Fibroblast activation protein-aα-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma

Tomoya Kawase, Yumiko Yasui, Sohji Nishina, Yuichi Hara, Izumi Yanatori, Yasuyuki Tomiyama, Yoshihiro Nakashima, Koji Yoshida, Fumio Kishi, Masafumi Nakamura, Keisuke Hino

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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-aα (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC. Methods: FAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line). Results: Stromal FAP expression was detected in 98 % (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb. Conclusions: The present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.

Original languageEnglish
Article number109
JournalBMC Gastroenterology
Volume15
Issue number1
DOIs
Publication statusPublished - Sep 2 2015

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Adenocarcinoma
Fibroblasts
Proteins
Coculture Techniques
Cell Cycle
Survival Rate
Cell Line
Retinoblastoma Protein
Retinoblastoma
Pancreatic Neoplasms

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Fibroblast activation protein-aα-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. / Kawase, Tomoya; Yasui, Yumiko; Nishina, Sohji; Hara, Yuichi; Yanatori, Izumi; Tomiyama, Yasuyuki; Nakashima, Yoshihiro; Yoshida, Koji; Kishi, Fumio; Nakamura, Masafumi; Hino, Keisuke.

In: BMC Gastroenterology, Vol. 15, No. 1, 109, 02.09.2015.

Research output: Contribution to journalArticle

Kawase, T, Yasui, Y, Nishina, S, Hara, Y, Yanatori, I, Tomiyama, Y, Nakashima, Y, Yoshida, K, Kishi, F, Nakamura, M & Hino, K 2015, 'Fibroblast activation protein-aα-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma', BMC Gastroenterology, vol. 15, no. 1, 109. https://doi.org/10.1186/s12876-015-0340-0
Kawase, Tomoya ; Yasui, Yumiko ; Nishina, Sohji ; Hara, Yuichi ; Yanatori, Izumi ; Tomiyama, Yasuyuki ; Nakashima, Yoshihiro ; Yoshida, Koji ; Kishi, Fumio ; Nakamura, Masafumi ; Hino, Keisuke. / Fibroblast activation protein-aα-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. In: BMC Gastroenterology. 2015 ; Vol. 15, No. 1.
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abstract = "Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-aα (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC. Methods: FAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line). Results: Stromal FAP expression was detected in 98 {\%} (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb. Conclusions: The present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.",
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AU - Kawase, Tomoya

AU - Yasui, Yumiko

AU - Nishina, Sohji

AU - Hara, Yuichi

AU - Yanatori, Izumi

AU - Tomiyama, Yasuyuki

AU - Nakashima, Yoshihiro

AU - Yoshida, Koji

AU - Kishi, Fumio

AU - Nakamura, Masafumi

AU - Hino, Keisuke

PY - 2015/9/2

Y1 - 2015/9/2

N2 - Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-aα (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC. Methods: FAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line). Results: Stromal FAP expression was detected in 98 % (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb. Conclusions: The present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.

AB - Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-aα (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC. Methods: FAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line). Results: Stromal FAP expression was detected in 98 % (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb. Conclusions: The present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.

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