Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

Abstract

Mesenchymal stem cells (MSCs) are emerging as vehicles for anti-tumor cytotherapy; however, investigation on its efficacy to target a specific cancer stem cell (CSC) population in non-small cell lung cancer (NSCLC) is lacking. Using assays to evaluate cell proliferation, apoptosis, and gene expression, we investigated the efficacy of MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) to target and destroy CD133+ (prominin-1 positive) NSCLC-derived CSCs. Characterization of TRAIL death receptor 5 (DR5) revealed that it was highly expressed in the CD133+ CSCs of both H460 and H2170 cell lines. The human MSC-TRAIL generated in the study maintained its multipotent characteristics, and caused significant tumor cell inhibition in NSCLC-derived CSCs in a co-culture. The MSC-TRAIL induced an increase in annexin V expression, an indicator of apoptosis in H460 and H2170 derived CD133+ CSCs. Through investigation of mitochondria membrane potential, we found that MSC-TRAIL was capable of inducing intrinsic apoptosis to the CSCs. Using pathway-specific gene expression profiling, we uncovered candidate genes such as NFKB1, BAG3, MCL1, GADD45A, and HRK in CD133+ CSCs, which, if targeted, might increase the sensitivity of NSCLC to MSC-TRAIL-mediated inhibition. As such, our findings add credibility to the utilization of MSC-TRAIL for the treatment of NSCLC through targeting of CD133+ CSCs.

Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness

“…Clinical data from several available cohorts, including TCGA and meta-base 1000 patients with lung cancer, indicated that the ALDOA-Oct4-TRAF4/DUSP4 axis is a potential prognostic indicator and may be a therapeutic target. In non-small cell lung cancer, scientists are developing various strategies and methods for targeting and specificity 42,43 . This finding has strong potential for the development of novel cancer therapies or combination therapies against CSCs in lung cancer.…”

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

“…In this study, we observed that TRAIL expression in ASCs was significantly increased by M1 macrophages, and TRAIL-expressing ASCs could effectively alleviate colon cancer by suppressing CD133 + CSCs and M2 macrophages in the tumor microenvironment. TRAIL can selectively kill only cancer cells; therefore, studies using TRAIL to treat cancer have been actively conducted [4,5]. Based on the homing characteristic of MSCs into the site of inflammation or tumor, MSCs are used to treat cancers as drug and therapeutic gene carriers [5,21,34,35].…”

“…TRAIL can selectively kill only cancer cells; therefore, studies using TRAIL to treat cancer have been actively conducted [4,5]. Based on the homing characteristic of MSCs into the site of inflammation or tumor, MSCs are used to treat cancers as drug and therapeutic gene carriers [5,21,34,35]. In particular, MSCs engineered with the TRAIL gene have demonstrated therapeutic effects in several tumor models [5,21,35].…”

“…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 is known as a potential CSC marker of tumors in the brain [6][7][8], liver [9], pancreas [10], and colon [11,12].…”

“…Moreover, SNU-475 hepatocellular carcinoma (HCC) cells express high levels of CD133 and are highly susceptible to TRAIL compared to other HCC cells with a low CD133 expression [4]. Additionally, 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]. In contrast, 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].…”