Thanasupawat Thatchawan, Mejia Yared Pages, Anandhan Santhosh S, Guo Yaxiong, Tiwana Jasneet, Fernando Adline, Glogowska Aleksandra, Shafai Talia, daSilva Simone, Kaur Nimrat, Begum Farhana, Zahedi Rene, Hombach-Klonisch Sabine, Klonisch Thomas
Department of Human Anatomy and Cell Science, Winnipeg, MB, Canada.
Department of Human Anatomy and Cell Science, Winnipeg, MB, Canada; Department of Pathophysiology, Basic Medical College, Hebei North University, Zhangjiakou, Hebei 075000, China.
Biochem Pharmacol. 2025 Feb;232:116722. doi: 10.1016/j.bcp.2024.116722. Epub 2024 Dec 19.
Glioblastoma (GB) is the most prevalent and aggressive primary brain tumor with fatal outcome due to a lack of effective treatments. We previously identified C1q-tumor necrosis factor-related protein 8 (CTRP8), a new member of the adiponectin family, as a novel agonist of the relaxin family peptide receptor 1 (RXFP1) and showed that the CTRP8-RXFP1 ligand-receptor system facilitates increased invasiveness and chemoresistance in GB cells. In the present study, we have investigated the role of the CTRP8-RXFP1 signaling axis in glioma progression using an orthotopic mouse model xenografted with human U251 glioma cells stably expressing CTRP8 and RXFP1. Our results demonstrate that this in-vivo U251-CTRP8/RXFP1 glioma model promoted the formation of aggressive, highly proliferative glioma that resulted in significantly shorter survival times of xenografted mice. CTRP8/RXFP1 xenografts showed strongly elevated mitotic activity, increased expression of cathepsin B at the migrating front and promoted a pro-inflammatory tumor microenvironment characterized by a strong upregulation of cytokines, among them eotaxin-2 and-3, interleukin (IL)-6, IL-18 and others. Proteomic analysis of xenografted mouse brain identified both human and mouse proteome signatures unique to CTRP8/RXFP1 xenografts compared to U251 xenografts. In conclusion, our results suggest that co-expression of CTRP8 and RXFP1 promotes signaling pathways that generate unique tissue proteomic and inflammatory cytokine signatures which promote glioma aggressiveness. The CTRP-RXFP1 signaling pathway may represent an effective therapeutic target for the treatment of fast-progressing and currently untreatable GB.
胶质母细胞瘤（GB）是最常见且侵袭性最强的原发性脑肿瘤，由于缺乏有效治疗手段，其预后往往是致命的。我们之前鉴定出脂联素家族的新成员C1q肿瘤坏死因子相关蛋白8（CTRP8）是松弛素家族肽受体1（RXFP1）的新型激动剂，并表明CTRP8-RXFP1配体-受体系统促进了GB细胞侵袭性和化疗耐药性的增加。在本研究中，我们使用稳定表达CTRP8和RXFP1的人U251胶质瘤细胞异种移植的原位小鼠模型，研究了CTRP8-RXFP1信号轴在胶质瘤进展中的作用。我们的结果表明，这种体内U251-CTRP8/RXFP1胶质瘤模型促进了侵袭性强、增殖性高的胶质瘤的形成，导致异种移植小鼠的存活时间显著缩短。CTRP8/RXFP1异种移植瘤显示出有丝分裂活性大幅升高，在迁移前沿组织蛋白酶B的表达增加，并促进了以细胞因子强烈上调为特征的促炎性肿瘤微环境，其中包括嗜酸性粒细胞趋化因子-2和-3、白细胞介素（IL）-6、IL-18等。对异种移植小鼠脑的蛋白质组学分析确定了与U251异种移植瘤相比，CTRP8/RXFP1异种移植瘤特有的人和小鼠蛋白质组特征。总之，我们的结果表明，CTRP8和RXFP1的共表达促进了信号通路的产生，这些信号通路产生独特的组织蛋白质组学和炎性细胞因子特征，从而促进胶质瘤的侵袭性。CTRP-RXFP1信号通路可能是治疗快速进展且目前无法治疗的GB的有效治疗靶点。
