title: Mesenchymal stem cells as carriers and amplifiers in CRAd delivery to tumors.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) have been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern, kinetic delivery of adenovirus, and therapeutic efficacy of the MSC loading of E1A mutant conditionally replicative adenovirus Adv-Stat3(-) which selectively replicated and expressed high levels of anti-sense Stat3 complementary DNA in breast cancer and melanoma cells.
  
  
  METHODS
  We assessed the release ability of conditionally replicative adenovirus (CRAd) from MSC using crystal violet staining, TCID(50) assay, and quantitative PCR. In vitro killing competence of MSCs carrying Adv-Stat3(-) toward breast cancer and melanoma was performed using co-culture system of transwell plates. We examined tumor tropism of MSC by Prussian blue staining and immunofluorescence. In vivo killing competence of MSCs carrying Adv-Stat3(-) toward breast tumor was analyzed by comparison of tumor volumes and survival periods.
  
  
  RESULTS
  Adv-Stat3(-) amplified in MSCs and were released 4 days after infection. MSCs carrying Adv-Stat3(-) caused viral amplification, depletion of Stat3 and its downstream proteins, and led to significant apoptosis in breast cancer and melanoma cell lines. In vivo experiments confirmed the preferential localization of MSCs in the tumor periphery 24 hours after tail vein injection, and this localization was mainly detected in the tumor parenchyma after 72 hours. Intravenous injection of MSCs carrying Adv-Stat3(-) suppressed the Stat3 pathway, down-regulated Ki67 expression, and recruited CD11b-positive cells in the local tumor, inhibiting tumor growth and increasing the survival of tumor-bearing mice.
  
  
  CONCLUSIONS
  These results indicate that MSCs migrate to the tumor site in a time-dependent manner and could be an effective platform for the targeted delivery of CRAd and the amplification of tumor killing effects.
authors: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors: Xi
authors: X
authors: Xia
authors: Teng
authors: T
authors: Ji
authors: Pingbo
authors: P
authors: Chen
authors: Xiao
authors: X
authors: Li
authors: Yong
authors: Y
authors: Fang
authors: Qinglei
authors: Q
authors: Gao
authors: Shujie
authors: S
authors: Liao
authors: Lanying
authors: L
authors: You
authors: Hongbin
authors: H
authors: Xu
authors: Quanfu
authors: Q
authors: Ma
authors: Peng
authors: P
authors: Wu
authors: Wencheng
authors: W
authors: Hu
authors: Mingfu
authors: M
authors: Wu
authors: Li
authors: L
authors: Cao
authors: Kezhen
authors: K
authors: Li
authors: Yanjie
authors: Y
authors: Weng
authors: Zhiqiang
authors: Z
authors: Han
authors: Junchen
authors: J
authors: Wei
authors: Ronghua
authors: R
authors: Liu
authors: Shixuan
authors: S
authors: Wang
authors: Gang
authors: G
authors: Xu
authors: Daowen
authors: D
authors: Wang
authors: Jianfeng
authors: J
authors: Zhou
authors: Ding
authors: D
authors: Ma
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000473:pathology* / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000473:pathology / Q000628:therapy; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D019394:Ki-67 Antigen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human