Enzyme‐Induced Matrix Softening Regulates Hepatocarcinoma Cancer Cell Phenotypes

• Published in: Macromolecular bioscience Vol. 17; no. 9
• Main Authors: Liang, Youyun, Clay, Nicholas Edwin, Sullivan, Kathryn M., Leong, Jiayu, Ozcelikkale, Altug, Rich, Max H., Lee, Min Kyung, Lai, Mei‐Hsiu, Jeon, Hojeong, Han, Bumsoo, Tong, Yen Wah, Kong, Hyunjoon
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.09.2017
• Subjects: Antigens, CD; Cadherins - genetics; Cancer; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - physiopathology; Carcinoma, Hepatocellular - radiotherapy; Cell Proliferation; Collagen; degradation; Detoxification; E-cadherin; Elastic Modulus; Extracellular matrix; extracellular matrix (ECM); Extracellular Matrix - metabolism; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatocytes; Humans; hydrogels; Interstitial collagenase; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - physiopathology; Liver Neoplasms - radiotherapy; Matrix metalloproteinase; Matrix Metalloproteinase 1 - metabolism; Matrix metalloproteinases; Mechanical properties; Metalloproteinase; Modulus of elasticity; Radiation Tolerance; Radiosensitivity; Spheroids; collagen; extracellular matrix (ECM); degradation; hydrogels; matrix metalloproteinases
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.201700117

The progression of cancer is often accompanied by changes in the mechanical properties of an extracellular matrix. However, limited efforts have been made to reproduce these biological events in vitro. To this end, this study demonstrates that matrix remodeling caused by matrix metalloproteinase (MMP)‐1 regulates phenotypic activities and modulates radiosensitivity of cancer cells exclusively in a 3D matrix. In this study, hepatocarcinoma cells are cultured in a collagen‐based gel tailored to present an elastic modulus of ≈4.0 kPa. The subsequent exposure of the gel to MMP‐1 decreases the elastic modulus from 4.0 to 0.5 kPa. In response to MMP‐1, liver cancer cells undergo active proliferation, downregulation of E‐cadherin, and the loss of detoxification capacity. The resulting spheroids are more sensitive to radiation than the spheroids cultured in the stiffer gel not exposed to MMP‐1. Overall, this study serves to better understand and control the effects of MMP‐induced matrix remodeling. Matrix metalloproteinases can alter extracellular matrix properties, in turn regulating cell behavior in different disease states. By exposing a liver cancer cell‐laden gel to matrix metalloproteinase for different lengths of time, a range of cancer phenotypes can be reproduced in vitro.