S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer

Hiromichi Nakayama, Akiko Yonenaga, Akiko Sagara, Yohei Ando, Shin Kibe, Shin Takesue, Toshiya Abe, Sho Endo, Kazuhiro Koikawa, Takashi Okumura, Koji Shido, Kei Miyoshi, Kohei Nakata, Taiki Moriyama, Yoshihiro Miyasaka, Shigetaka Inoue, Ohtsuka Takao, Kazuhiro Mizumoto, Kenoki Ouchida, Masafumi Nakamura

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)211-222
Number of pages12
JournalInternational journal of oncology
Volume55
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

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Pancreatic Neoplasms
Endothelial Cells
Neoplasms
Neoplasm Metastasis
Lymph Nodes
Cultured Cells
Time-Lapse Imaging
Lymphatic Metastasis
Lymphatic Vessels
Calcium-Binding Proteins
Microarray Analysis
Coculture Techniques
Cell Wall
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer. / Nakayama, Hiromichi; Yonenaga, Akiko; Sagara, Akiko; Ando, Yohei; Kibe, Shin; Takesue, Shin; Abe, Toshiya; Endo, Sho; Koikawa, Kazuhiro; Okumura, Takashi; Shido, Koji; Miyoshi, Kei; Nakata, Kohei; Moriyama, Taiki; Miyasaka, Yoshihiro; Inoue, Shigetaka; Takao, Ohtsuka; Mizumoto, Kazuhiro; Ouchida, Kenoki; Nakamura, Masafumi.

In: International journal of oncology, Vol. 55, No. 1, 01.01.2019, p. 211-222.

Research output: Contribution to journalArticle

Nakayama, H, Yonenaga, A, Sagara, A, Ando, Y, Kibe, S, Takesue, S, Abe, T, Endo, S, Koikawa, K, Okumura, T, Shido, K, Miyoshi, K, Nakata, K, Moriyama, T, Miyasaka, Y, Inoue, S, Takao, O, Mizumoto, K, Ouchida, K & Nakamura, M 2019, 'S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer', International journal of oncology, vol. 55, no. 1, pp. 211-222. https://doi.org/10.3892/ijo.2019.4812
Nakayama, Hiromichi ; Yonenaga, Akiko ; Sagara, Akiko ; Ando, Yohei ; Kibe, Shin ; Takesue, Shin ; Abe, Toshiya ; Endo, Sho ; Koikawa, Kazuhiro ; Okumura, Takashi ; Shido, Koji ; Miyoshi, Kei ; Nakata, Kohei ; Moriyama, Taiki ; Miyasaka, Yoshihiro ; Inoue, Shigetaka ; Takao, Ohtsuka ; Mizumoto, Kazuhiro ; Ouchida, Kenoki ; Nakamura, Masafumi. / S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer. In: International journal of oncology. 2019 ; Vol. 55, No. 1. pp. 211-222.
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abstract = "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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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 - Takao, Ohtsuka

AU - Mizumoto, Kazuhiro

AU - Ouchida, Kenoki

AU - Nakamura, Masafumi

PY - 2019/1/1

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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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