Abstract
Liver fibrosis is characterized by the progressive accumulation of extracellular matrix (ECM) and is a strong predictor of hepatocellular carcinoma (HCC) development and progression. However, the effect of ECM in fibrotic livers on HCC cells is poorly understood. The aims of this study were to create a new culture system that retained the natural ECM of fibrotic model livers and to establish whether natural ECM regulated the characteristics of HCC cells. Using an organ decellularization technique, we created a new culture system that preserved the tissue-specific ECM of fibrotic model livers from CCl4-treated rats. The content of ECM in fibrotic model liver scaffolds was increased and the ECM microstructure was distorted. Quantitative polymerase chain reaction and immunofluorescence assays of HCC cells cultured in fibrotic model liver scaffolds for 7 days showed an epithelial-mesenchymal transition phenotype. Moreover, the ECM of fibrotic model livers promoted proliferation and chemoresistance of HCC cells. These results showed a novel effect of natural ECM in fibrotic model livers on the malignant behaviour of HCC cells. This new culture system will be useful for both understanding the cell biology of fibrotic livers and developing novel anti-cancer drugs.
Highlights
Liver fibrosis is characterized by the progressive accumulation of extracellular matrix (ECM) and is a strong predictor of hepatocellular carcinoma (HCC) development and progression
Reports based on conventional two-dimensional or gel three-dimensional culture systems indicate that the proliferation and chemotherapeutic response of HCC cells is related to increases in matrix stiffness, which is one aspect of the microenvironment in fibrotic livers[5, 6]
To demonstrate the underlying mechanism of accelerating epithelial-mesenchymal transition (EMT) phenotype, proliferation and chemoresistance of HCC cells in fibrotic model liver scaffolds, we evaluated the expression of integrins and FAK
Summary
Liver fibrosis is characterized by the progressive accumulation of extracellular matrix (ECM) and is a strong predictor of hepatocellular carcinoma (HCC) development and progression. Reports based on conventional two-dimensional or gel three-dimensional culture systems indicate that the proliferation and chemotherapeutic response of HCC cells is related to increases in matrix stiffness, which is one aspect of the microenvironment in fibrotic livers[5, 6]. Decellularized scaffolds retain the natural tissue-specific ECM that consists of complex microstructural and functional proteins such as collagen, laminin, fibronectin, and other matrix components[9] This natural ECM allows cells to maintain their tissue-specific phenotype and this is one of the advantages over conventional two-dimensional and three-dimensional culture systems[8,9,10,11]. We demonstrated that the decellularized fibrotic model livers accelerated the epithelial-mesenchymal transition (EMT) phenotype, proliferation and drug resistance of HCC cells This novel culture system is ideal for studying cancer cell niches in fibrotic livers
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