Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma.

Aparna Jayachandran,Jason C Steel,Bijay Dhungel

doi:10.1186/s13045-016-0307-9

Aparna Jayachandran, Jason C Steel + Show 1 more

Open Access

https://doi.org/10.1186/s13045-016-0307-9

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Abstract

Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide despite the development of various therapeutic strategies. A better understanding of the mechanisms responsible for HCC initiation and progression is essential for the development of more effective therapies. The cancer stem cell (CSC) model has provided new insights into the development and progression of HCC. CSCs are specialized tumor cells that are capable of self-renewal and have long-term repopulation potential. As they are important mediators of tumor proliferation, invasion, metastasis, therapy resistance, and cancer relapse, the selective targeting of this crucial population of cells has the potential to improve HCC patient outcomes and survival. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC has gained increasing attention. This multi-step reprograming process resulting in a phenotype switch from an epithelial to a mesenchymal cellular state has been closely associated with the acquisition of stem cell-like attributes in tumors. Moreover, CSC mediates tumor metastasis by maintaining plasticity to transition between epithelial or mesenchymal states. Therefore, understanding the molecular mechanisms of the reprograming switches that determine the progression through EMT and generation of CSC is essential for developing clinically relevant drug targets. This review provides an overview of the proposed roles of CSC in HCC and discusses recent results supporting the emerging role of EMT in facilitating hepatic CSC plasticity. In particular, we discuss how these important new insights may facilitate rational development of combining CSC- and EMT-targeted therapies in the future.

Highlights

Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver and is the third most frequent cause of cancer mortality worldwide [1,2,3,4]
The notion that cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) phenotypes play important roles in HCC progression, metastatic competence, therapy resistance, and relapse is a rapidly evolving concept that is contributing to our understanding of HCC pathogenesis and development of effective treatment options for this cancer
Emerging research data indicate that the existence of EMT and CSCs may be related to a high risk for recurrence and poor prognosis for many tumor types

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver and is the third most frequent cause of cancer mortality worldwide [1,2,3,4]. These studies demonstrated that the induction of EMT in immortalized human mammary epithelial cells lead to the expression of both mesenchymal markers and CD44highCD24low cell surface marker profile characteristic of breast CSCs. Notably, these cell populations acquired self-renewal properties and enhanced tumor-initiating ability [62, 66]. Similar studies have revealed the co-expression of both EMT- and CSC-associated genes at the invasive front of colorectal cancer and in spindle tumor cells inside the blood vessels of patients with metastasis [63, 67].

Results

Conclusion