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Cancer Stem Cell Study Uncovers Potential Means to Improve Disease Treatment

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Review of “Colorectal Cancer Stem Cells Acquire Chemoresistance through the Upregulation of FBXW7 and the Consequent Degradation of c-Myc” from STEM CELLS by Stuart P. Atkinson

To study possible treatments for colorectal cancer (CRC), researchers from the lab of Takatsugu Ishimoto (Kumamoto University, Japan) had previously established a human CRC cell line (PLR123) that expressed multiple markers of cancer stem cells (CSCs) [1]. In this model system, proliferating CSCs (LGR5+) exit the cell cycle and enter a quiescent state (LGR5-) after anti-cancer agent treatment and then reactivate proliferation after anti-cancer agent withdrawal; a nifty anti-cancer agent resistance mechanism to study!

In their new STEM CELLS study, the team has applied their model system to discover just what drives CSC quiescence in response to anti-cancer treatment in the hope of enhancing CRC treatment via the sensitization of CRC-CSCs to anti-cancer agents [2]; let’s read on!

The team’s primary analysis demonstrated that reversion of proliferative CSCS to a quiescent state following treatment with anti-cancer agents (Irinotecan and Oxaliplatin) correlated to a loss of the pro-proliferative c-Myc protein. However, removal of the anti-cancer agents led to rapid c-Myc reappearance, suggesting regulation at the protein level rather than at the transcriptional level. 

This supposition resulted in the discovery that F-box/WD repeat-containing protein 7 (FBXW7), which interacts with and mediates the ubiquitination and degradation of c-Myc, increased following anti-cancer agent exposure and could, therefore, mediate CSC chemoresistance. Encouragingly, the siRNA mediated knockdown of FBXW7 mRNA in CSCs induced cell sensitivity to anti-cancer agents, and so suggested that reducing FBXW7 expression or functionality may represent an exciting means to treat CRC alongside conventional chemotherapeutics. 

However, the authors appreciated that their findings might simply represent a “quirk” in their model system, and so they moved in vivo to validate their claims. Encouragingly, analysis of resected metastatic colorectal tumors in the livers of 64 patients revealed higher FBXW7 expression and lower c-Myc expression in patients receiving chemotherapy than those that did not receive chemotherapy, so indicating that the chemoresistance mechanism established in the CSC model holds true.

This exciting study not only uncovers one mechanism of chemoresistance but also provides us with a target to create a more efficient CSC-targeted therapeutic approach for CRC. An enticing thought is that this mechanism, or a similar mechanism, may exist in other CSCs in other cancers, and so, anti-cancer drug sensitization may represent a broader means to improve anti-cancer treatments. Indeed, the authors note that a previous study indicated that FBXW7 knockout in leukemia-initiating cells (LICs) increased sensitivity to imatinib, leading to in greater depletion of LICs in mice [3].

Keep your eyes on the Stem Cells Portal to stay abreast of all the news on CSCs and related anti-cancer strategies!

References

  1. Kobayashi S, Yamada-Okabe H, Suzuki M, et al. LGR5-Positive Colon Cancer Stem Cells Interconvert with Drug-Resistant LGR5-Negative cells and are Capable of Tumor Reconstitution. STEM CELLS 2012;30:2631-2644.
  2. Izumi D, Ishimoto T, Miyake K, et al. Colorectal Cancer Stem Cells Acquire Chemoresistance Through the Upregulation of F-Box/WD Repeat-Containing Protein 7 and the Consequent Degradation of c-Myc. Stem Cells 2017;35:2027-2036.
  3. Takeishi S, Matsumoto A, Onoyama I, et al. Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence. Cancer Cell 2013;23:347-361.