期刊
BIOMATERIALS
卷 192, 期 -, 页码 355-367出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.11.023
关键词
Fibrosis; Extracellular matrix remodeling; 3D culture; Pancreatic stellate cell; SPARC
资金
- KAKENHI [26293119, 15H04804, 18H02797]
- Okayama University
- Kato Memorial Bioscience Foundation
- Mitsui Life Social Welfare Foundation
- Smoking Research Foundation
- Pancreas Research Foundation of Japan
- JSPS
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [15H04804, 26293119, 18H02797] Funding Source: KAKEN
Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-beta/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.
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