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Resistance to Molecular Therapies for Hepatocellular Carcinoma pp 65–91Cite as

Contribution of the Cancer Stem Cell Phenotype to Hepatocellular Carcinoma Resistance

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 13))

Abstract

The cancer stem cell (CSC) hypothesis is an increasingly accepted concept in cancer research that provides a plausible explanation for the considerable phenotypic and molecular heterogeneities observed in hepatocellular carcinoma (HCC) which hampers therapeutic progress. The hypothesis infers that CSCs share functional properties similar to adult stem cells, such as self-renewal and differentiation capacity, and are exclusively responsible for tumor evolution. By definition, CSCs are held responsible not only for tumor initiation and progression but also acquisition of chemoresistance and the fueling of relapse after therapy. Therefore, the CSC model has significant implications both for translational research as well as clinical applications, in particular for the development of novel treatment strategies. Implicit in the concept is the need for therapeutic targeting of CSCs to effectively diminish tumor growth. Therefore, a better understanding of the molecular mechanisms that lead to induction of stemness and drive CSCs in HCC is of crucial importance. In this chapter, we aim to highlight important aspects of the CSC biology in the context of clinical and therapeutic progress. Besides a critical reflection of the cellular origin of CSCs, this will also include discussion on the importance of the diseased hepatic microenvironment for oncogenic reprogramming and induction of stemness in HCC. Moreover, we will highlight the relevance of CSC markers as diagnostic and/or predictive biomarkers. Most importantly, we will delineate the potential of therapeutic targeting of CSCs to overcome therapeutic resistance and improve the HCC patients’ outcome.

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Abbreviations

ABC:

Adenosine triphosphate (ATP)-binding cassette

ABCG2:

Adenosine triphosphate (ATP)-binding cassette G2

AFP:

Alpha-fetoprotein

AKT:

AKT8 virus oncogene cellular homolog

BCL-2:

B-cell lymphoma 2

BEC:

Biliary epithelial cell

CD13:

Cluster of differentiation 13; aminopeptidase N

CD133:

Cluster of differentiation 133; prominin 1

CD24:

Cluster of differentiation 24; mucin-like cell surface glycoprotein; heat stable antigen

CD44:

Cluster of differentiation 44

CD45:

Cluster of differentiation 45; leucocyte common antigen

CD90:

Cluster of differentiation 90; thymus cell antigen

c-Kit:

Tyrosine-protein kinase Kit

CSC:

Cancer stem cell

CUDR:

Long noncoding RNA cancer upregulated drug resistant

DCP:

Des-gamma-carboxy prothrombin

DNA:

Deoxyribonucleic acid

DNMT1:

DNA methyltransferase 1

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial–mesenchymal transition

EpCAM:

Epithelial cell adhesion molecule

FGF:

Fibroblast growth factor

GP73:

Golgi protein-73

HCC:

Hepatocellular carcinoma

HDAC:

Histone deacetylases

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Acknowledgement

J.U.M. is supported by grants from the German Research Foundation (MA 4443/2-2), the German Cancer Aid (DKH 110989) and the Volkswagen Foundation (Lichtenberg program). C.C. is supported by a fellowship grant from the Transmed Program of the Universitätsmedizin Mainz.

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    1. Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, Johannes Gutenberg University, Mainz, Germany

      Darko Castven, Carolin Czauderna & Jens U. Marquardt

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    2. Carolin Czauderna
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    Correspondence to Jens U. Marquardt .

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    1. Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Graduate School of Biomedical Sciences, New York, New York, USA

      Augusto Villanueva

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    Castven, D., Czauderna, C., Marquardt, J.U. (2017). Contribution of the Cancer Stem Cell Phenotype to Hepatocellular Carcinoma Resistance. In: Villanueva, A. (eds) Resistance to Molecular Therapies for Hepatocellular Carcinoma. Resistance to Targeted Anti-Cancer Therapeutics, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-56197-4_4

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