Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer

Abstract

Over the past 2 decades, cancer stem cells (CSCs) have been identified as the root cause of cancer occurrence, progression, chemoradioresistance, recurrence, and metastasis. Targeting CSCs is a novel therapeutic strategy for cancer management and treatment. Liver cancer (LC) is a malignant disease that can endanger human health. Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer. In this review, we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells (LCSCs) in liver cancer progression. We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis. Finally, we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer. Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

Keywords: Liver cancer; cancer stem cells; mechano-microenvironment; mechanotherapy; tumor heterogeneity.

Figure 1

Pathological changes in liver tissue stiffness, detected by ultrasound transient elastography. The tissue stiffness increases from normal liver tissue to liver fibrosis and cirrhosis. The stiffness of normal liver tissue is below 6 kPa. The stiffness of the non-cirrhotic stage of fibrosis (F1–F3) is 7–9.5 kPa. The stiffness of F4 fibrosis (cirrhosis) is > 12.5 kPa. The range of liver cirrhosis stiffness is similar to that of liver cancer tissue. Liver stiffness > 12.0 kPa is an independent risk factor for new HCC development. Liver cancer tissue > 30 kPa is a significant adverse predictor of survival in patients with advanced HCC.

Figure 2

The mechanical microenvironment of the liver is closely associated with pathological changes in the liver. (A) Hepatocytes and LSECs are separated by the space of Disse, which contains minimal ECM in healthy liver tissue. Quiescent HSCs reside in the space of Disse. Kupffer cells exist in the sinusoid. (B) In liver fibrosis/cirrhosis, HSCs are activated and contribute to the production and deposition of ECM, thereby contributing to stiffening. (C) Liver cirrhosis with elevated stiffness is strongly associated with the development of liver cancer. Quiescent HSCs and other cell types are transformed into CAFs, which produce large amounts of ECM deposition around liver tumors. ECM deposition and vascular penetration contribute to increased stiffness and mechanical heterogeneity in liver tumors. (D) Liver cancer tissue displays mechanical heterogeneity, gradually increasing in stiffness from the core to the invasive periphery.

Figure 3

Potential origin and heterogeneity of LCSCs. LCSCs may originate from non-LCSCs that undergo dedifferentiation and share many similar characteristics with normal stem cells. LCSC heterogeneity in different subpopulations is identified by the expression of various LCSC markers. Different LCSC subpopulations are independently associated with the prognosis of HCC and contribute to intratumor heterogeneity and tumor progression.

Figure 4

Relationships among mechanical heterogeneity, LCSCs, and EMT. The distribution of LCSCs within liver cancer tissue is heterogeneous and preferentially distributed in the stiffer invasive front. The stiffer invasive front of liver cancer tissue facilitates EMT in LCSCs, thus resulting in cancer tissue invasion, dissemination, and growth at metastatic sites.

Figure 5

Liver cancer therapy targeting the mechanical microenvironment and LCSCs. The increased cancer cell density, ECM deposition and crosslinking, increased vascular permeability and IFP, and necrosis in the core of liver cancer tissue contribute to the mechanical heterogeneity of liver cancer tissue. Common HCC therapeutic strategies, such as TACE and immunotherapy, are associated with tumor stiffness. The distribution of LCSCs in liver cancer tissue is affected by the mechanical heterogeneity of liver cancer tissue. Increased matrix stiffness contributes to LCSC stemness maintenance. Focusing on the mechanical microenvironment and LCSCs in liver carcinogenesis may provide theoretical guidance for preventing and treating liver cancer in clinical settings.