Gastrointest Tumors. 2014 Jun;1(2):76-83. doi: 10.1159/000362579. Epub 2014 May 09.

Hepatocellular Carcinoma: Basic and Transitional Research.

Gastrointestinal tumors

Chuan Yin, Wei-Fen Xie

PMID: 26675991 PMCID: PMC4645578 DOI: 10.1159/000362579

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. The outcome of HCC therapy depends on the stage of HCC. Early-stage HCC patients can be cured with radical treatment approaches, whereas no standard treatment regimens can be recommended for patients with advanced disease.

SUMMARY: In-depth basic research into the molecular mechanisms of HCC has contributed to the development of novel therapeutic agents. This article reviews several key classes of novel therapeutic agents that are under development, including molecular-targeted therapies, cancer stem cell (CSC)-based therapy and differentiation therapy.

KEY MESSAGE: A greater understanding of the molecular pathogenesis of HCC has contributed to the development of novel therapeutic agents. This article reviews several key classes of novel therapeutic agents that are under development, including molecular-targeted therapies, CSC-based therapy and differentiation therapy.

PRACTICAL IMPLICATIONS: Molecular-targeted therapies based on signaling pathways involved in hepatocarcinogenesis and progression are being evaluated in several clinical trials. There are three main categories of targeted agents: tyrosine kinase inhibitors (TKIs), monoclonal antibodies and enzyme inhibitors. The best-established agent is sorafenib, a non-specific TKI that is accepted as first-line therapy for specific patients. Other similar agents under investigation include erlotinib, linifanib and brivanib. CSC-based therapies are still in the earlier stages of development and include a neutralizing anti-CD44 antibody, small interfering RNA to suppress epithelial cell adhesion molecular levels, a neutralizing anti-CD13 antibody and a CD13 inhibitor. An important point is that CSC-targeted therapy should be combined with conventional therapies to achieve complete tumor regression. Differentiation therapy is defined as a strategy that induces malignant reversion of tumor cells. Hepatocyte nuclear factor 4α or 1α, important transcriptional factors for hepatocyte differentiation and phenotype maintenance, have shown significant antitumor effects by inducing differentiation of both non-CSCs and CSCs in HCC towards a hepatocyte-like phenotype.

Keywords: Cancer stem cells; Differentiation; Hepatocellular carcinoma; Molecular-targeted therapies; Signaling pathways

References

1. Hepatology. 2011 Mar;53(3):1020-2 - PubMed
2. Hepatology. 2011 Sep 2;54(3):868-78 - PubMed
3. Ann Oncol. 2012 Oct;23 Suppl 7:vii41-8 - PubMed
4. Gut. 2010 Feb;59(2):236-46 - PubMed
5. Hepatology. 2013 Dec;58(6):1977-91 - PubMed
6. Leukemia. 2003 Aug;17(8):1454-63 - PubMed
7. Liver Int. 2009 Aug;29(7):955-65 - PubMed
8. Adv Exp Med Biol. 2013;779:67-90 - PubMed
9. Cancer Res. 2010 Oct 1;70(19):7640-51 - PubMed
10. J Cell Mol Med. 2012 Jan;16(1):160-73 - PubMed
11. Science. 2002 May 31;296(5573):1648-9 - PubMed
12. J Clin Oncol. 2010 Jan 1;28(1):92-8 - PubMed
13. Gastroenterology. 2012 Dec;143(6):1641-1649.e5 - PubMed
14. Nat Biotechnol. 2005 Sep;23(9):1073-8 - PubMed
15. Curr Cancer Drug Targets. 2012 Nov 1;12(9):1081-94 - PubMed
16. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29 - PubMed
17. J Clin Oncol. 2010 Dec 20;28(36):5321-6 - PubMed
18. Hepatology. 2008 Nov;48(5):1528-39 - PubMed
19. Nat Rev Drug Discov. 2006 Oct;5(10):835-44 - PubMed
20. Cancer Cell. 2008 Feb;13(2):153-66 - PubMed
21. Oncol Rep. 2012 May;27(5):1303-11 - PubMed
22. Cell. 2011 Dec 9;147(6):1233-47 - PubMed
23. Hepatology. 2011 Dec;54(6):2036-47 - PubMed
24. PLoS One. 2013;8(2):e55945 - PubMed
25. J Hepatol. 2012 Apr;56(4):908-43 - PubMed
26. Hepatology. 2013 Dec;58(6):1964-76 - PubMed

Publication Types

• Journal Article
• Review