目的:C-X-C基序趋化因子受体4(CXCR4)及其配体的复合物,C-X-C基序趋化因子配体12(CXCL12),在癌细胞增殖中起着至关重要的作用,入侵,和转移。这些是新兴的治疗靶点,最近有研究报道抑制CXCL12-CXCR4信号通路可增强免疫检查点抑制剂的作用。因此,我们旨在研究高级别浆液性卵巢癌(HGSOC)中CXCL12和CXCR4的组织表达,并确定其作为预后标志物的潜力.
方法:我们使用初治化疗,从原发性细胞减灭术时晚期HGSOC患者获得的福尔马林固定石蜡包埋的原发性卵巢癌组织。组织学重新评估后,我们构建了组织微阵列,并对CXCL12和CXCR4进行了免疫组织化学染色.此后,比较了高表达组和低表达组的临床病理特征和生存结局.
结果:共包括97例FIGOIIIC-IV期HGSOC患者:15例(15.5%),66(68.0%),13例(13.4%)患者显示CXCL12、CXCR4高表达,分别。各蛋白的表达水平与种系BRCA1/2突变状态无关,FIGO阶段,或原发性细胞减灭术后残留的肿瘤。在校正了混杂因素的多变量分析中,高CXCL12表达被确定为无进展生存期的独立不良预后生物标志物(调整后的风险比,1.990;95%置信区间=1.090-3.633;p=0.025)。然而,CXCR4表达与患者生存结果无关。
结论:CXCL12表达水平可能代表HGSOC的预后生物标志物。与CXCL12/CXCR4复合物相关的蛋白质可作为HGSOC治疗中的治疗靶标。
OBJECTIVE: The complex of C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), plays an essential role in cancer cell proliferation, invasion, and metastasis. These are emerging therapeutic targets, and recent studies have reported that inhibition of CXCL12-CXCR4 signaling pathway enhances the effects of immune checkpoint inhibitors. Thus, we aimed to investigate tissue expression of CXCL12 and CXCR4 in high-grade serous ovarian carcinoma (HGSOC) and to determine their potential as prognostic markers.
METHODS: We used chemotherapy-naïve, formalin-fixed paraffin-embedded primary ovarian cancer tissues obtained from patients with advanced-stage HGSOC at the time of primary cytoreductive surgery. After histological reassessment, we constructed a tissue microarray and performed immunohistochemical staining for CXCL12 and CXCR4. Thereafter, clinicopathological characteristics and survival outcomes were compared between the high- and low-expression groups.
RESULTS: A total of 97 patients with FIGO stage IIIC-IV HGSOC were included: 15 (15.5%), 66 (68.0%), and 13 (13.4%) patients showed high expression of CXCL12, CXCR4, and both, respectively. The expression level of each protein was not associated with germline BRCA1/2 mutational status, FIGO stage, or residual tumor after primary cytoreductive surgery. In multivariate analysis adjusted for confounders, high CXCL12 expression was identified as an independent poor prognostic biomarker for progression-free survival (adjusted hazards ratio, 1.990; 95% confidence interval=1.090-3.633; p=0.025). However, CXCR4 expression was not associated with patient survival outcomes.
CONCLUSIONS: The CXCL12 expression level may represent a prognostic biomarker for HGSOC. Proteins related to the CXCL12/CXCR4 complex may serve as therapeutic targets in HGSOC treatment.