Targeting tumor stroma using engineered mesenchymal stem cells reduces the growth of pancreatic carcinoma.
OBJECTIVE
To analyze the efficacy of engineered mesenchymal stem cell based therapy directed towards pancreatic tumor stroma.


BACKGROUND
Mesenchymal stem cells (MSC) are actively recruited to tumor stroma where they enhance tumor growth and metastases. Upregulation of chemotactic cytokine (CCL5) by MSCs within the tumor stroma has been shown to play a central role in this process. Murine MSCs were engineered to express reporter genes or therapeutic genes under control of the CCL5 promoter and adoptively transferred into mice with growing pancreatic tumors. The effect on tumor growth and metastases was then evaluated.


METHODS
MSCs isolated from bone marrow of C57/Bl6 p53 mice were stably transfected with red fluorescent protein (RFP), enhanced green fluorescent protein (eGFP), or herpes simplex virus (HSV) thymidine kinase (Tk) gene driven by the RANTES promoter. MSCs were intravenously applied once per week over 3 weeks to mice carrying an orthotopic, syngeneic pancreatic Panc02 tumor.


RESULTS
eGFP and RFP signals driven by the CCL5 promoter were detected by fluorescence in treated pancreatic tumor samples. The HSV-Tk therapy group treated intraperitoneal with the prodrug ganciclovir 5 to 7 days after stem cell application lead to a 50% reduction of primary pancreatic tumor growth (P < 0.0003, student t test) and reduced liver metastases (0% vs. 60%).


CONCLUSIONS
The active homing of MSCs into primary pancreatic tumor stroma and activation of the CCL5 promoter was verified using eGFP- and RFP-reporter genes. In the presence of ganciclovir, HSV-Tk transfected MSCs led to a significant reduction of primary pancreatic tumor growth and incidence of metastases.
Zischek
Christoph
C
Clinical Biochemistry Group, Medical Policlinic, University of Munich, Munich, Germany.
Niess
Hanno
H
Ischenko
Ivan
I
Conrad
Claudius
C
Huss
Ralf
R
Jauch
Karl-Walter
KW
Nelson
Peter J
PJ
Bruns
Christiane
C
D000818:Animals; D002465:Cell Movement; D018946:Chemokine CCL5 / Q000235:genetics; D017930:Genes, Reporter; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D007274:Injections, Intraperitoneal; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D023822:Tissue Engineering
D018946:Chemokine CCL5; D013937:Thymidine Kinase