title: Malignant transformation of rat bone marrow-derived mesenchymal stem cells treated with 4-nitroquinoline 1-oxide.
abstract: Recent studies indicated that extensive culture of bone marrow-derived mesenchymal stem cells (BMSCs) can lead to malignant transformation, supporting the concept that tumor may originate from adult stem cells. Also, neoplastic transformation of BMSCs induced by virus and ionizing radiation were verified. However, the capacity for BMSCs to become mutated by chemical carcinogens and become precursors of cancer is still poorly understood. In this study, BMSCs were used to test the hypothesis that tumorigenesis can originate from the mutation of stem cells induced by chemical carcinogen. BMSCs were intermittently treated with 10(-6)M 4-nitroquinoline 1-oxide (4-NQO) from population doublings level (PDL) 3 until senescence occurred. Proliferation data demonstrated that BMSCs treated with 4-NQO bypassed the senescence phase and exhibited unlimited proliferation and anchorage independence. These cells underwent a malignant transformation that resulted in tumor formation in 12/12 immunodeficient mice that received the cells by tail vein injection. In contrast, spontaneous transformation of BMSCs was observed in 6/12 immunodeficient mice injected with BMSCs that had been cultured over PDL 30 in vitro. For both BMSCs treated with 4-NQO, and BMSCs maintained in long-term culture, their transformation into neoplastic cells was found to involve chromosomal abnormalities, increased telomerase activity, and reduced, or absent, expression of p53. Our results also indicate that BMSCs are susceptible to carcinogen-induced malignant transformation rather than spontaneous transformation. Therefore, carcinogen-induced BMSCs transformation models may be ideal for studying mechanisms associated with the promotion of tumor formation by chemical carcinogens.
authors.affiliation: Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Education Department of Heilongjiang Province, 157 Bao Jian Road, Harbin 150081, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Han
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Kong
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Guangyou
authors.initials: G
authors.lastname: Wang
authors.forename: Lili
authors.initials: L
authors.lastname: Mu
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.forename: Yumei
authors.initials: Y
authors.lastname: Liu
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D007621:Karyotyping; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019098:Telomerase / Q000378:metabolism
chemical_list: C120195:4-nitroquinolone-1-oxide; D015363:Quinolones; D015112:4-Nitroquinoline-1-oxide; D019098:Telomerase