非生殖性肿瘤进展通过CXCL10-IL18R1轴损害卵巢功能
Non-reproductive tumor progression impairs ovarian function through CXCL10-IL18R1 axis.
摘要(中文译文)
卵巢易受有害环境因素的影响。肿瘤进展（TP）是一种体内有害环境因素。已知TP可通过促炎细胞因子损伤邻近组织。然而，非生殖系统肿瘤进展（NRTP）是否以及如何损害卵巢功能尚不清楚。本研究以MCA205（小鼠纤维肉瘤）细胞同种异体移植的B6小鼠作为基础模型（M组）；同时，我们建立了两种常用的治疗模型——同种异体移植小鼠注射PD-1单克隆抗体（PD-1组）和同种异体移植小鼠注射全肿瘤细胞疫苗（WCV）（WCV组）——以促进发现过程。正如预期，M组的TP多方面降低卵巢功能。有趣的是，WCV注射显著逆转了这些异常，而PD-1则没有。接下来，血浆细胞因子微阵列鉴定出CXCL10在M组中增量最大，且在WCV组中挽救效果最佳。随后，我们在卵巢内捕获了唯一的CXCL10受体IL18R1。接着，我们发现CXCL10直接结合IL18R1，通过三条途径损害卵巢功能：通过p-JNK→p-JUN→COL1A1诱导卵巢纤维化，通过p-AKT→p-FOXO3A促进原始卵泡过度激活，以及通过p-P65→IFNγ增加卵巢炎症。我们还在MC38（小鼠结肠癌细胞）同种异体移植和B16F10（小鼠黑色素瘤细胞）同种异体移植的B6小鼠中初步验证了CXCL10-IL18R1轴及上述三条下游途径。最后，我们通过使用CXCL10抗体或CXCL10-IL18R1界面肽CIBB阻断CXCL10→IL18R1途径，挽救了M组中降低的卵巢功能。本研究提供了NRTP如何损害卵巢功能以及如何在NRTP下靶向保护卵巢的机制证据和转化策略。
Abstract
The ovary is susceptible to harmful environmental factors. Tumor progression (TP) is an intracorporal harmful environmental factor. It is known that TP could impair adjacent tissues through pro-inflammatory cytokines. However, it is unclear whether and how non-reproductive tumor progression (NRTP) impairs ovarian function. In this study, we used MCA205 (mouse fibrosarcoma) cell-allotransplanted B6 mice as a basic model (M group); meanwhile, we established two popular therapeutic models - PD-1 monoclonal antibody injection in allotransplanted mice (PD-1 group) and whole cancer cell vaccine (WCV) injection in allotransplanted mice (WCV group) - to facilitate the discovery process. As expected, TP in M group decreased ovarian function multifacetedly. Interestingly, WCV injection significantly reversed these abnormalities, whereas PD-1 did not. Next, plasma cytokine microarray characterized CXCL10 with both the biggest increment in M group and best rescue in WCV group. Next, we baited the only CXCL10 receptor, IL18R1, within ovaries. Next, we found that CXCL10 directly bound to IL18R1 to impair ovarian function through three pathways: inducing ovarian fibrosis through p-JNK→p-JUN → COL1A1, promoting primordial follicle overactivation through p-AKT→p-FOXO3A, and increasing ovarian inflammation through p-P65 → IFNγ. We have also preliminarily verified the CXCL10-IL18R1 axis and the upper three downstream pathways in MC38 (mouse colon cancer cells)-allotransplanted and B16F10 (mouse melanoma cells)-allotransplanted B6 mice. Finally, we rescued the decreased ovarian function in the M group by blocking the CXCL10 → IL18R1 pathway with CXCL10 antibody or a CXCL10-IL18R1 interface peptide, CIBB. This study provides mechanical evidence and translational strategies of how NRTP impairs ovarian functions and how to target-protect ovaries under NRTP.
如何引用
AMA
Shi-Ya Xie, Shu-Ping Zhang, Cong-Rong Li, Yan Liu, Xian-Zhe Gu, Yan-Jie Yang, et al. Non-reproductive tumor progression impairs ovarian function through CXCL10-IL18R1 axis.. Experimental & molecular medicine. 2026; doi:10.1038/s12276-026-01790-4.
APA
Shi-Ya Xie, Shu-Ping Zhang, Cong-Rong Li, Yan Liu, Xian-Zhe Gu, Yan-Jie Yang, et al (2026). Non-reproductive tumor progression impairs ovarian function through CXCL10-IL18R1 axis.. Experimental & molecular medicine. https://doi.org/10.1038/s12276-026-01790-4
GB/T 7714
Shi-Ya Xie, Shu-Ping Zhang, Cong-Rong Li, Yan Liu, Xian-Zhe Gu, Yan-Jie Yang, et al. Non-reproductive tumor progression impairs ovarian function through CXCL10-IL18R1 axis.[J]. Experimental & molecular medicine, 2026 doi:10.1038/s12276-026-01790-4.
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