Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma.

Duoduo Lv,Lingyun Zhou,Lingyao Du,Hong Tang,Liyu Chen

doi:10.3389/fcell.2021.691410

Abstract

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.

Highlights

Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality due to its resistance to chemotherapy, high rates of recurrence and metastasis, and poor prognosis (Bray et al, 2013; Torre et al, 2015; Sia et al, 2017)
Increased invasiveness Resulted in HCC with spontaneous lung metastases Lead to tumor growth and chemoresistance CD24 was found to drive liver cancer stem cells (LCSCs) genesis Maintain the LCSC population Causes CD133 + enrichment in HCC Connects hepatic inflammation with LCSC expansion Induces epithelialmesenchymal transition (EMT) to increase stemness potential and migratory and invasive capacities Regulate LCSC self-renewal Attenuate cancer stem cells (CSCs)-like features Increase stemness of self-renewal and tumorigenicity Contributes to hepatocarcinogenesis CD133 + Hepa 1–6 cells Inhibited apoptosis to facilitate the stemness characteristics of CD90 + cells Self-renewal Proliferation of LCSCs
There is a growing body of evidence indicating that CSCs are the root cause of cancers and are responsible for metastasis, resistance to conventional treatments, and tumor recurrence; the molecular mechanisms underlying the potential roles of LCSCs in HCC origin and progression have not been fully elucidated

Summary

Introduction

Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality due to its resistance to chemotherapy, high rates of recurrence and metastasis, and poor prognosis (Bray et al, 2013; Torre et al, 2015; Sia et al, 2017). Increased invasiveness Resulted in HCC with spontaneous lung metastases Lead to tumor growth and chemoresistance CD24 was found to drive LCSC genesis Maintain the LCSC population Causes CD133 + enrichment in HCC Connects hepatic inflammation with LCSC expansion Induces EMT to increase stemness potential and migratory and invasive capacities Regulate LCSC self-renewal Attenuate CSC-like features Increase stemness of self-renewal and tumorigenicity Contributes to hepatocarcinogenesis CD133 + Hepa 1–6 cells Inhibited apoptosis to facilitate the stemness characteristics of CD90 + cells Self-renewal Proliferation of LCSCs

Results

Conclusion