Open AccessTRAIL-transduced multipotent mesenchymal stromal cells (TRAIL-MSC) overcome TRAIL resistance in selected CRC cell lines in vitro and in vivo
Author(s) -
Lutz Peter Mueller,
Jana Luetzkendorf,
Miriam Widder,
Katrin Nerger,
Henrike Caysa,
Thomas Mueller
Publication year - 2010
Publication title -
cancer gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.535
H-Index - 86
eISSN - 1476-5500
pISSN - 0929-1903
DOI - 10.1038/cgt.2010.68
Subject(s) - mesenchymal stem cell , stromal cell , cancer research , in vivo , apoptosis , tumor necrosis factor alpha , cell culture , biology , immunology , microbiology and biotechnology , genetics
Tumor-integrating multipotent mesenchymal stromal cells (MSC) expressing transgenes with anti-tumor activity may serve as vehicles for tumor therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents such a factor; however, TRAIL-resistant tumor cells exist. Based on our previous work, here we investigated whether MSC with lentiviral TRAIL expression (TRAIL-MSC) inhibit the growth of TRAIL-resistant colorectal carcinoma (CRC) cells. Our data show that TRAIL-MSC induce apoptosis in selected TRAIL-resistant CRC cell lines and effectively inhibit the growth of TRAIL-resistant HCT8 cells. This sensitization to TRAIL-induced apoptosis required the presence of MSC-expressed TRAIL. However, for the first time we show that selected CRC cells are resistant to TRAIL-MSC. In the cell line HT29, this resistance could be overcome by concomitant subapoptotic genotoxic damage in vitro. However, such sensitization was not achieved in vivo as treatment of mixed HT29/TRAIL-MSC xenografts with 5-FU rather resulted in enhanced growth. Taken together, our data prove that TRAIL-MSC overcome TRAIL resistance in selected CRC cells through direct intercellular interaction and may, therefore, represent a clinical tool to overcome TRAIL resistance. However, such potential clinical use requires further preclinical studies as our data also prove that TRAIL-MSC-resistant CRC cells exist. Our data add to the notion that TRAIL resistance of CRC cells is conferred by different mechanisms.