Abstract
Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype.
Highlights
Cancer stem cell (CSC) theory is the concept that cancer tissue contains a minor population of cells with stem cell properties [1]
The long-lived, low proliferative CSCs are resistant to cytotoxic conditions, whereas the actively proliferating cancer progenitor cells have an advantage of tumor propagation
Bonnet and Dick reported that CD44+/CD38− leukemia cells possessed CSC properties, i.e., self-renewal, potential for proliferation and differentiation, and tumor formation ability, in nude mice [3]
Summary
Another fraction of intestinal stem cells is located at the +4 position counting Paneth cell nuclei from the crypt bottom. Bmi1+ cells, as well as label-retaining cells, give rise to Lgr5+ cells and maintain intestinal crypts after artificial ablation of Lgr5-expressing cells [70]. This suggests that BMI1+ cells are a stem cell source held in reserve in case of critical damage of intestinal crypts. Downregulation of BMI1 inhibits tumor cell growth, which is associated with a reduced fraction of tumor-initiating cells [71] This suggests that the functional significance of BMI1 is maintenance of stem cell properties in colon cancer cells. Other quiescent stem cell markers such as homeodomain-only protein (HOPX) [76], doublecortin-like kinase 1 (DCLK1) [77], telomerase reverse transcriptase (TERT) [78], and leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) [79] are associated with colon tumorigenesis, but their detailed function and clinical significance remain unclear
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