TY - JOUR
T1 - Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma
AU - Koikawa, Kazuhiro
AU - Ohuchida, Kenoki
AU - Ando, Yohei
AU - Kibe, Shin
AU - Nakayama, Hiromichi
AU - Takesue, Shin
AU - Endo, Sho
AU - Abe, Toshiya
AU - Okumura, Takashi
AU - Iwamoto, Chika
AU - Moriyama, Taiki
AU - Nakata, Kohei
AU - Miyasaka, Yoshihiro
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 17H04284 , 17K19602 , 15K10185 , 16K15621 , 16K10601 , 16H05417 , 15H04933 , 16H05418 , 17K19605 ).
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.
AB - Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.
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U2 - 10.1016/j.canlet.2018.03.031
DO - 10.1016/j.canlet.2018.03.031
M3 - Article
C2 - 29580808
AN - SCOPUS:85056318980
SN - 0304-3835
VL - 425
SP - 65
EP - 77
JO - Cancer Letters
JF - Cancer Letters
ER -
