Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Cancer Sci. 2020 Apr;111(4):1291-1302. doi: 10.1111/cas.14332. Epub 2020 Feb 22.
Postoperative distant metastasis dramatically affects rectal cancer patients who have undergone neoadjuvant chemoradiotherapy (NACRT). Here, we clarified the association between NACRT-mediated mammalian target of rapamycin (mTOR) signaling pathway activation and rectal cancer metastatic potential. We performed immunohistochemistry for phosphorylated mTOR (p-mTOR) and phosphorylated S6 (p-S6) on surgical specimen blocks from 98 rectal cancer patients after NACRT (cohort 1) and 80 colorectal cancer patients without NACRT (cohort 2). In addition, we investigated the association between mTOR pathway activity, affected by irradiation, and the migration ability of colorectal cancer cells in vitro. Based on the results of the clinical study, p-mTOR was significantly overexpressed in cohort 1 (with NACRT) as compared to levels in cohort 2 (without NACRT) (P < .001). High p-mTOR and p-S6 levels correlated with the development of distant metastasis only in cohort 1. Specifically, high p-S6 expression (HR 4.51, P = .002) and high pathological T-stage (HR 3.73, P = .020) after NACRT were independent predictors of the development of distant metastasis. In vitro, p-S6 levels and migration ability increased after irradiation in SW480 cells (TP53 mutation-type) but decreased in LoVo cells (TP53 wild-type), suggesting that irradiation modulates mTOR signaling and migration through cell type-dependent mechanisms. We next assessed the expression level of p53 by immunostaining in cohort 1 and demonstrated that p-S6 was overexpressed in samples with high p53 expression as compared to levels in samples with low p53 expression (P = .008). In conclusion, p-S6 levels after NACRT correlate with postoperative distant metastasis in rectal cancer patients, suggesting that chemoradiotherapy might modulate the mTOR signaling pathway, promoting metastasis.
术后远处转移显著影响接受新辅助放化疗（NACRT）的直肠癌患者。在这里，我们阐明了 NACRT 介导的哺乳动物雷帕霉素靶蛋白（mTOR）信号通路激活与直肠癌转移潜能之间的关系。我们对 98 例接受 NACRT 后的直肠癌患者（队列 1）和 80 例未接受 NACRT 的结直肠癌患者（队列 2）的手术标本块进行了磷酸化 mTOR（p-mTOR）和磷酸化 S6（p-S6）的免疫组织化学染色。此外，我们还研究了体外照射影响的 mTOR 通路活性与结直肠癌细胞迁移能力之间的关系。基于临床研究结果，与队列 2（未接受 NACRT）相比，队列 1（接受 NACRT）中 p-mTOR 的表达明显上调（P<0.001）。高 p-mTOR 和 p-S6 水平仅在队列 1中与远处转移的发生相关。具体而言，NACRT 后高 p-S6 表达（HR 4.51，P=0.002）和高病理 T 分期（HR 3.73，P=0.020）是远处转移发生的独立预测因子。在体外，SW480 细胞（TP53 突变型）照射后 p-S6 水平和迁移能力增加，而 LoVo 细胞（TP53 野生型）则降低，表明照射通过细胞类型依赖性机制调节 mTOR 信号和迁移。我们随后在队列 1 中通过免疫染色评估了 p53 的表达水平，并证明与低 p53 表达水平相比，p-S6 在高表达 p53 的样本中表达上调（P=0.008）。总之，NACRT 后 p-S6 水平与直肠癌患者术后远处转移相关，提示放化疗可能调节 mTOR 信号通路，促进转移。
