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.

Young Woo Eom,Suji Lee,Wanlu Li,Mee-Yon Cho,Rokeya Akter,Soonjae Hwang,Jiye Kim

doi:10.3390/ijms21113887

Abstract

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, CD133knockout 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.

Highlights

Death receptors (DR) targeted by the tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) are expressed only in tumor cells and not in normal cells [1,2,3]
Colitis is known to increase the incidence of colorectal cancer; we investigated whether TRAIL-expressing adipose tissue-derived stem cells (ASCs) could alleviate colitis-associated colon cancer induced in Balb/c wild-type mice by Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS)
The influence of M1 macrophages on the TRAIL expression of ASCs was analyzed by next-generation sequencing (NGS), immunoblotting, and Enzyme-Linked Immunosorbent Assay (ELISA)

Summary

Introduction

Death receptors (DR) targeted by the tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) are expressed only in tumor cells and not in normal cells [1,2,3]. TRAIL can regulate CD133+ cancer stem cells (CSC) and induce tumor cell-specific apoptosis [4,5]. CD133+ CSCs of both H460 and H2170 cell lines of non-small cell lung cancer highly express death receptor 5 (DR5) and undergo apoptosis when treated with TRAIL-expressing mesenchymal stem cells (MSCs) [5]. Jurkat and breast cancer MCF-7 cells expressing high levels of CD133 are resistant to TRAIL owing to the up-regulation of FLICE-inhibitory protein (FLIP) [16]. Several studies have been conducted to treat tumors using engineered MSC-expressing genes such as TRAIL to induce tumor cell-specific apoptosis

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Conclusion