Advances in Liver Cancer Stem Cell Isolation and their Characterization

Abstract

Over the last decade research on cancer stem cells (CSC) significantly contributed to a better understanding of tumor biology. Given their similarity to normal stem cells, i.e. self-renewal and pluripotency the need arises to develop robust protocols for the isolation and characterization of CSCs. As with other malignancies, hepatic tumors are composed of a heterogeneous population of cells including liver cancer stem cells (LCSC). Yet, a precise understanding of why stem cells become cancerous is still lacking. There is unmet need to develop robust protocols for the successful isolation of LCSCs from human tissue resection material as to assist in the development of molecular targeted therapies. Here we review the research progress made in the isolation and characterization of LCSCs by considering a wide range of cell surface markers and sorting methods, as applied to side populations, microsphere cultures and the gradient centrifugation method. We emphasize the different fluorescence activated cell sorting methods and the possibility to enrich LCSCs by immunomagnetic beads. We review the specificity of functional assays by considering ABCG transporter and ALDH1 enzyme activities and evaluate the in vivo tumorigenicity of LCSCs in highly sensitive bioassays. Finally, we evaluate different LCSC markers in association with viral and non-viral liver disease and explore the potential of novel drug delivery systems targeting CD133, EpCAM, CD13 and CD90 for the development of molecular targeted therapies.

Graphical Abstract

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Data Availability

All information is given in the manuscript.

Abbreviations

LCSC:

liver cancer stem cells

IARC:

International Agency for Research on Cancer

CSCs:

cancer stem cells

HCC:

hepatocellular carcinoma

AML:

acute myelocytic leukemia

HPCs:

hepatic progenitor cells

ALDH1:

aldehyde Dehydrogenase 1

OCT-4:

octamer-binding transcription factor 4

PLB:

plumbagin

FGF2:

fibroblast growth factor 2

GEM:

gemcitabine

EGFR:

epidermal growth factor receptor

AFP:

alpha-fetoprotein

SCID:

severe combined immunodeficient

CK19:

cytokeratin19

EpCAM:

epithelial cell adhesion molecule

FACS:

fluorescence-activated cell sorting

MACS:

magnetic activated cell sorting

IMS:

immunomagnetic bead sorting

TMs:

thermosensitive magneto liposomes

17-AAG:

17-allylamino-17-demethoxgeldanamycin

SFCs:

sphere forming cells

SP:

side population

Rho123:

Rhodamine 123

ABCG2:

ATP Binding Cassette Subfamily G Member 2

UV:

ultraviolet

DCV:

Dye Cycle Violet

LDA:

limited dilution method

HGF:

hepatocyte growth factor

BAAA:

BODIPY®-amino acetaldehyde

PDGC:

percoll discontinuous gradient centrifugation method

MMAF:

monomethyl auristatin F

5-FU:

fluorouracil

CDDP:

cisplatin

DXR:

doxorubicin

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

CAR-T:

T cell chimeric antigen receptor

HBV:

hepatitis B virus

HCV:

hepatitis C virus

RPMI-1640:

Gibco Roswell Park Memorial Institute (RPMI) 1640 Medium

DMEM:

Dulbecco’s Modified Eagle’s Medium

PDX:

patient derived xenograft

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Author Lu Liu performed the initial literature search and prepared the Figures and Tables. Both authors contributed equally to the writing; JB wrote the final manuscript.

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Correspondence to Jürgen Borlak.

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Liu, L., Borlak, J. Advances in Liver Cancer Stem Cell Isolation and their Characterization. Stem Cell Rev and Rep (2021). https://doi.org/10.1007/s12015-020-10114-6

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Keywords

  • Liver cancer
  • Cancer stem cells isolation
  • Cancer stem cells characterization
  • Drug treatment
  • Targeted drug delivery