TY - JOUR
T1 - Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness
AU - Tanaka, Hiroyoshi Y.
AU - Kitahara, Kentaro
AU - Sasaki, Naoki
AU - Nakao, Natsumi
AU - Sato, Kae
AU - Narita, Hirokazu
AU - Shimoda, Hiroshi
AU - Matsusaki, Michiya
AU - Nishihara, Hiroshi
AU - Masamune, Atsushi
AU - Kano, Mitsunobu R.
N1 - Funding Information:
The authors deeply thank Dr. Hiromi Matsubara and Dr. Aiko Ogawa (National Hospital Organization Okayama Medical Center) for the generous provision of experimental facilities, Dr. Kazuki Nagashima (Stanford University) for valuable discussion and assistance, and Prof. Michael W. Miller for editorial work. The authors are furthermore grateful to the members of the lab, especially Taiki Oosato, Yuuki Kurahashi, Chiharu Morii, Yoshiko Okita, Kengo Harada, and Haruko Ohta for insightful discussion and valuable technical assistance. This study was supported in part by Grant-in-Aid for Scientific Research (KAKENHI) ( 26293119 , 15H04804 , 18H02797 ), Okayama University , Kato Memorial Bioscience Foundation , the Mitsui Life Social Welfare Foundation , the Smoking Research Foundation , the Pancreas Research Foundation of Japan , and JSPS Core-to-Core Program, A. Advanced Research Networks. H.Y.T. was supported by a Ph.D. scholarship from the Takeda Science Foundation .
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/2
Y1 - 2019/2
N2 - 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)-β/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.
AB - 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)-β/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.
KW - 3D culture
KW - Extracellular matrix remodeling
KW - Fibrosis
KW - Pancreatic stellate cell
KW - SPARC
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U2 - 10.1016/j.biomaterials.2018.11.023
DO - 10.1016/j.biomaterials.2018.11.023
M3 - Article
C2 - 30476717
AN - SCOPUS:85059323773
SN - 0142-9612
VL - 192
SP - 355
EP - 367
JO - Biomaterials
JF - Biomaterials
ER -
