Expression of an Exogenous Human Oct-4 Promoter Identifies Tumor-Initiating Cells in Osteosarcoma

    Authors

    P. P. Levings; S. V. McGarry; T. P. Currie; D. M. Nickerson; S. McClellan; S. C. Ghivizzani; D. A. Steindler;C. P. Gibbs

    Abbreviated Journal Title

    Cancer Res.

    Keywords

    CANCER STEM-CELLS; PRIMARY BIOASSAY; BREAST-CANCER; SOMATIC-CELLS; HYBRID-CELLS; IN-VITRO; PLURIPOTENCY; BIOLOGY; CLONES; CYCLE; Oncology

    Abstract

    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 green fluorescent protein (GFP) reporter to generate the transgenic line OS521Oct-4p. In culture, only similar to 24% of the OS521Oct-4p cells were capable of activating the transgenic Oct-4 promoter; yet, xenograft tumors generated in NOD/SCID mice contained similar to 67% GFP(+) cells, which selectively expressed the mesenchymal stem cell-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 <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. [Cancer Res 2009;69(14):5648-55]

    Journal Title

    Cancer Research

    Volume

    69

    Issue/Number

    14

    Publication Date

    1-1-2009

    Document Type

    Article

    Language

    English

    First Page

    5648

    Last Page

    5655

    WOS Identifier

    WOS:000268360300008

    ISSN

    0008-5472

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