Figure 1.

ECM regulating the “hallmarks of liver cancer” and its status in healthy liver, chronic disease conditions, and hepatocellular carcinoma

(A) The liver ECM network as a molecular sink that harbors structural components, proteoglycans, and several growth factors. The impact of key ECM components (light blue boxes) known to regulate the specific cancer hallmark (reddish brown) are highlighted.

(B) ECM in healthy liver tissues that act to maintain liver homeostasis by controlling the proliferation of hepatocytes and sustaining immune-suppressive functions. When chronic liver diseases develop, the ECM is altered by increases in collagen deposition, which enhance stiffness, elastin-derived peptides (EDPs), and PGs, as well as augments the influx of fibroblasts. This initiates an ECM corruption process, as manifested by a low immune response that impacts the hepatocytes, activates HSCs, and promotes abnormal vasculature leading to liver fibrosis. Increased ECM disorganization, in turn, increases the mechanosignaling and contractility of the hepatocytes, which leads to their neoplastic transformation. Cancerous hepatocytes further increase ECM disorganization, causing a vicious oncogenic feedforward loop accompanied by enhanced tissue rigidity, resistance to targeted therapies, and immune-escape mechanisms.