Cancer Res Treat.  2020 Apr;52(2):604-621. 10.4143/crt.2019.444.

Activation of Tyrosine Metabolism in CD13+ Cancer Stem Cells DrivesRelapse in Hepatocellular Carcinoma

Affiliations
  • 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
  • 2The Nursing Department, Shanghai Public Health Clinical Center, Shanghai, China
  • 3The First Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
  • 4The Third Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China

Abstract

Purpose
Cancer stem cells (CSCs) are naturally resistant to chemotherapy, explaining why tumor relapse frequently occurs after initial regression upon administration of chemotherapeutic agents in most cases. A CSC population characterized by CD13 expression has been identified in hepatocellular carcinoma (HCC). In the current study, we aimed to clarify the molecular mechanism by which it escapes conventional therapies.
Materials and Methods
Here, we used flow cytometry to examine the percentage of CD13+ CSCs in HepG2 and HuH7 cells after chemotherapy. Using in vitro isotope labeling technique, we compared metabolic pathways between CD13+ and CD13– subpopulations. Using co-immunoprecipitation and western blotting, we determined the target expressions in protein levels under different conditions. We also performed immunohistochemistry to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of tyrosine metabolism in post-chemotherapeutic relapse in vivo.
Results
We observed that quiescent CD13+ CSCs are enriched after chemotherapy in HCCs, and serve as a reservoir for recurrence. Mechanistically, CD13+ CSCs were dependent on aerobic metabolism of tyrosine rather than glucose as energy source. Tyrosine metabolism also generated nuclear acetyl-CoA to acetylate and stabilize Foxd3, thereby allowing CD13+ CSCs cells to sustain quiescence and resistance to chemotherapeutic agents.
Conclusion
These findings encourage further exploration of eliminating CD13+ cells by targeting specific metabolic pathways to prevent recurrence in HCCs.

Keyword

CD13+ CSCs; Foxd3; Hepatocellular carcinoma; Quiescence; Tyrosine metabolism
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