Radiation increases invasion of gene-modified mesenchymal stem cells into tumors.
OBJECTIVE
Mesenchymal stem cells (MSCs) are multipotent cells in the bone marrow that have been found to migrate to tumors, suggesting a potential use for cancer gene therapy. MSCs migrate to sites of tissue damage, including normal tissues damaged by radiation. In this study, we investigated the effect of tumor radiotherapy on the localization of lentivirus-transduced MSCs to tumors.


METHODS
MSCs were labeled with a lipophilic dye to investigate their migration to colon cancer xenografts. Subsequently, the MSCs were transduced with a lentiviral vector to model gene therapy and mark the infused MSCs. LoVo tumor xenografts were treated with increasing radiation doses to assess the effect on MSC localization, which was measured by quantitative polymerase chain reaction. MSC invasion efficiency was determined in an invasion assay.


RESULTS
MSCs migrated to tumor xenografts of various origins, with few cells found in normal tissues. A lentiviral vector efficiently transduced MSCs in the presence, but not the absence, of hexadimethrine bromide (Polybrene). When LoVo tumors were treated with increasing radiation doses, more MSCs were found to migrate to them than to untreated tumors. Irradiation increased MSC localization in HT-29 and MDA-MB-231, but not UMSCC1, xenografts. Monocyte chemotactic protein-1 expression in tumors did not correlate with the basal levels of MSC infiltration; however, monocyte chemotactic protein-1 was modestly elevated in irradiated tumors. Media from irradiated LoVo cells stimulated MSC invasion into basement membranes.


CONCLUSIONS
These findings suggest that radiation-induced injury can be used to target MSCs to tumors, which might increase the effectiveness of MSC cancer gene therapy. The production of tumor-derived factors in response to radiation stimulates MSC invasion.
Zielske
Steven P
SP
Department of Radiation Oncology, University of Michigan, 1331 E. Ann St., Ann Arbor, MI 48109, USA. szielske@med.umich.edu
Livant
Donna L
DL
Lawrence
Theodore S
TS
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy; D003131:Combined Modality Therapy / Q000379:methods; D003470:Culture Media / Q000494:pharmacology; D005260:Female; D005456:Fluorescent Dyes; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use; D019073:HT29 Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy; D006583:Hexadimethrine Bromide / Q000494:pharmacology; D006801:Humans; D007211:Indoles; D016086:Lentivirus / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy*; D009928:Organ Specificity; D014161:Transduction, Genetic / Q000379:methods; D014183:Transplantation, Heterologous
D018932:Chemokine CCL2; D003470:Culture Media; D005456:Fluorescent Dyes; D007211:Indoles; C007293:DAPI; D006583:Hexadimethrine Bromide