Abstract
Therapies designed to target cancer stem cells (CSCs) in colorectal cancer (CRC) may improve treatment outcomes. Different markers have been used to identify CSCs or CSC-like cells in CRC, but the enrichment of CSCs using these markers has yet to be optimized. We recently reported the importance of Lgr5-positive CRC cells in cancer growth. Here, we studied the possibility of using Lgr5 and CXCR4 as CSC markers for CRC. We detected high Lgr5 and CXCR4 levels in stage IV CRC specimens. Both high Lgr5 and CXCR4 levels were associated with poor prognosis in stage IV CRC patients. In vitro, Lgr5+CXCR4-, CXCR4+Lgr5- and Lgr5+CXCR4+ cells were purified in human CRC cell lines and examined for their CSC properties. We found that compared to the unsorted cells, CXCR4+Lgr5-, Lgr5+CXCR4-, and Lgr5+/CXCR4+ cells showed significantly greater cancer mass after subcutaneous transplantation, greater tumor sphere formation, higher resistance to chemotherapy, and higher incidence of tumor formation after serial adoptive transplantation into NOD/SCID mice. Taken together, our data suggest that the combined use of Lgr5 and CXCR4 may facilitate the enrichment of CSCs in CRC, and that treating Lgr5+/CXCR4+ CRC cells may improve the outcome of CRC therapy.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide [1,2,3], but the mechanisms regulating tumorigenesis have yet to be elucidated
Lgr5 has been shown to be expressed in CRC cells and has been used as a cancer stem cells (CSCs) marker [27,28,29,30,31]
We found that CRC tissue expressed high levels of Lgr5 (Figure 1A) and CXCR4 (Figure 1B), by immunohistochemistry
Summary
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide [1,2,3], but the mechanisms regulating tumorigenesis have yet to be elucidated. The recent discovery of cancer stem cells (CSCs) has important implications for the development of novel therapies for CRC [4]. CSCs have characteristics of stem cells, are tumorigenic, and are responsible for cancer relapse and metastasis [5,6,7,8]. Cell surface markers are generally used for isolation of CSCs by flow cytometry, none of these CSC-markers has been found to be 100% specific. These CSC-markers just enrich CSCs from a certain tumor, rather than purify CSCs. most characterized “CSCs” are CSClike cells [9,10,11,12,13]. The gold standard for identifying CSCs or CSC-like cells is tumor sphere formation and tumor formation in serial adoptive transplantation
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