Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
Cancer Immunol Immunother. 2023 Nov;72(11):3651-3664. doi: 10.1007/s00262-023-03517-0. Epub 2023 Aug 19.
Colorectal cancer is a disease of unmet medical need. Although extracellular vesicles (EVs) have been implicated in anti-tumor responses, discrepancies were observed among studies. We analyzed the role of tumor-derived EVs (TEVs) in tumor progression in vivo by focusing on regulatory T (Treg) cells, which play essential roles in tumor development and progression.
A mouse model of colorectal cancer lung metastasis was generated using BALB/c mice by tail vein injection of the BALB/c colon adenocarcinoma cell line Colon-26. TEVs derived from Colon-26 and BALB/c lung squamous cell carcinoma ASB-XIV were retrieved from the culture media supernatants. A TEV equivalent to 10 µg protein was injected every other day for 2 weeks.
Histology and immunohistochemistry studies revealed that lung tumors reduced in the Colon-26-EV group when compared to the phosphate-buffered saline (PBS) group. The population of CD4 + FoxP3 + cells in the lung was upregulated in the PBS group mice when compared to the healthy mice (P < 0.001), but was significantly downregulated in the Colon-26-EV group mice when compared to the PBS group mice (P < 0.01). Programmed cell death protein 1, glucocorticoid-induced TNFR-related protein, and CD69 expression in lung Treg cells were markedly upregulated in the PBS group when compared to the healthy mice, but downregulated in the Colon-26-EV group when compared to the PBS group. The changes in expression were dose-dependent for Colon-26-EVs. ASB-EVs also led to significantly downregulated Treg cell expression, although non-cancer line 3T3-derived EVs did not.
Our study suggests that TEVs possess components for tumor suppression.
结直肠癌是一种未满足医疗需求的疾病。尽管细胞外囊泡 (EVs) 已被认为与抗肿瘤反应有关，但研究结果存在差异。我们通过关注在肿瘤发生和发展中起重要作用的调节性 T (Treg) 细胞，分析了肿瘤衍生的 EVs (TEVs) 在体内肿瘤进展中的作用。
通过尾静脉注射 BALB/c 结肠腺癌细胞系 Colon-26 ，在 BALB/c 小鼠中建立结直肠癌肺转移模型。从 Colon-26 和 BALB/c 肺鳞癌细胞系 ASB-XIV 的培养上清液中提取 TEVs。每隔一天注射相当于 10μg 蛋白的 TEV，共 2 周。
组织学和免疫组织化学研究表明，与磷酸盐缓冲盐水 (PBS) 组相比，Colon-26-EV 组的肺肿瘤减少。与健康小鼠相比，PBS 组小鼠肺中的 CD4+FoxP3+细胞数量增加 (P<0.001)，但与 PBS 组小鼠相比，Colon-26-EV 组小鼠的数量明显减少 (P<0.01)。与健康小鼠相比，PBS 组小鼠肺中的程序性细胞死亡蛋白 1、糖皮质激素诱导的 TNFR 相关蛋白和 CD69 在 Treg 细胞中的表达明显上调，但与 PBS 组相比，Colon-26-EV 组下调。Colon-26-EVs 的表达变化呈剂量依赖性。ASB-EVs 也导致 Treg 细胞表达明显下调，尽管非癌细胞系 3T3 衍生的 EVs 没有。
我们的研究表明，TEVs 具有肿瘤抑制成分。
