Abstract
Targeting cancer stem cells (CSCs) without damaging normal stem cells could contribute to the development of novel radical cancer therapies. Cells expressing leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) constitute a cancer-causing population in the colon; therefore, targeting of Lgr5+ cells is expected to provide an opportunity to mitigate colon cancer. However, the expression of Lgr5 in normal stem cells makes it difficult to prove the efficacy of therapies targeted exclusively at Lgr5+ cancer cells. We used a modified photodynamic therapy technique involving cellular radiative transfer between green fluorescent protein (GFP)-expressing cells and a rose bengal photosensitizer. After treatment, tumors containing GFP-Lgr5+ cells were observed to be significantly suppressed or retarded with little effect on GFP-Lgr5+ stem cells at the crypt bottom. Lgr5+ CSCs were specifically eradicated in situ, when localized based on the depth from the colon lumen, revealing the potential preventive efficacy of Lgr5-targeted therapy on tumor growth. This study supports the idea that Lgr5+ cells localized near the colon luminal surface are central to colorectal cancer. With further development, the targeting of localized Lgr5+ cancer stem cells, which this study demonstrates in concept, may be feasible for prevention of colon cancer in high-risk populations.
Highlights
Cancer stem cells (CSCs) are a malignant population of cancer cells with stem-cell-like properties that help develop and maintain cancer [1]
In mice treated with AOM/dextran sulfate sodium (DSS), the leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)+ cells were observed to migrate observed to migrate to the luminal surface after AOM treatment followed by DSS administration to the luminal surface after AOM treatment followed by DSS administration (Figure 1B), and these (Figure 1B), and these were considered to be colon cancer stem cells
Many Lgr5+ cells were observed inside the observed inside the colonic adenoma using fluorescence microscopy
Summary
Cancer stem cells (CSCs) are a malignant population of cancer cells with stem-cell-like properties that help develop and maintain cancer [1]. Lgr5+ cells are an attractive treatment target in terms of drug development, since the structure of Lgr was fully determined and Lgr is localized on the cellular surface This was recently demonstrated via antibody–drug conjugates targeting Lgr5+ cells, which resulted in a reduction in tumor size, extended patient survival, and prevention of cancer recurrence [16,17]. Since Lgr is expressed in CSCs, as well as normal stem cells, non-selective therapies targeting Lgr may lead to significant damage of noncancerous (normal) colon stem cells and destruction of normal colon homeostasis.
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