Conditioned Medium From Azurin-Expressing Human Mesenchymal Stromal Cells Demonstrates Antitumor Activity Against Breast and Lung Cancer Cell Lines

Abstract

Recently, cell-based therapies have been explored as a strategy to enhance the specificity of anticancer therapeutic agents. In this perspective, human mesenchymal stromal cells (MSC) hold a promising future as cell delivery systems for anticancer proteins due to their unique biological features. In this study, we engineered human MSC to secrete a human codon-optimized version of azurin (hazu), a bacterial protein that has demonstrated anticancer activity toward different cancer models both in vitro and in vivo . To this end, microporation was used to deliver plasmid DNA encoding azurin into MSC derived from bone marrow (BM) and umbilical cord matrix (UCM), leading to expression and secretion of hazu to the conditioned medium (CM). Engineered hazu-MSC were shown to preserve tumor tropism toward breast (MCF-7) and lung (A549) cancer cell lines, comparable to non-modified MSC. Azurin was detected in the CM of transfected MSC and, upon treatment with hazu-MSC-CM, we observed a decrease in cancer cell proliferation, migration, and invasion, and an increase in cell death for both cancer cell lines. Moreover, expression of azurin caused no changes in MSC expression profile of cytokines relevant in the context of cancer progression, thus suggesting that the antitumoral effects induced by hazu-MSC secretome might be due to the presence of azurin independently. In conclusion, data shown herein indicate that MSC-produced azurin in a CM configuration elicits an anticancer effect.

3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment

“…In a 2D study by Chao et al, in 2012, UC-MSC co-cultured with a breast tumour cell line exhibited an antitumour effect [265]. Further understanding on MSC effects and their different sources is still required, especially as MSC have been proposed as a therapeutic vehicle for antitumour treatments [266,267].…”

Conditioned media from human pluripotent stem cell‐derived cardiomyocytes inhibit the growth and migration of lung cancer cells

“…The secretome of several cell types has been reported to exhibit anticancer effects. CM derived from azurin‐expressing human mesenchymal stromal cells induced cell death in breast‐ and lung cancer cells 27 . Moreover, unmodified mesenchymal stem cell‐derived conditioned medium (MSC‐CM) was previously shown to reduce cancer cell proliferation, migration and invasion in A549 lung cancer and HCC hepatocellular carcinoma cells 28,29 .…”

Challenges and advances in clinical applications of mesenchymal stromal cells

“…In the context of neuronal damage, it has been established that the presence of BDNF, GDNF, NGF, and IGF in the MSCs secretome is necessary for the neuronal survival in vitro and in vivo [ 94 , 95 ]. MSCs-CM has demonstrated therapeutic efficacy in some other disease models including chronic kidney disease, certain lung, and liver diseases [ 96 , 97 ].…”