Abstract
Heterogeneity of cancer stem/progenitor cells that give rise to different forms of cancer has been well demonstrated for leukemia. However, this fundamental concept has yet to be established for solid tumors including breast cancer. In this communication, we analyzed solid tumor cancer stem cell markers in human breast cancer cell lines and primary specimens using flow cytometry. The stem/progenitor cell properties of different marker expressing-cell populations were further assessed by in vitro soft agar colony formation assay and the ability to form tumors in NOD/SCID mice. We found that the expression of stem cell markers varied greatly among breast cancer cell lines. In MDA-MB-231 cells, PROCR and ESA, instead of the widely used breast cancer stem cell markers CD44+/CD24-/low and ALDH, could be used to highly enrich cancer stem/progenitor cell populations which exhibited the ability to self renew and divide asymmetrically. Furthermore, the PROCR+/ESA+ cells expressed epithelial-mesenchymal transition markers. PROCR could also be used to enrich cells with colony forming ability from MB-361 cells. Moreover, consistent with the marker profiling using cell lines, the expression of stem cell markers differed greatly among primary tumors. There was an association between metastasis status and a high prevalence of certain markers including CD44+/CD24−/low, ESA+, CD133+, CXCR4+ and PROCR+ in primary tumor cells. Taken together, these results suggest that similar to leukemia, several stem/progenitor cell-like subpopulations can exist in breast cancer.
Highlights
The recently emerged concept of cancer stem cells has led to new hypotheses about tumor progression
It has been reported that HER2 overexpression could drive tumorigenesis and aldehyde dehydrogenase (ALDH) expression [31], our cell line data did not support such a relationship
While ABCG2 was not expressed in all cell lines except a few MCF-7 cells, high level of CD133 was detected in almost all MDA-MB-468 cells, but not in other cell lines
Summary
The recently emerged concept of cancer stem cells has led to new hypotheses about tumor progression. A more recent study showed that aldehyde dehydrogenase (ALDH) was increased in a subpopulation of both normal and cancerous human mammary epithelial cells that exhibit stem/progenitor cell properties This subpopulation is tumorigenic, capable of self-renewal, and able to generate tumors that had the heterogeneity of the parental tumor [21]. Each of these markers has been studied individually, they have not been used together to determine the overall marker profile of individual tumors and the possible heterogeneous origins in tumors To address this fundamental question, we first performed cancer stem cell marker profile analysis using human breast cancer cell lines and specimens to further define and characterize different stem cell populations by flow cytometry, along with in vitro and in vivo assays to verify the stem cell properties of different cell isolates. These results suggest existence of multiple subpopulations of breast cancer stem cells, as in the case for leukemia
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