15]	Deng Z, Zhang L, Sun C, et al. Identification of molecular subtypes, prognostic status and immunotherapy response in cervical cancer based on angiogenic signature genes[J]. Heliyon, 2024, 10(19):e38488. doi: 10.1016/j.heliyon.2024.e38488.
[16]	Yang S, Liu Y, Xia B, et al. DLL4 as a predictor of pelvic lymph node metastasis and a novel prognostic biomarker in patients with early-stage cervical cancer[J]. Tumour Biol, 2016, 37(4):5063-5074. doi: 10.1007/s13277-015-4312-3.
[17]	孙娜. LTD1、DLL4与VEGF在肺腺癌、肝细胞肝癌、宫颈癌的表达及临床意义研究[D]. 兰州: 兰州大学, 2018.
[18]	Wang L, Wang C, He Y, et al. Identification of a prognostic model based on immune and hypoxia-related gene expressions in cervical cancer[J]. J Obstet Gynaecol, 2023, 43(2):2277242. doi: 10.1080/01443615.2023.2277242.
[19]	Lin Y, Zhang R, Pan H, et al. A Novel Immune-Related Signature to Predict Prognosis and Immune Infiltration of Cervical Cancer[J]. Med Sci Monit, 2023, 29:e938660. doi: 10.12659/MSM.938660.
[20]	Fasoulakis Z, Galazios G, Koukourakis M, et al. Expression of Delta Like Ligand 4 (DLL4) in endometrial carcinomas and tumor vasculature[J]. J BUON, 2021, 26(4):1327-1332. pmid: 34564988
[21]	Mitsuhashi Y, Horiuchi A, Miyamoto T, et al. Prognostic significance of Notch signalling molecules and their involvement in the invasiveness of endometrial carcinoma cells[J]. Histopathology, 2012, 60(5):826-837. doi: 10.1111/j.1365-2559.2011.04158.x. pmid: 22348356
[22]	Huang J, Hu W, Hu L, et al. Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth[J]. Mol Cancer Ther, 2016, 15(6):1344-1352. doi: 10.1158/1535-7163.MCT-15-0144. pmid: 27009216
[23]	Li R, Liu X, Huang X, et al. Single-cell transcriptomic analysis deciphers heterogenous cancer stem-like cells in colorectal cancer and their organ-specific metastasis[J]. Gut, 2024, 73(3):470-484. doi: 10.1136/gutjnl-2023-330243.
[24]	Ren JS, Bai W, Ding JJ, et al. Hypoxia-induced AFAP1L1 regulates pathological neovascularization via the YAP-DLL4-NOTCH axis[J]. J Transl Med, 2023, 21(1):651. doi: 10.1186/s12967-023-04503-x.
[25]	Kuhnert F, Chen G, Coetzee S, et al. Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer[J]. Cancer Res, 2015, 75(19):4086-4096. doi: 10.1158/0008-5472.CAN-14-3773. pmid: 26377940
[26]	孔艺燕, 应小燕. 复发性卵巢癌治疗的应用进展[J]. 中国妇产科临床杂志, 2023, 24(5):550-552. doi: 10.13390/j.issn.1672-1861.2023.05.040.
[27]	田东立, 李芳梅, 芦恩婷, 等. 铂耐药复发性卵巢癌诊治中国专家共识(2025年版)[J]. 肿瘤学杂志, 2025, 31(2):83-93. doi: 10.11735/j.issn.1671-170X.2025.02.B001.
[28]	Jimeno A, Moore KN, Gordon M, et al. A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors[J]. Invest New Drugs, 2019, 37(3):461-472. doi: 10.1007/s10637-018-0665-y.
[29]	Coleman RL, Handley KF, Burger R, et al. Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial[J]. Gynecol Oncol, 2020, 157(2):386-391. doi: 10.1016/j.ygyno.2020.01.042. pmid: 32037195
[30]	Chiorean EG, LoRusso P, Strother RM, et al. A Phase Ⅰ First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors[J]. Clin Cancer Res, 2015, 21(12):2695-2703. doi: 10.1158/1078-0432.CCR-14-2797.