title: Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging.
abstract: The aim of this study was to assess the efficacy human mesenchymal stem cells (hMSC) for targeting microscopic tumors and suicide gene or cytokine gene therapy. Immunodeficient mice were transplanted s.c. with human colon cancer cells of HT-29 Inv2 or CCS line, and 3 to 4 days later, i.v. with "tracer" hMSCs expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) and enhanced green fluorescent protein (EGFP) reporter genes. Subsequently, these tumors were examined for specificity and magnitude of HSV1-TK(+), EGFP(+) stem cell engraftment and proliferation in tumor stroma by in vivo positron emission tomography (PET) with (18)F-labeled 9-(4-fluoro-3-hydroxymethylbutyl)-guanine ([(18)F]-FHBG). In vivo PET images of tumors growing for 4 weeks showed the presence of HSV1-TK(+) tumor stroma with an average of 0.36 +/- 0.24% ID/g [(18)F]-FHBG accumulation. In vivo imaging results were validated by in situ correlative histochemical, immunofluorescent, and cytometric analyses, which revealed EGFP expression in vWF(+) and CD31(+) endothelial cells of capillaries and larger blood vessels, in germinal layer of dermis and hair follicles proximal to the s.c. tumor site. These differentiated HSV1-TK(+), GFP(+) endothelial cells had limited proliferative capacity and a short life span of <2 weeks in tumor fragments transplanted into secondary hosts. We conclude that hMSCs can target microscopic tumors, subsequently proliferate and differentiate, and contribute to formation of a significant portion of tumor stroma. PET imaging should facilitate clinical translation of stem cell-based anticancer gene therapeutic approaches by providing the means for in vivo noninvasive whole-body monitoring of trafficking, tumor targeting, and proliferation of HSV1-tk-expressing "tracer" hMSCs in tumor stroma.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Nankang, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
authors.forename: Win-Ping
authors.initials: WP
authors.lastname: Deng
authors.forename: Wen K
authors.initials: WK
authors.lastname: Yang
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Lee
authors.forename: Tzu-Chi
authors.initials: TC
authors.lastname: Su
authors.forename: Rue-Jen
authors.initials: RJ
authors.lastname: Lin
authors.forename: Den-Mei
authors.initials: DM
authors.lastname: Yang
authors.forename: Chi-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Chen
authors.forename: Hon-Jian
authors.initials: HJ
authors.lastname: Wei
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D049268:Positron-Emission Tomography / Q000379:methods*; D014176:Protein Biosynthesis; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors
chemical_list: D016207:Cytokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D049452:Green Fluorescent Proteins