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Growth inhibition of colorectal carcinoma by lentiviral TRAIL-transgenic human mesenchymal stem cells requires their substantial intratumoral presence.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2010 Sep; Vol. 14 (9), pp. 2292-304. - Publication Year :
- 2010
-
Abstract
- 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.<br /> (© 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Subjects :
- Animals
Apoptosis
Cell Line, Tumor
Cell Membrane metabolism
Cell Proliferation
Cell Transformation, Neoplastic pathology
Drug Resistance, Neoplasm
Humans
Mesenchymal Stem Cell Transplantation
Mice
Mice, Nude
Solubility
Transduction, Genetic
Xenograft Model Antitumor Assays
Colorectal Neoplasms metabolism
Colorectal Neoplasms pathology
Lentivirus genetics
Mesenchymal Stem Cells metabolism
TNF-Related Apoptosis-Inducing Ligand genetics
TNF-Related Apoptosis-Inducing Ligand therapeutic use
Transgenes genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 14
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 19508388
- Full Text :
- https://doi.org/10.1111/j.1582-4934.2009.00794.x