Growth inhibition of colorectal carcinoma by lentiviral TRAIL-transgenic human mesenchymal stem cells requires their substantial intratumoral presence
| Autor: | Katrin Nerger, Jana Luetzkendorf, Lutz P. Mueller, Henrike Caysa, Hans-Joachim Schmoll, Thomas Mueller |
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| Rok vydání: | 2009 |
| Předmět: |
Genetic enhancement
Mice Nude TRAIL Apoptosis Biology Mesenchymal Stem Cell Transplantation Malignant transformation Viral vector MSC resistance TNF-Related Apoptosis-Inducing Ligand Mice chemistry.chemical_compound colorectal carcinoma Transduction Genetic Cell Line Tumor medicine Animals Humans Neoplasm Transgenes Cell Proliferation lentiviral Cell growth Cell Membrane Lentivirus Mesenchymal stem cell Mesenchymal Stem Cells Articles Cell Biology medicine.disease gene therapy Xenograft Model Antitumor Assays Cell Transformation Neoplastic Solubility chemistry Drug Resistance Neoplasm Immunology Cancer research Molecular Medicine Growth inhibition Colorectal Neoplasms |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-1838 |
| DOI: | 10.1111/j.1582-4934.2009.00794.x |
| Popis: | Colorectal carcinoma (CRC) constitutes a common malignancy with limited therapeutic options in metastasized stages. Mesenchymal stem cells (MSC) home to tumours and may therefore serve as a novel therapeutic tool for intratumoral delivery of antineoplastic factors. Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) which promises apoptosis induction preferentially in tumour cells represents such a factor. We generated TRAIL-MSC by transduction of human MSC with a third generation lentiviral vector system and analysed their characteristics and capacity to inhibit CRC growth. (1) TRAIL-MSC showed stable transgene expression with neither changes in the defining MSC characteristics nor signs of malignant transformation. (2) Upon direct in vitro coculture TRAIL-MSC induced apoptosis in TRAIL-sensitive CRC-cell lines (DLD-1 and HCT-15) but also in CRC-cell lines resistant to soluble TRAIL (HCT-8 and SW480). (3) In mixed subcutaneous (s.c.) xenografts TRAIL-MSC inhibited CRC-tumour growth presumably by apoptosis induction but a substantial proportion of TRAIL-MSC within the total tumour cell number was needed to yield such anti-tumour effect. (4) Systemic application of TRAIL-MSC had no effect on the growth of s.c. DLD-1 xenografts which appeared to be due to a pulmonary entrapment and low rate of tumour integration of TRAIL-MSC. Systemic TRAIL-MSC caused no toxicity in this model. (5) Wild-type MSC seemed to exert a tumour growth-supporting effect in mixed s.c. DLD-1 xenografts. These novel results support the idea that lentiviral TRAIL-transgenic human MSC may serve as vehicles for clinical tumour therapy but also highlight the need for further investigations to improve tumour integration of transgenic MSC and to clarify a potential tumour-supporting effect by MSC. |
| Databáze: | OpenAIRE |
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