Abstract
Cancer stem cells (CSCs) have been identified in a multiple of cancer types and resistant to traditional cancer therapies such as chemotherapeutic agents and radiotherapy, which may destroy bulk tumor cells but not all CSCs, contributing to reformation tumor masses and subsequent relapse. Moreover, it is very difficult to effectively identify and eliminate CSCs because they share some common phenotypic and functional characteristics of normal stem cells. Therefore, finding better therapeutic strategies to selectively target CSCs might be helpful to reduce subsequent malignancies. In the present study, we found that caffeic acid effectively suppresses self-renewal capacity, stem-like characteristics, and migratory capacity of CD44+ and CD133+ colorectal CSCs in vitro and in vivo. In addition, we also revealed that PI3K/Akt signaling may be linked to multiple colorectal CSC-associated characteristics, such as radio-resistance, stem-like property, and tumorigenic potential. To the best of our knowledge, this is the first study demonstrating that caffeic acid effectively targets colorectal CSC populations by inhibiting the growth and/or self-renewal capacity of colorectal CSCs through PI3K/Akt signaling in vitro and in vivo.
Highlights
The incidence and mortality rates for colorectal cancer remain considerably high in the western world and the United States (Siegel et al, 2013)
We further analyzed the expression levels of multiple pluripotency-related related genes in these putative Cancer stem cells (CSCs)-marker positive cells; CD44− CD133− and CD44+ CD133+ cells were sorted by dual-color flow cytometry
Consistent with the Akt signaling activation results, the inhibitory effects of caffeic acid on colorectal CSC-sphere formation (Figure 5F) and the percentage of the total cell population that consisted of CD44+ and CD133+ cells (Figure 5G) were synergized by Akt signaling inhibition. These results suggested that the inhibitory effects of caffeic acid on the self-renewal and stem-like properties of colorectal CSCs may be achieved by disrupting the PI3K/Akt signaling axis
Summary
The incidence and mortality rates for colorectal cancer remain considerably high in the western world and the United States (Siegel et al, 2013). Selectively targeting and eliminating CSCs will improve outcomes for patients undergoing colorectal cancer treatments. A drawback is that currently available knowledge about colorectal CSCs is largely influenced by the biological features of normal stem cells. Targeting these common biological characteristics to eliminate colorectal CSCs may reduce normal stem cells and subsequently prevent normal gut regeneration. In this context, special attention has been recently devoted to selectively targeting colorectal CSCs without affecting normal stem or non-stem cells
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