Highlights
- •Co-activation of both Akt/mTOR and Wnt/ β-catenin signaling pathways was found in 14.4% of patients with HCC.
- •Co-activation of these pathways confers worse survival compared to Akt/mTOR or Wnt/β-catenin activation alone.
- •Akt/β-catenin tumors contained a subpopulation of cells with stem/progenitor-like characteristics.
- •MDR1 was the main driver of SP phenotype in the Akt/β-catenin-driven HCC.
- •Activated Stat3 regulates the self-renewing and tumorigenic population of SP/CD44+ cells in Akt/β-catenin tumors.
Background & Aims
Hepatic resection and liver transplantation with adjuvant chemo- and radiotherapy
are the mainstay of hepatocellular carcinoma (HCC) treatment, but the 5-year survival
rate remains poor because of frequent recurrence and intrahepatic metastasis. Only
sorafenib and lenvatinib are currently approved for the first-line treatment of advanced,
unresected HCC, but they yield modest survival benefits. Thus, there is a need to
identify new therapeutic targets to improve current HCC treatment modalities.
Methods
The HCC tumor model was generated by hydrodynamic transfection of AKT1 and β-catenin (CTNNB1) oncogenes. Cancer cells with stemness properties were characterized following isolation
using side population (SP) and CD44 surface markers by flow cytometry. The effect
of Jak/Stat inhibitors was analyzed in vitro by using tumorsphere culture and in vivo using an allograft mouse model.
Results
Co-activation of both Wnt/β-catenin and Akt/mTOR pathways was found in 14.4% of our
HCC patient cohort. More importantly, these patients showed poorer survival than those
with either Wnt/β-catenin or Akt/mTOR pathway activation alone, demonstrating the
clinical relevance of our study. In addition, we observed that Akt/β-catenin tumors
contained a subpopulation of cells with stem/progenitor-like characteristics identified
through SP analysis and expression of the cancer stem cell-like marker CD44, which
may contribute to tumor self-renewal and drug resistance. Consequently, we identified
small molecule inhibitors of the Jak/Stat pathway that demonstrated efficacy in mitigating
tumor proliferation and formation in Akt/β-catenin-driven HCC.
Conclusions
In conclusion, we have shown that Akt/β-catenin tumors contain a subpopulation of
tumor-initiating cells with stem/progenitor-like characteristics which can be effectively
targeted with inhibitors of the Jak/Stat pathway, demonstrating that inhibition of
the Jak/Stat pathway could be an alternative method to overcome drug resistance and
effectively treat Akt/β-catenin-driven HCC tumors.
Lay summary
The prognosis for patients with hepatocellular carcinoma is poor, partly because of
the lack of effective treatment options for those with more advanced disease. In this
study, we identified a subpopulation of cancer cells with stem cell-like properties
that were critical for tumor maintenance and growth in a mouse model of hepatocellular
carcinoma. Through further experiments, we demonstrated that the Jak/Stat pathway
is a promising therapeutic target in hepatocellular carcinoma.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 18, 2019
Accepted:
August 29,
2019
Received in revised form:
August 20,
2019
Received:
April 1,
2019
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
