Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma.
Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma.
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DOI：
10.1158/0008-5472.can-08-3580
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Gibbs CP
中科院分区：
文献类型：
--
作者：
Levings PP;McGarry SV;Currie TP;Nickerson DM;McClellan S;Ghivizzani SC;Steindler DA;Gibbs CP
We explored the nature of the tumor-initiating cell in osteosarcoma, a bone malignancy that predominately occurs in children. Previously we observed expression of Oct-4, an embryonal transcriptional regulator, in osteosarcoma cell cultures and tissues. To examine the relationship between Oct-4 and tumorigenesis, cells from an osteosarcoma biopsy (OS521) were stably transfected with a plasmid containing the human Oct-4 promoter driving a GFP reporter, to generate the transgenic line OS521Oct-4p. In culture, only ∼24% of the OS521Oct-4p cells were capable of activating the transgenic Oct-4 promoter; yet, xenograft tumors generated in NOD/SCID mice contained approximately 67% GFP+ cells, which selectively expressed the MSC-associated surface antigens CD105 and ICAM-1. Comparison of the tumor-forming capacity of GFP-enriched and GFP-depleted cell fractions revealed that the GFP-enriched fractions were at least 100-fold more tumorigenic, capable of forming tumors at doses of less than 300 cells, and formed metastases in the lung. Clonal populations derived from a single Oct-4/GFP+ cell were capable of forming tumors heterogeneous for Oct-4/GFP expression. These data are consistent with the cancer stem cell model of tumorigenesis in osteosarcoma and implicate a functional link between the capacity to activate an exogenous Oct-4 promoter and tumor formation. This osteosarcoma tumor-initiating cell appears highly prolific and constitutes a majority of the cell population in a primary xenograft tumor, which may provide a biological basis for the particular virulence of this type of cancer.
