Abstract
Mesenchymal stem cells (MSCs) are currently exploited as gene delivery systems for transient in situ expression of cancer therapeutics. As an alternative to the prevailing viral expression, we here describe a murine MSC line stably expressing a therapeutic protein for up to 42 passages, yet fully maintaining MSC features. Because of superior antitumoral activity of hexavalent TNF-related apoptosis-inducing ligand (TRAIL) formats and the advantage of a tumor-targeted action, we choose expression of a dimeric EGFR-specific diabody single-chain TRAIL (Db-scTRAIL) as a model. The bioactivity of Db-scTRAIL produced from an isolated clone (MSC.TRAIL) was revealed from cell death induction in Colo205 cells treated with either culture supernatants from or cocultured with MSC.TRAIL. In vivo, therapeutic activity of MSC.TRAIL was shown upon peritumoral injection in a Colo205 xenograft tumor model. Best antitumor activity in vitro and in vivo was observed upon combined treatment of MSC.TRAIL with bortezomib. Importantly, in vivo combination treatment did not cause apparent hepatotoxicity, weight loss, or behavioral changes. The development of well characterized stocks of stable drug-producing human MSC lines has the potential to establish standardized protocols of cell-based therapy broadly applicable in cancer treatment.
Highlights
Mesenchymal stem cells (MSCs) are multipotent stem cells that have generated a great deal of interest since their first identification in 1960s by Friedenstein [1, 2] due to their exceptional capabilities, foremost multilineage differentiation potential [3, 4], and hypoimmunogenic properties [5, 6]
As a prerequisite to study the application of MSCs as cell-based therapy for Db-scTRAIL fusion protein expression, we first investigated the TNF-related apoptosis-inducing ligand (TRAIL) sensitivity of these cells in comparison to a colorectal cancer (CRC) cell line Colo205
We explored the possibility of generating stable MSC producer cell lines as delivery system for the expression of an antitumor protein drug, using a tumor-targeted variant of the proapoptotic protein TRAIL as a model substance
Summary
Mesenchymal stem cells (MSCs) are multipotent stem cells that have generated a great deal of interest since their first identification in 1960s by Friedenstein [1, 2] due to their exceptional capabilities, foremost multilineage differentiation potential [3, 4], and hypoimmunogenic properties [5, 6] Because of these features, MSCs were early on applied in the field of regenerative medicine [7] and subsequently in a variety of other diseases, including autoimmune disorders, cardiovascular malignancies, and liver diseases [reviewed by Squillaro et al [8]]. Two studies have reported antitumoral activity of human MSC expressing antibodies in a diabody format [23, 24]
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