Targeting eradication of malignant cells derived from human bone marrow mesenchymal stromal cells.
Human bone marrow mesenchymal stromal cells (hBMSC) have been shown to participate in malignant transformation. However, hampered by the low frequency of malignant transformation of hBMSC, we do not yet know how to prevent malignant transformation of implanted hBMSC. In this study, in order to establish a model for the eradication of hBMSC-derived malignant cells, a gene fusion consisting of a human telomerase (hTERT) promoter modified with both c-Myc and myeloid zinc finger protein2 (MZF-2) binding elements and followed by the E. coli cytosine deaminase (CD) and luciferase genes was stably transferred into hBMSC via lentiviral transduction; n-phosphonacelyl-L-aspartic acid (PALA) selection was used to generate malignant cell colonies derived from transduced hBMSC after treatment with the carcinogenic reagent BPDE. Cells that were amplified after PALA selection were used for transplantation and 5-FC pro-drug cytotoxicity tests. The results showed that PALA-resistant malignant cells could be generated from hBMSC co-induced with lentiviral transduction and treatment with Benzo(a)pyrene Diol Epoxide (BPDE); the modification of c-Myc and MZF-2 binding elements could remarkably enhance the transcriptional activities of the hTERT promoter in malignant cells, whereas transcriptional activity was depressed in normal hBMSC; malignant cells stably expressing CD under the control of the modified hTERT promoter could be eliminated by 5-FC administration. This study has provided a method for targeted eradication of malignant cells derived from hBMSC.
Yang
Yingbin
Y
Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
Cai
Shaoxi
S
Yang
Li
L
Yu
Shuhui
S
Jiang
Jiahuan
J
Yan
Xiaoqing
X
Zhang
Haoxing
H
Liu
Lan
L
Liu
Qun
Q
Du
Jun
J
Cai
Shaohui
S
Sung
K L Paul
KL
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology* / Q000627:therapeutic use; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism; D043525:Cytosine Deaminase / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics; D005437:Flucytosine / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology*; D019098:Telomerase / Q000235:genetics; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D015703:Antigens, CD; D000963:Antimetabolites; D029968:Escherichia coli Proteins; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001224:Aspartic Acid; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C013195:sparfosic acid; D005437:Flucytosine; D008156:Luciferases; C509186:TERT protein, human; D019098:Telomerase; D043525:Cytosine Deaminase; C468827:codA protein, E coli; D010746:Phosphonoacetic Acid