Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential
Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential
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DOI：
10.3109/1547691x.2012.693547
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发表时间：
2012-07-01
影响因子：
3.3
通讯作者：
Gaipl, Udo S.
中科院分区：
文献类型：
--
作者：
Frey, Benjamin;Stache, Christina;Gaipl, Udo S.
化疗药物 (CT) 和电离辐射 (X 射线) 会引起 DNA 损伤，主要目的是阻止肿瘤细胞的增殖。然而，多模式抗癌疗法最终应该导致肿瘤细胞死亡，最好是诱导全身抗肿瘤免疫。由于不同的治疗诱导的肿瘤细胞死亡形式可能会产生免疫激活肿瘤微环境，因此本研究检查了结直肠癌治疗中使用的单独 CT 治疗或与 X 射线联合治疗是否会导致具有免疫原性潜力的结直肠肿瘤细胞死亡。 5-氟尿嘧啶 (5-FU)、奥沙利铂 (Oxp) 或伊立替康 (Irino) 与 X 射线联合使用都是结直肠肿瘤细胞集落形成的有效抑制剂。然后，本研究通过膜联蛋白 A5-FITC/碘化丙啶染色检查了细胞死亡的形式。坏死是 CT 和/或 X 射线诱导的细胞死亡的主要形式。虽然仅 Irino 与 X 射线的组合在治疗后 1 天就已导致死亡诱导，但 Oxp 或 5-FU 与 X 射线的组合以及单独 X 射线在治疗后的较晚时间点也导致高坏死率。抑制细胞凋亡增加了坏死肿瘤细胞的数量，表明 CT + X 射线可以诱导程序性坏死。单独使用 5-FU 和 Oxp 或与 X 射线和 Irino 加 X 射线组合对于增加 RIP、IRF-5 和 p53（参与坏死和凋亡细胞死亡途径的蛋白质）的表达最为有效。所有治疗均进一步导致免疫激活危险信号高迁移率族蛋白 1 (HMGB1) 和热休克蛋白 70 (HSP70) 的释放。处理过的肿瘤细胞的上清液诱导树突状细胞成熟。因此，得出的结论是，CT 与 X 射线的组合能够诱导具有免疫原性潜力的结直肠肿瘤的体外细胞死亡形式。
Chemotherapeutic agents (CT) and ionizing radiation (X-ray) induce DNA damage and primarily aim to stop the proliferation of tumor cells. However, multimodal anti-cancer therapies should finally result in tumor cell death and, best, in the induction of systemic anti-tumor immunity. Since distinct therapy-induced tumor cell death forms may create an immune activating tumor microenvironment, this study examined whether sole treatment with CT that are used in the therapy for colorectal cancer or in combination with X-ray result in colorectal tumor cell death with immunogenic potential. 5-Fluorouracil (5-FU), Oxaliplatin (Oxp), or Irinotecan (Irino) in combination with X-ray were all potent inhibitors of colorectal tumor cell colony formation. This study then examined the forms of cell death with AnnexinA5-FITC/Propidium Iodide staining. Necrosis was the prominent form of cell death induced by CT and/or X-ray. While only a combination of Irino with X-ray leads to death induction already 1 day after treatment, also the combinations of Oxp or 5-FU with X-ray and X-ray alone resulted in high necrosis rates at later time points after treatment. Inhibition of apoptosis increased the amount of necrotic tumor cells, suggesting that a programmed form of necrosis can be induced by CT + X-ray. 5-FU and Oxp alone or in combination with X-ray and Irino plus X-ray were most effective in increasing the expression of RIP, IRF-5, and p53, proteins involved in necrotic and apoptotic cell death pathways. All treatments further resulted in the release of the immune activating danger signals high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). The supernatants of the treated tumor cells induced maturation of dendritic cells. It is, therefore, concluded that combination of CT with X-ray is capable of inducing in vitro cell death forms of colorectal tumors with immunogenic potential.