Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
BMC Cancer. 2018 Mar 27;18(1):321. doi: 10.1186/s12885-018-4254-4.
We sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.
From July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.
Preoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.
Pretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.
我们试图确定癌胚抗原（CEA）作为直肠癌放射抵抗的标志物。
从 1997 年 7 月至 2008 年 1 月，104 例接受术后放疗（PORT）的 II 期或 III 期直肠癌患者纳入本研究。放疗剂量为 45 至 54.6 Gy。在术前测量 CEA 水平。我们使用 Kaplan-Meier 曲线分析总生存（OS）、远处转移（DM）和局部复发（LR）的累积率。使用 Cox 回归模型进行多变量分析。我们使用 THP-1 单核细胞系进行巨噬细胞分化（M0、M1 或 M2）。从巨噬细胞中提取的 RNA 在核心实验室通过基因组方法进行分析。比较 CEA 刺激的巨噬细胞条件培养基存在和不存在时，CEA 丰富的 LS1034 细胞的放射敏感性。
术前 CEA 水平≥10ng/ml 是 OS（p=0.005）、DM（p=0.026）和 LR（p=0.004）的独立预测因素。术前 CEA 水平<10ng/ml 和≥10ng/ml 的患者 OS 率分别为 64.5%和 35.9%（p=0.004）。相应的 DM 发生率分别为 40.6%和 73.1%（p=0.024）。相应的 LR 发生率分别为 6.6%和 33.9%（p=0.002）。在 M0 巨噬细胞中，外源性 CEA 与 M2 分化呈剂量反应关系。在 CEA 刺激的 M0 细胞中，一些 mRNA 被上调多达 5 倍，包括 MMP12、GDF15 和 JAG1。在 CEA 刺激的 M2 细胞中，GADD45G mRNA 被上调 4 倍。CEA 刺激的 M2 细胞条件培养基可增加 LS180、SW620 和 LS1034 细胞在照射后的数量。CEA 导致巨噬细胞的 M2 分化。
术前 CEA 水平≥10ng/ml 是 PORT 治疗直肠癌后 OS、DM 和 LR 的显著危险因素。CEA 在 M2 巨噬细胞存在的情况下引起放射抵抗。建议对 CEA 水平≥10ng/ml 的患者进行更全面的术前检查和强化辅助治疗。需要进一步研究这些机制。
