M1 Macrophages Promote TRAIL Expression in Adipose Tissue-Derived Stem Cells, Which Suppresses Colitis-Associated Colon Cancer by Increasing Apoptosis of CD133+ Cancer Stem Cells and Decreasing M2 Macrophage Population
M1 Macrophages Promote TRAIL Expression in Adipose Tissue-Derived Stem Cells, Which Suppresses Colitis-Associated Colon Cancer by Increasing Apoptosis of CD133+ Cancer Stem Cells and Decreasing M2 Macrophage Population
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DOI：
10.3390/ijms21113887
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发表时间：
2020-06-01
影响因子：
5.6
通讯作者：
Cho, Mee-Yon
中科院分区：
文献类型：
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作者：
Eom, Young Woo;Akter, Rokeya;Cho, Mee-Yon
我们之前报道过，高细胞密度培养的脂肪组织源性干细胞（ASC）可以通过表达I型干扰素和肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）来诱导癌细胞死亡。在这里，我们研究了 M1 巨噬细胞诱导的表达 TRAIL 的 ASC 是否可以在氧化偶氮甲烷 (AOM)/葡聚糖硫酸钠 (DSS) 动物模型中减轻结肠炎相关癌症。 M1巨噬细胞显着增加ASC中TRAIL的表达，从而以TRAIL依赖性方式诱导LoVo细胞凋亡。然而，使用 CRISPR-Cas9 基因编辑系统生成的 CD133（敲除）LoVo 细胞对 TRAIL 具有抗性。在 AOM/DSS 诱导的结肠炎相关癌症模型中，腹膜内移植表达 TRAIL 的 ASC 显着抑制结肠癌的发展。此外，免疫组织化学染色显示，与未治疗组的肿瘤相比，AOM/DSS + ASC 组的肿瘤中 CD133 表达较低。此外，相对于未治疗组的动物，ASC 治疗选择性地减少了 AOM/DSS + ASC 治疗组动物肿瘤 (45.7 +/- 4.2) 和非肿瘤粘膜 (30.3 +/- 1.5) 中 M2 巨噬细胞的数量（肿瘤 71.7 +/- 11.2，非肿瘤 94.3 +/- 12.5；p < 0.001）。因此，表达TRAIL的ASC是有前途的抗肿瘤治疗药物，特别是通过诱导CD133(+)癌症干细胞凋亡和减少M2巨噬细胞群来减轻结肠癌。
We have previously reported that adipose tissue-derived stem cells (ASCs) cultured at high cell density can induce cancer cell death through the expression of type I interferons and tumor necrosis factor (TNF)-related apoptosis-inducing ligands (TRAIL). Here, we investigated whether TRAIL-expressing ASCs induced by M1 macrophages can alleviate colitis-associated cancer in an azoxymethane (AOM)/dextran sodium sulfate (DSS) animal model. M1 macrophages significantly increased the TRAIL expression in ASCs, which induced the apoptosis of LoVo cells in a TRAIL-dependent manner. However, CD133(knockout) LoVo cells, generated using the CRISPR-Cas9 gene-editing system, were resistant to TRAIL. In the AOM/DSS-induced colitis-associated cancer model, the intraperitoneal transplantation of TRAIL-expressing ASCs significantly suppressed colon cancer development. Moreover, immunohistochemical staining revealed a low CD133 expression in tumors from the AOM/DSS + ASCs group when compared with tumors from the untreated group. Additionally, the ASC treatment selectively reduced the number of M2 macrophages in tumoral (45.7 +/- 4.2) and non-tumoral mucosa (30.3 +/- 1.5) in AOM/DSS + ASCs-treated animals relative to those in the untreated group (tumor 71.7 +/- 11.2, non-tumor 94.3 +/- 12.5; p < 0.001). Thus, TRAIL-expressing ASCs are promising agents for anti-tumor therapy, particularly to alleviate colon cancer by inducing the apoptosis of CD133(+) cancer stem cells and decreasing the M2 macrophage population.