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Validation of a hierarchical stem cell population in inflammatory breast cancer (IBC) by comparative genomic analysis
Author(s) -
Barsky Sanford H.,
Ye Yin,
Little Sean,
Sandy April,
Xiao Yi
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.470.5
Subject(s) - homeobox protein nanog , sox2 , stem cell , biology , cancer stem cell , population , stem cell marker , cancer research , microbiology and biotechnology , embryonic stem cell , induced pluripotent stem cell , genetics , medicine , gene , environmental health
The existence of stem cells in human solid tumors has been presumed based on clinical observations and biomarker and clonal dilution studies. Our previous studies with a human xenograft model (MARY‐X) of IBC, a model that forms spheroids in vitro that resemble a blastocyst, have demonstrated the presence of a prominent stem cell‐like population of cells. Comparing MARY‐X with non‐IBC breast carcinoma and normal lines, we found known embryonal stem cell markers (Stellar, H19, Rex‐1, Nestin, CD133) present. RT‐PCR analysis also revealed the expression of OCT4, SOX2, and Nanog, transcriptional determinants essential for the pluripotency and self‐renewal of human embryonal stem cells. However these findings do not prove that there is truly a hierarchical reserve stem cell population since both stem cell markers and functions could be reversibly derived from the proliferating population. We reasoned that true hierarchical stem cells should have fewer genomic alterations (gains and losses) than the proliferating population. To this end we conducted array CGH and identified 10 regions of amplification and 10 regions of loss. We then derived probes from each of these regions and conducted multicolor FISH on individual cells disadhered from the spheroids. Each of the probes recognized a specific chromosomal region in normal HMECs. All of the probes derived from amplified regions or deleted regions showed marked amplification (5–20 fold) or loss in >99% of the cells. However there was a distinct subpopulation of <1% of human cancer cells that contained markedly fewer genomic alterations (gains or losses). The existence of this distinct subpopulation suggests that a truly hierarchical stem cell population exists in IBC. This comparative genomic approach may be generally applicable to the identification and study of stem cells in many solid tumors.