Human Mesenchymal Stem Cells Lack Tumor Tropism but Enhance the Antitumor Activity of Oncolytic Adenoviruses in Orthotopic Lung and Breast Tumors
- 1 July 2007
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 18 (7), 627-641
- https://doi.org/10.1089/hum.2007.034
Abstract
Systemic adenoviral delivery into tumors is inefficient because of liver sequestration of intravenously administered virus. One potential solution for improving bioavailability is the use of carrier cells such as human mesenchymal stem cells (MSCs), which have been suggested to have inherent tumor tropism. Here we investigated the capacity of capsid-modified adenoviruses to infect and replicate in MSCs. Further, biodistribution and tumor-killing efficacy of MSCs loaded with oncolytic adenoviruses were evaluated in orthotopic murine models of lung and breast cancer. In vitro, heparan sulfate proteoglycan- and αvβ integrin-targeted viruses enhanced gene delivery to bone marrow- and adipose tissue-derived MSCs up to 11,000-fold over adenovirus serotype 5 (Ad5). Infectivity-enhanced oncolytic adenoviruses showed notably higher rates of cytolysis of in vitro-passaged MSCs in comparison with wild-type virus. In vivo, intravenously injected MSCs homed primarily to the lungs, and virus was released into advanced orthotopic breast and lung tumors for therapeutic efficacy and increased survival. When the same dose of virus was injected intravenously without MSCs, only transduction of the liver was seen. These results suggest that MSCs loaded with oncolytic adenoviruses might be a useful approach for improving the bioavailability of systemically administered oncolytic adenoviruses.Keywords
This publication has 52 references indexed in Scilit:
- A New Group B Adenovirus Receptor Is Expressed at High Levels on Human Stem and Tumor CellsJournal of Virology, 2006
- Gene Transfer Approaches for Gynecological DiseasesMolecular Therapy, 2006
- A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Δ24, for the treatment of advanced breast cancerGene Therapy, 2006
- Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, or Adipose TissueThe International Journal of Cell Cloning, 2006
- Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarctionNature Medicine, 2006
- Fiber-modified adenovirus vectors mediate efficient gene transfer into undifferentiated and adipogenic-differentiated human mesenchymal stem cellsBiochemical and Biophysical Research Communications, 2005
- Adenovirus Binding to Blood Factors Results in Liver Cell Infection and HepatotoxicityJournal of Virology, 2005
- Approaches to Utilize Mesenchymal Progenitor Cells as Cellular VehiclesThe International Journal of Cell Cloning, 2003
- Cancer Cell CyclesScience, 1996
- Tumors: Wounds That Do Not HealNew England Journal of Medicine, 1986