TY - JOUR
T1 - S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer
AU - Nakayama, Hiromichi
AU - Yonenaga, Akiko
AU - Sagara, Akiko
AU - Ando, Yohei
AU - Kibe, Shin
AU - Takesue, Shin
AU - Abe, Toshiya
AU - Endo, Sho
AU - Koikawa, Kazuhiro
AU - Okumura, Takashi
AU - Shido, Koji
AU - Miyoshi, Kei
AU - Nakata, Kohei
AU - Moriyama, Taiki
AU - Miyasaka, Yoshihiro
AU - Inoue, Shigetaka
AU - Ohtsuka, Takao
AU - Mizumoto, Kazuhiro
AU - Ohuchida, Kenoki
AU - Nakamura, Masafumi
N1 - Funding Information:
This work was supported in part by the Japan Society for the Promotion of Science Grants‑in‑Aid for Scientific Research and Scientific Research on Innovative Areas (grant nos. 17H04284, 17K19602, 16K10601, 16H05418 and 17K19605) and the Shinnihon Foundation of Advanced Medical Treatment Research (grant no. SN201705).
Publisher Copyright:
© 2019 Spandidos Publications. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent-induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co-culture system was then used to analyze the mechanisms of tumor cell-mediated disruption of lymphatic vessels. Time-lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.
AB - Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent-induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co-culture system was then used to analyze the mechanisms of tumor cell-mediated disruption of lymphatic vessels. Time-lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.
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U2 - 10.3892/ijo.2019.4812
DO - 10.3892/ijo.2019.4812
M3 - Article
C2 - 31180531
AN - SCOPUS:85068403717
VL - 55
SP - 211
EP - 222
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 1
ER -