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S128 Reduction of lung metastasis by engineered Mesenchymal stem cells expressing secreted soluble TRAIL
  1. ZQY Yuan,
  2. KK Kolluri
  1. University College London, London, UK

Abstract

Bone marrow–derived mesenchymal stem cells (MSC) are promising tools for cancer therapy because they are able to home to and incorporate within tumour tissue. Tumour necrosis factor–related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic protein that induces selective apoptosis of tumour cells, while sparing normal cells. Therefore it is expected that MSCs engineered to produce TRAIL would home to and kill cancer cells in a lung metastatic cancer model. Two lentiviral vectors were constructed to express the full-length (FL) TRAIL and a truncated soluble form (ILZ-sT), respectively. A secretion peptide and an isoleucine zipper (ILZ) peptide were added to the N-terminal of the soluble form to force its secreted expression and to enhance its trimerization. Human MSCs were transduced with viruses and both constructs produced soluble TRAIL into cell media that can rapidly induced apoptosis of cancer cells. However the ILZ-sT fusion construct expresses significantly higher level of soluble TRAIL, and causes better in vitro lung cancer cell (A549) killing than the FL one.

In coculture experiments both construct viruses transduced MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death with similar efficiencies. A synergistic effect of cancer cell killing was observed for the combinational treatment of MSC-TRAIL cells with Saha, a histone deactylase inhibitor. When systemically delivered both MSC-FLT and MSC-ILZ-sT cells showed significant reduction of lung metastasis in a pulmonary metastasis murine model. Interestingly, ILZ-sT expressing cells demonstrated higher efficiency of metastasis reduction than FLT cells. These findings suggests that TRAIL expressing MSCs particularly ILZ-sT cells could be potentially developed as a therapy for lung metastasis diseases.

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