Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Anticancer Res. 2023 Jul;43(7):3331-3340. doi: 10.21873/anticanres.16509.
BACKGROUND/AIM: 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.
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.
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.
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.
背景/目的：C-X-C 基序趋化因子受体 4（CXCR4）及其配体 C-X-C 基序趋化因子配体 12（CXCL12）复合物在癌细胞增殖、侵袭和转移中发挥着重要作用。这些是新兴的治疗靶点，最近的研究报告表明，抑制 CXCL12-CXCR4 信号通路可增强免疫检查点抑制剂的疗效。因此，我们旨在研究 CXCL12 和 CXCR4 在高级别浆液性卵巢癌（HGSOC）中的组织表达，并确定它们作为预后标志物的潜力。
我们使用来自接受初次细胞减灭术的晚期 HGSOC 患者的未经化疗的福尔马林固定石蜡包埋的原发性卵巢癌组织。在组织学重新评估后，我们构建了组织微阵列并进行了 CXCL12 和 CXCR4 的免疫组织化学染色。此后，我们比较了高表达组和低表达组之间的临床病理特征和生存结局。
共纳入 97 例 FIGO 分期为 IIIC-IV 期的 HGSOC 患者：15 例（15.5%）、66 例（68.0%）和 13 例（13.4%）患者的 CXCL12、CXCR4 和两者的表达水平分别较高。每种蛋白的表达水平与胚系 BRCA1/2 突变状态、FIGO 分期或初次细胞减灭术后残留肿瘤无关。在调整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（调整后的危险比，1.990；95%置信区间，1.090-3.633；p=0.025）。然而，CXCR4 表达与患者生存结局无关。
CXCL12 表达水平可能是 HGSOC 的预后生物标志物。与 CXCL12/CXCR4 复合物相关的蛋白可能成为 HGSOC 治疗的治疗靶点。
