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G. M. Seigel, A. S. Hackam, F. Gonzalez-Fernandez; Cancer Stem Cell Markers in Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3986.
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© ARVO (1962-2015); The Authors (2016-present)
Cancer stem cells represent a new challenge in cancer therapeutics. Although cancer stem cells comprise less than 1% of a tumor, their involvement in metastases and their resistance to chemotherapy make them especially important to identify and characterize. In this study, we examined the expression of stem cell markers in retinoblastoma tumors and cell lines to identify potential cancer stem cells and new targets for RB therapeutics.
All human studies were conducted as per our IRB-approved protocol and the Declaration of Helsinki. Retinoblastoma tumors from human patients were examined, as well as the human retinoblastoma cell lines--Y79 and WERI-RB27. We examined cells and tissues by immunohistochemistry and RT-PCR, while microarray analyses were performed on Y79 cells by Ocean Ridge Biosciences (Jupiter, FL) using 70-mer oligo arrays. Y79 and WERI-RB27 cell lines underwent studies of BrdU incorporation and neurosphere formation to assess their potential for the stem cell properties of slow cell cycling and self-renewal, respectively.
Microarray analyses (n=6) of Y79 human retinoblastoma cells revealed expression of the following stem cell markers: musashi-1 and 2, prominin1 (CD 133), sialomucin (CD164), PAX6, nestin, neuroD1, jagged1 and 2, noggin, smoothened, frizzled2, numb, patched, NCAM-1, Notch4, reelin, paxillin, VISX1, leukemia inhibitory factor, HESX1, MCM2, NET1, as well as a number of homeobox (HOX) genes. Musashi-1 expression in RB was further confirmed by RT-PCR and immunohistochemical analysis of human RB tumors. Both the Y79 and WERI-RB27 cell lines were able to generate neurospheres at low cell density that could be maintained over a number of passages, a hallmark of stem cell self-renewal. Additionally, the cell lines contained a subpopulation of slowly-cycling cells, as evidenced by BrdU incorporation, another characteristic of stem cells.
These findings are consistent with the hypothesis that RB is a heterogeneous tumor comprised of subpopulations with stem cell-like properties. By identifying a variety of cancer stem cell markers in retinoblastoma, we provide further evidence for a cancer stem cell component in RB, as well as potential avenues for targeted therapies.
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