Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Sep 29:2019:2962580.
doi: 10.1155/2019/2962580. eCollection 2019.

Epithelial Mesenchymal and Endothelial Mesenchymal Transitions in Hepatocellular Carcinoma: A Review

Simona Gurzu  1   2   3 , Laszlo Kobori  4 , Decebal Fodor  1   4   5 , Ioan Jung  1
Affiliations
Review

Epithelial Mesenchymal and Endothelial Mesenchymal Transitions in Hepatocellular Carcinoma: A Review

Simona Gurzu et al. Biomed Res Int. .

Abstract

Purpose: To present a comprehensive review of the literature data, published between 2000 and 2019 on the PubMed and Web of Science databases, in the field of the tumor microenvironment in hepatocellular carcinoma (HCC). All the data were combined with the personal experiences of the authors.

Design: From 1002 representative papers, we selected 86 representative publications which included data on epithelial-to-mesenchymal transition (EMT), angiogenesis, cancer stem-like cells (CSCs), and molecular background of chemoresistance or resistance to radiotherapy.

Results: Although the central event concerns activation of the Wnt/β-catenin pathway, other signal pathways, such as c-Met/HGF/Snail, Notch-1/NF-κB, TGF-β/SMAD, and basic fibroblast growth factor-related signaling, play a role in the EMT of HCC cells. This pathway is targeted by specific miRNAs and long noncoding RNAs, as explored in this paper. A central player in the tumor microenvironment proved to be the CSCs which can be marked by CD133, CD44, CD90, EpCAM, and CD105. CSCs can induce resistance to cytotoxic therapy or, alternatively, can be synthesized, de novo, after chemo- or radiotherapy, especially after transarterial chemoembolization- or radiofrequency ablation-induced hypoxia. The circulating tumor cells proved to have epithelial, intermediate, or mesenchymal features; their properties have a critical prognostic role.

Conclusion: The metastatic pathway of HCC seems to be related to the Wnt- or, rather, TGFβ1-mediated inflammation-angiogenesis-EMT-CSCs crosstalk link. Molecular therapy should target this molecular axis controlling the HCC microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to report.

Figures

Figure 1
Figure 1
Preferred reported items for systematic reviews and meta-analyses (PRISMA) flow diagram, adapted for data on the tumor microenvironment in hepatocellular carcinoma from the PubMed and Web of Science databases between 2000 and 2019.
Figure 2
Figure 2
Molecular pathway signaling of angiogenesis-induced epithelial-mesenchymal transition in hepatocellular carcinoma.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gurzu S., Silveanu C., Fetyko A., Butiurca V., Kovacs Z., Jung I. Systematic review of the old and new concepts in the epithelial-mesenchymal transition of colorectal cancer. World Journal of Gastroenterology. 2016;22(30):6764–6775. doi: 10.3748/wjg.v22.i30.6764. - DOI - PMC - PubMed
    1. Gui Y., Khan M. G. M., Bobbala D., et al. Attenuation of MET-mediated migration and invasion in hepatocellular carcinoma cells by SOCS1. World Journal of Gastroenterology. 2017;23(36):6639–6649. doi: 10.3748/wjg.v23.i36.6639. - DOI - PMC - PubMed
    1. Zhang J.-P., Zeng C., Xu L., Gong J., Fang J.-H., Zhuang S.-M. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene. 2014;33(31):4069–4076. doi: 10.1038/onc.2013.369. - DOI - PubMed
    1. Qiu L., Wang T., Xu X., et al. Long non-coding RNAs in hepatitis B virus-related hepatocellular carcinoma: regulation, functions, and underlying mechanisms. International Journal of Molecular Sciences. 2017;18(12):p. 2505. doi: 10.3390/ijms18122505. - DOI - PMC - PubMed
    1. Mao X., Zhang Y., Lin N. Application and perspectives of traditional Chinese medicine in the treatment of liver cancer. Cancer Translational Medicine. 2015;1(3):101–107. doi: 10.4103/2395-3977.159538. - DOI

MeSH terms