Supercharged eGFP-TRAIL Decorated NETs to Ensnare and Kill Disseminated Tumor Cells
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Cellular and Molecular Bioengineering, Vol. 13, No. 4, August 2020 (Ó 2020) pp. 359–367 https://doi.org/10.1007/s12195-020-00639-8
Original Article
Supercharged eGFP-TRAIL Decorated NETs to Ensnare and Kill Disseminated Tumor Cells THONG M. CAO and MICHAEL R. KING Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA (Received 3 May 2020; accepted 20 July 2020; published online 6 August 2020)
tumor development by secreting pro-inflammatory and pro-angiogenesis chemokines and cytokines such as matrix metallopeptidase 9 (MMP9) and interleukin 6 (IL-6).1,15,19 Tumor metastasis via hematogenous dissemination involves circulating tumor cells (CTCs) shedding from the primary tumor site and reaching distant organs through the circulatory system. In a recent study, neutrophils have been found to support CTC survival during hematogenous dissemination.18 Furthermore, neutrophils have been identified as the main driver in establishing the pre-metastatic microenvironment in several mouse breast cancer models.20 NETosis is a unique form of innate immune response elicited primarily by neutrophils to combat microbial infections.3 In the presence of antigens, neutrophils undergo NETosis by following a program of cell death and releasing condensed DNA fibers decorated with cationic antimicrobial proteins, collectively called NETs, into the extracellular space.16 Tumor cells release tumor-derived interleukin 8 (IL-8), a potent neutrophil chemoattractant, to increase tumor growth and metastatic potential by: (i) promoting tumor neovascularization, and (ii) inducing infiltrating neutrophils to release pro-metastatic enzymes.4
Abstract Background—NETosis is an innate immune response elicited by activated neutrophils to fight microbial infections. Activated neutrophils release DNA fibers decorated with antimicrobial proteins called neutrophil extracellular traps (NETs) into the extracellular space to trap and kill surrounding microbes. Methods—Here, we show that tumor-derived IL-8 released by cancer cells also activates the release of NETs. Until now, there have been no existing technologies that leverage NETs as an anti-tumor drug delivery vehicle. In this study, we demonstrate the re-engineering of neutrophils to express an apoptosis-inducing chimeric protein, supercharged eGFPTRAIL, on NETs that can ensnare and kill tumor cells while retaining their anti-microbial capabilities. Results—We observed significant TRAIL-induced apoptosis in tumor cells captured by TRAIL-decorated NETs. Conclusions—This work demonstrates NETs as a promising technology to deliver protein in response to local cytokine signals. Keywords—NETosis, Neutrophil, Apoptosis, Protein engineering.
Metastasis,
TRAIL,
INTRODUCTION Neutrophils play a significant role in all stages of tumorigenesis, from the initial genotoxic insult, to metastasis to distant organs. Chronic inflammation drives neutrophils to release mutagenetic agents, including reactive oxygen species (ROS) and hypochlorous acid (HOCl) that induce DNA damage and mutagenicity
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