TY - JOUR
T1 - Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180
AU - Koikawa, Kazuhiro
AU - Ohuchida, Kenoki
AU - Takesue, Shin
AU - Ando, Yohei
AU - Kibe, Shin
AU - Nakayama, Hiromichi
AU - Endo, Sho
AU - Abe, Toshiya
AU - Okumura, Takashi
AU - Horioka, Kohei
AU - Sada, Masafumi
AU - Iwamoto, Chika
AU - Moriyama, Taiki
AU - Nakata, Kohei
AU - Miyasaka, Yoshihiro
AU - Ohuchida, Riichi
AU - Manabe, Tatsuya
AU - Takao, Ohtsuka
AU - Nagai, Eishi
AU - Mizumoto, Kazuhiro
AU - Hashizume, Makoto
AU - Nakamura, Masafumi
N1 - Funding Information:
This work was supported in part by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (B) and (C) and Scientific Research on Innovative Areas (Grant numbers 26108010 , 26293305 , 15K10185 , 25713050 , 16K15621 , 16K10601 , 16K10600 , 16H05417 , 15K15498 , 15H04933 , and 16H05418 ).
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Specific cell populations leading the local invasion of cancer are called “leading cells”. However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.
AB - Specific cell populations leading the local invasion of cancer are called “leading cells”. However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.
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U2 - 10.1016/j.canlet.2017.10.010
DO - 10.1016/j.canlet.2017.10.010
M3 - Article
C2 - 29061505
AN - SCOPUS:85032707374
SN - 0304-3835
VL - 412
SP - 143
EP - 154
JO - Cancer Letters
JF - Cancer Letters
ER -
