Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany.
Sci Rep. 2024 Sep 4;14(1):20589. doi: 10.1038/s41598-024-71616-8.
In esophageal adenocarcinoma, the presence of lymph node metastases predicts patients' survival even after curative resection. Currently, there is no highly accurate marker for detecting the presence of lymph node metastasis. The SEMA3F/NRP2 axis was initially characterized in axon guidance and recent evidence has revealed its significant involvement in lymphangiogenesis, angiogenesis, and carcinogenesis. Hence, the objective of this study was to elucidate the roles of SEMA3F and its receptor NRP2 in esophageal adenocarcinoma. We conducted an immunohistochemical evaluation of SEMA3F and NRP2 protein expression in 776 patients with esophageal adenocarcinoma who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. Total and positive cancer cell counts were digitally analyzed using QuPath and verified by experienced pathologists to ensure accuracy. Positive expression was determined as a cell percentage exceeding the 50th percentile threshold. In our cohort, patients exhibiting SEMA3F positive expression experience significantly lower pT- and pN-stages. In contrast, positive NRP2 expression is associated with the presence of lymph node metastases. Survival analyses showed that the expression status of NRP2 had no impact on patient survival. However, SEMA3F positivity was associated with a favorable patient survival outcome (median OS: 38.9 vs. 26.5 months). Furthermore, SEMA3F could be confirmed as an independent factor for better patient survival in patients with early tumor stage (pT1N0-3: HR = 0.505, p = 0.014, pT1-4N0: HR = 0.664, p = 0.024, pT1N0: HR = 0.483, p = 0.040). In summary, SEMA3F emerges as an independent predictor for a favorable prognosis in patients with early-stage esophageal adenocarcinoma. Additionally, NRP2 expression is linked to a higher risk of lymph node metastases occurrence. We hypothesize that low SEMA3F expression could identify patients with early-stage tumors who might benefit from more aggressive treatment options or intensified follow-up. Furthermore, SEMA3F and its associated pathways should be explored as potential tumor-suppressing agents.
在食管腺癌中，即使经过根治性切除，淋巴结转移的存在也预示着患者的生存。目前，尚无高度准确的标志物来检测淋巴结转移的存在。SEMA3F/NRP2 轴最初在轴突导向中得到描述，最近的证据表明它在淋巴管生成、血管生成和癌变中具有重要作用。因此，本研究的目的是阐明 SEMA3F 及其受体 NRP2 在食管腺癌中的作用。我们对在科隆大学医院接受 Ivor-Lewis 食管切除术的 776 例食管腺癌患者进行了 SEMA3F 和 NRP2 蛋白表达的免疫组织化学评估。使用 QuPath 对总阳性癌细胞计数和阳性癌细胞计数进行数字分析，并由经验丰富的病理学家进行验证，以确保准确性。阳性表达被确定为超过第 50 个百分位阈值的细胞百分比。在我们的队列中，表达 SEMA3F 的患者经历的 pT 和 pN 分期明显较低。相比之下，阳性 NRP2 表达与淋巴结转移的存在相关。生存分析表明，NRP2 的表达状态对患者的生存没有影响。然而，SEMA3F 阳性与患者生存结果较好相关（中位 OS：38.9 与 26.5 个月）。此外，在肿瘤早期阶段的患者中，SEMA3F 可被确认为独立的生存获益因素（pT1N0-3：HR=0.505，p=0.014，pT1-4N0：HR=0.664，p=0.024，pT1N0：HR=0.483，p=0.040）。总之，SEMA3F 成为早期食管腺癌患者预后良好的独立预测因子。此外，NRP2 表达与发生淋巴结转移的风险增加相关。我们假设低 SEMA3F 表达可以识别出早期肿瘤患者，这些患者可能受益于更积极的治疗方案或强化随访。此外，应探索 SEMA3F 及其相关途径作为潜在的肿瘤抑制因子。
