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.
Highlights
Epithelial-mesenchymal transition (EMT) is a process first known to be involved in embryogenesis and tissue repair [1]
More than 200 papers appear every year in the English-language literature, regarding the EMT of hepatocellular carcinoma (HCC) cells, the exact pathway and interaction of this process with other particular events of the tumor microenvironment, such as angiogenesis, inflammation, and stemness features, are still poorly understood. e main aim of this review is to synthesize the information in the literature regarding the particularities of the HCC microenvironment, taking into account the tissue and circulating biomarkers and the background of peritumor liver parenchyma
In carcinomas, the tumor microenvironment is defined by the old concept of EMT, this has proven to be more challenging for HCC. is comprehensive review of the literature has revealed that similar to other carcinomas, the Wnt pathway is the central event in the EMT of HCC cells, but it does not define the tumor microenvironment
Summary
Epithelial-mesenchymal transition (EMT) is a process first known to be involved in embryogenesis and tissue repair [1]. E acquisition of positivity for mesenchymal markers induces the increased mobility of the tumor cells and a high risk of lymph node or distant metastases. More than 200 papers appear every year in the English-language literature, regarding the EMT of hepatocellular carcinoma (HCC) cells, the exact pathway and interaction of this process with other particular events of the tumor microenvironment, such as angiogenesis, inflammation, and stemness features, are still poorly understood. In some Asiatic regions, such as Taiwan, HCC is the leading cause of cancer-related death [7]. In addition to multifocality (intrahepatic metastases), which is a factor of aggressiveness, it has been proven that HCC is one of the tumors with the highest metastatic capacity and that it has a high risk of recurrence. As very limited and poorly effective therapeutic options exist for HCC [2], the possible predictive role of EMT for the targeted therapy of HCC is explored in this paper
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