Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma

Padraic P. Levings, Sean V. McGarry, Thomas P. Currie, David M. Nickerson, Steven McClellan, Steven C. Ghivizzani, Dennis A. Steindler, C. Parker Gibbs

Research output: Contribution to journalArticle

129 Scopus citations

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 ∼24% of the OS521Oct-4p cells were capable of activating the transgenic Oct-4 promoter; yet, xenograft tumors generated in NOD/SCID mice contained ∼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.

Original languageEnglish (US)
Pages (from-to)5648-5655
Number of pages8
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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