Background: Colorectal cancer(CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide in 2012. In the past 20 years, strong evidence suggests that cancer stem cells are the main c...Background: Colorectal cancer(CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide in 2012. In the past 20 years, strong evidence suggests that cancer stem cells are the main culprit of cancer metastasis,chemotherapy resistance, and relapse.Methods: To further understand the unique biological properties of cancer stem cells and uncover novel molecular targets to eradicate them, we first established a panel of patient-derived xenograft(PDX) tumor models using tumors surgically removed from human colorectal cancer patients. We then isolated CRC cancer stem cells based on their ALDH activity using fluorescent-activated cell sorting(FACS)and characterized their metabolic properties.Results: Interestingly, we found that the CRC cancer stem cells(ie, CRC cells with higher ALDH activity, or ALDH+) express higher level of antioxidant genes and have lower level of reactive oxygen species(ROS) than non-CRC cancer stem cells(ie, CRC cells with lower ALDH activity, or ALDHà). The CRC cancer stem cells also possess more mitochondria mass and show higher mitochondrial activity. More intriguingly,we observed higher AMP-activated protein kinase(AMPK) activities in these CRC cancer stem cells. Inhibition of the AMPK activity using 2 AMPK inhibitors, Compound C and Iodotubercidin, preferentially induces cell death in CRC cancer stem cells.Conclusion: We propose that AMPK inhibitors may help to eradicate the CRC cancer stem cells and prevent the relapse of CRCs.展开更多
文摘Background: Colorectal cancer(CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide in 2012. In the past 20 years, strong evidence suggests that cancer stem cells are the main culprit of cancer metastasis,chemotherapy resistance, and relapse.Methods: To further understand the unique biological properties of cancer stem cells and uncover novel molecular targets to eradicate them, we first established a panel of patient-derived xenograft(PDX) tumor models using tumors surgically removed from human colorectal cancer patients. We then isolated CRC cancer stem cells based on their ALDH activity using fluorescent-activated cell sorting(FACS)and characterized their metabolic properties.Results: Interestingly, we found that the CRC cancer stem cells(ie, CRC cells with higher ALDH activity, or ALDH+) express higher level of antioxidant genes and have lower level of reactive oxygen species(ROS) than non-CRC cancer stem cells(ie, CRC cells with lower ALDH activity, or ALDHà). The CRC cancer stem cells also possess more mitochondria mass and show higher mitochondrial activity. More intriguingly,we observed higher AMP-activated protein kinase(AMPK) activities in these CRC cancer stem cells. Inhibition of the AMPK activity using 2 AMPK inhibitors, Compound C and Iodotubercidin, preferentially induces cell death in CRC cancer stem cells.Conclusion: We propose that AMPK inhibitors may help to eradicate the CRC cancer stem cells and prevent the relapse of CRCs.
