Abstract
Human salivary adenoid cystic carcinoma (SACC) is one of the most common malignant tumours of the salivary gland and has strong migratory and invasive ability, which often lead to poor prognosis and lower survival rate. Tumour tissue tends to stiffen during solid tumour progression. This study aimed to investigate the influence of various substrate stiffness on the migration and invasion of SACC. Salivary adenoid cystic carcinoma cell line ACC2 cells were cultured on polydimethylsiloxane substrates (PDMS) with varying stiffness for investigating the effects of substrate stiffness on the activities of MMPs and TIMPs. The underlying mechanism was also explored. When ACC2 cells were cultured on various stiffness of PDMS, the expressions of matrix metalloproteinases 2 (MMP2), MMP9, MMP14, RhoA, Rac1, Rho-associated protein kinase 1 (ROCK1) and ROCK2 were up-regulated with increasing substrate stiffness, whereas that of tissue inhibitor of matrix metalloproteinase 1 (TIMP1), TIMP2 and TIMP4 were down-regulated with increasing substrate stiffness. Our results showed that substrate stiffness regulated the activities of MMPs and TIMPs and then modulate migratory and invasive ability of ACC2 cells via RhoA/ROCK pathway. This work indicate that matrix stiffness played an important role in progression of SACC, which not only can help understand the strong invasive ability of SACC, but also suggested that therapeutically targeting matrix stiffness may help reduce migration and invasion of SACC and improve effective therapies.
Highlights
Salivary adenoid cystic carcinoma (SACC) is one of the most common malignant tumours of the salivary gland, accounting for about 18% of all salivary gland malignancies and about 1% of all head and neck malignant tumours.[1,2,3] Typical clinical and biological characteristics of SACC include perineural invasion, blood vessel invasion and distant metastasis, which often lead to poor prognosis and lower survival rate
The results showed that substrate stiffness, acting as mechanical stimulus, regulated the expressions of MMPs and TIMPs in ACC2 cells
Matrix metalloproteinases belong to a family of Zn2+-binding and Ca2+-dependent proteolytic enzymes whose basic function is extracellular matrix (ECM) degradation, a process that is required for cell migration and invasion.[21]
Summary
Salivary adenoid cystic carcinoma (SACC) is one of the most common malignant tumours of the salivary gland, accounting for about 18% of all salivary gland malignancies and about 1% of all head and neck malignant tumours.[1,2,3] Typical clinical and biological characteristics of SACC include perineural invasion, blood vessel invasion and distant metastasis, which often lead to poor prognosis and lower survival rate. The precise mechanisms underlying migration and invasion of SACC are not known. The normal breast has the Young’s modulus of 0.8-1.2 kpa.[6] The Young’s modulus of breast cancer of different grades and category is from 20 to 200 kpa.[7] Numerous studies have shown that mechanical changes in the cell microenvironment may be responsible for specific behaviours of cells, such as adhesion, proliferation and migration.[8] Substrate stiffness has been reported to be powerful regulators of cell migration. We investigated in this study, whether substrate stiffness modulates migration and invasion ability of SACC by the expressions of MMPs and TIMPs, using ACC2 cell line and polydimethylsiloxane substrates (PDMS) substrates of varying stiffness.
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