title: Selective targeting of genetically engineered mesenchymal stem cells to tumor stroma microenvironments using tissue-specific suicide gene expression suppresses growth of hepatocellular carcinoma.
abstract: BACKGROUND
  The use of engineered mesenchymal stem cells (MSCs) as therapeutic vehicles for the treatment of experimental pancreatic and breast cancer has been previously demonstrated. The potential application of MSCs for the treatment of hepatocellular carcinoma (HCC) has been controversial. The general approach uses engineered MSCs to target different aspects of tumor biology, including angiogenesis or the fibroblast-like stromal compartment, through the use of tissue-specific expression of therapeutic transgenes. The aim of the present study was (1) to evaluate the effect of exogenously added MSCs on the growth of HCC and (2) the establishment of an MSC-based suicide gene therapy for experimental HCC.
  
  
  METHODS
  Mesenchymal stem cells were isolated from bone marrow of C57/Bl6 p53(-/-) mice. The cells were injected into mice with HCC xenografts and the effect on tumor proliferation and angiogenesis was evaluated. The cells were then stably transfected with red fluorescent protein (RFP) or Herpes simplex virus thymidine kinase (HSV-Tk) gene under control of the Tie2 promoter/enhancer or the CCL5 promoter. Mesenchymal stem cells were injected intravenously into mice with orthotopically growing xenografts of HCC and treated with ganciclovir (GCV).
  
  
  RESULTS
  Ex vivo examination of hepatic tumors revealed tumor-specific recruitment, enhanced tumor growth, and increased microvessel density after nontherapeutic MSC injections. After their homing to the hepatic xenografts, engineered MSCs demonstrated activation of the Tie2 or CCL5 promoter as shown by RFP expression. Application of CCL5/HSV-TK transfected MSCs in combination with GCV significantly reduced tumor growth by 56.4% as compared with the control group and by 71.6% as compared with nontherapeutic MSC injections. CCL5/HSV-TK(+) transfected MSCs proved more potent in tumor inhibition as compared with Tie2/HSV-TK(+) MSCs.
  
  
  CONCLUSIONS
  Exogenously added MSCs are recruited to growing HCC xenografts with concomitant activation of the CCL5 or Tie2 promoters within the MSCs. Stem cell-mediated introduction of suicide genes into the tumor followed by prodrug administration was effective for treatment of experimental HCC and thus may help fill the existing gap in bridging therapies for patients suffering from advanced HCCs.
authors: Department of Surgery, University of Munich, Campus Großhadern, Munich, Germany.
authors: Hanno
authors: H
authors: Niess
authors: Qi
authors: Q
authors: Bao
authors: Claudius
authors: C
authors: Conrad
authors: Christoph
authors: C
authors: Zischek
authors: Mike
authors: M
authors: Notohamiprodjo
authors: Felix
authors: F
authors: Schwab
authors: Bettina
authors: B
authors: Schwarz
authors: Ralf
authors: R
authors: Huss
authors: Karl-Walter
authors: KW
authors: Jauch
authors: Peter J
authors: PJ
authors: Nelson
authors: Christiane J
authors: CJ
authors: Bruns
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D002454:Cell Differentiation; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2; D014162:Transfection; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D000998:Antiviral Agents; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D015774:Ganciclovir