Fibroblasts in liver cancer: functions and therapeutic translation

Accumulation of fibroblasts in the premalignant or malignant liver is a characteristic feature of liver cancer, but has not been therapeutically leveraged despite evidence for pathophysiologically relevant roles in tumour growth. Hepatocellular carcinoma is a largely non-desmoplastic tumour, in which fibroblasts accumulate predominantly in the pre-neoplastic fibrotic liver and regulate the risk for hepatocellular carcinoma development through a balance of tumour-suppressive and tumour-promoting mediators. By contrast, cholangiocarcinoma is desmoplastic, with cancer-associated fibroblasts contributing to tumour growth. Accordingly, restoring the balance from tumour-promoting to tumour-suppressive fibroblasts and mediators might represent a strategy for hepatocellular carcinoma prevention, whereas in cholangiocarcinoma, fibroblasts and their mediators could be leveraged for tumour treatment. Importantly, fibroblast mediators regulating hepatocellular carcinoma development might exert opposite effects on cholangiocarcinoma growth. This Review translates the improved understanding of tumour-specific, location-specific, and stage-specific roles of fibroblasts and their mediators in liver cancer into novel and rational therapeutic concepts.