Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.

Clonorchis sinensis infection amplifies hepatocellular carcinoma stemness, predicting unfavorable prognosis

“…Cancer stem cells orchestrate a spectrum of crucial roles in hepatocellular carcinoma growth, invasion, metastasis, recurrence, and therapy resistance [ 44 ]. C .…”

The role of alpha-fetoprotein in the tumor microenvironment of hepatocellular carcinoma

“…Previous studies indicated that AFP can enhance the expansion of LCSCs by activating the PI3K/Akt signaling pathway ( 39 , 40 ). To investigate the impact of AFP on LCSCs, researchers measured the AFP expression in HCC cells firstly, then demonstrated that AFP not only facilitates the expression of proteins associated with cell reprogramming but also promotes the expression of LCSCs markers, including CD44, CD133, and EpCAM.…”

Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy

“…TGFβ orchestrates the initiation of EMT across various GI malignancies, including GC, CRC and HCC ( Calon et al, 2015 ; Krzysiek-Maczka et al, 2019 ; Jeng et al, 2023 ). It directly upregulates the production of multiple EMT transcription factors such as SNAIL, TWIST, SLUG and ZEB1 ( Lee and Massague, 2022 ; Trelford et al, 2022 ), and also promotes EMT by introducing epigenetic alterations.…”

“…Notably, the Notch pathway exhibits dual effects in tumor progression, acting as an oncogene or a tumor suppressor depending on varied receptor/ligand expressions or upstream regulators ( Li et al, 2023c ). Aberrant overexpression of Notch, as observed in GC, PDAC, CRC and HCC ( Vinson et al, 2016 ; Hibdon et al, 2019 ; Tyagi et al, 2020 ; Chung and Xu, 2023 ; Jeng et al, 2023 ), relates the Notch gene to tumor types characterized by increased aggressiveness, promoted drug resistance and poor clinical prognosis. The Notch pathway upregulates CSC activities by interacting with CSC surface markers.…”