Chen Hong-Hwa, Luo Chi-Wen, Chen Yi-Ling, Chiang John Y, Huang Chi-Ruei, Wang Yi-Ting, Chen Chih-Hung, Guo Jun, Yip Hon-Kan
Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
Int J Biol Sci. 2024 Nov 11;20(15):6162-6180. doi: 10.7150/ijbs.101051. eCollection 2024.
This study tested the hypothesis that combined therapy with probiotics and cytokine-induced killer (CIK) cells was superior to merely one on suppressing the peritoneal carcinomatosis and liver metastasis of colorectal cancer (CRC) cells in nude mice. The study revealed that in HCT 116/SW620 CRC cell lines, cell viability, proliferation, colony formation, migratory ability, wound healing, and protein expression of PD-L1 and FAK were significantly and comparably suppressed and that apoptosis was significantly and comparably increased by probiotics and CIK cells, and these effects were further significantly enhanced by combined probiotics + CIK cell therapy (all p<0.001). Nude mice were categorized into Groups 1 (SC), 2 (HCT 116), 3 (HCT 116 + probiotics), 4 (HCT 116 + CIK cells), and 5 (HCT 116 + probiotics + CIK cells). CRC cells were intraperitoneally implanted into Groups 2 to 5, and the animals were euthanized by Day 28. The results demonstrated that the abdominal dissemination of CRC cells, tumor numbers, tumor weights, liver weights, liver necrosis areas and the expression of γ-H2AX/PD-L1/FAK in harvested liver tumors were lowest in Group 1, highest in Group 2, and significantly and progressively decreased in Groups 3 to 5 (all p<0.0001). The protein expression levels of apoptotic and DNA damage biomarkers (Bax/c-caspase 3/c-PARP/γ-H2AX), a metastatic biomarker (FAK) and three tumor proliferation and survival signaling biomarkers (JAK-STAT1, PI3K/Akt/m-TOR and Ras/Raf/MEK/ERK) exhibited identical patterns to that of a tumor immune escape biomarker (PD-L1) among the groups (all p<0.0001). The combination of probiotics and CIK cells was superior to either therapy alone in suppressing CRC cell growth, proliferation, liver metastasis and survival, mainly through downregulating cell proliferation and survival signaling pathways.
益生菌与细胞因子诱导的杀伤（CIK）细胞联合治疗在抑制裸鼠结直肠癌（CRC）细胞的腹膜癌转移和肝转移方面优于单一治疗。研究表明，在HCT 116/SW620 CRC细胞系中，益生菌和CIK细胞显著且同等程度地抑制了细胞活力、增殖、集落形成、迁移能力、伤口愈合以及PD-L1和FAK的蛋白表达，并且显著且同等程度地增加了细胞凋亡，而益生菌+CIK细胞联合治疗进一步显著增强了这些效果（所有p<0.001）。将裸鼠分为1组（SC）、2组（HCT 116）、3组（HCT 116+益生菌）、4组（HCT 116+CIK细胞）和5组（HCT 116+益生菌+CIK细胞）。将CRC细胞腹腔内植入2至5组，在第28天对动物实施安乐死。结果表明，CRC细胞的腹腔播散、肿瘤数量、肿瘤重量、肝脏重量、肝坏死面积以及收获的肝肿瘤中γ-H2AX/PD-L1/FAK的表达在1组中最低，在2组中最高，在3至5组中显著且逐渐降低（所有p<0.0001）。凋亡和DNA损伤生物标志物（Bax/c-半胱天冬酶3/c-PARP/γ-H2AX）、转移生物标志物（FAK）以及三种肿瘤增殖和存活信号生物标志物（JAK-STAT1、PI3K/Akt/m-TOR和Ras/Raf/MEK/ERK）的蛋白表达水平在各组中与肿瘤免疫逃逸生物标志物（PD-L1）呈现相同模式（所有p<0.0001）。益生菌与CIK细胞联合治疗在抑制CRC细胞生长、增殖、肝转移和存活方面优于单独的任何一种治疗，主要是通过下调细胞增殖和存活信号通路实现的。
