Mechano-Signaling Aspects of Hepatocellular Carcinoma

Abstract

HCC is one of the leading causes of cancer related death worldwide and comprises about 90% of the cases of primary liver cancer. It is generally accompanied by chronic liver fibrosis characterised by deposition of collagen fibres, which, in turn, causes enhanced stiffness of the liver tissue. Changes of tissue stiffness give rise to alterations of signalling pathways that are associated to mechanical properties of the cells and the extracellular matrix, and that can be subsumed as "mechano-signaling pathways", like, e.g., the YAP/TAZ pathway, or the SRF pathway. Stiffness of the liver tissue modulates mechanical regulation of many genes involved in HCC progression. However, mechano-signaling is still rather underrepresented in our concepts of cancer in comparison to "classical" biochemical signalling pathways. This review aims to give an overview of various stiffness induced mechano-biological aspects of HCC.

Influence of extracellular matrix composition on tumour cell behaviour in a biomimetic in vitro model for hepatocellular carcinoma

“…As liver disease progresses, an increased deposition of high molecular weight, crosslinked fibrin(ogen) becomes tightly colocalized with collagen, forming a dense fibrous network 10 . The overall increased deposition of ECM, in addition to its molecular remodelling will result in various biological and physical changes in the microenvironment, including solid stress, increased matrix stiffness and interstitial hydraulic pressure 11 . In a healthy human liver, the stiffness ranges between 0.4 and 0.6 kPa, which during HCC can increase by a tenfold 6 , 11 .…”

“…The overall increased deposition of ECM, in addition to its molecular remodelling will result in various biological and physical changes in the microenvironment, including solid stress, increased matrix stiffness and interstitial hydraulic pressure 11 . In a healthy human liver, the stiffness ranges between 0.4 and 0.6 kPa, which during HCC can increase by a tenfold 6 , 11 . This stiffening of the liver is not only a consequence of fibrosis, but also an active driver of the disease.…”

Parafibromin Is Highly Expressed in Hepatocellular Carcinoma and Its Expression Correlates with Poor Prognosis

“…HCC is the most common primary liver cancer and the second leading cause of cancer-related mortality worldwide [ 1 ]. Human HCC is an inflammation-induced cancer, and its primary causes are HBV, HCV, alcoholic steatohepatitis, and NASH [ 2 , 3 ]. Chronic viral hepatitis, alcohol abuse, and metabolic liver diseases cause chronic inflammation, which leads to continuous cycles of hepatocytes destruction and regeneration, and during compensatory hepatic regeneration, genetic abnormalities accumulate and contribute to the pathogenesis and progression of HCC [ 3 , 7 , 8 , 9 , 10 ].…”

“…Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related death worldwide [ 1 ]. Hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH) are the major causative factors of HCC development [ 2 , 3 ]. In most cases, HCC develops in chronic liver disease that provides the basis for premalignant lesions such as dysplastic foci and dysplastic nodules through multistep hepatocarcinogenesis [ 4 ].…”

Advancing Key Gaps in the Knowledge of Plasmodium vivax Cryptic Infections Using Humanized Mouse Models and Organs-on-Chips

“…The native ECM composes up to 10% of the liver volume, providing structural support, and has a Young’s Elastic Modulus that ranges between 300 and 600 Pa ( Wu et al., 2018 ; Passi and Zahler, 2021 ) to provide structural support. Most notably, it has been shown that a healthy liver ECM is composed by more than 150 different proteins, including the most abundant, fibronectins, elastin, and fibrillar collagens ( Naba et al., 2014 ; Arteel and Naba, 2020 ).…”