OBJECTIVES: Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs. METHODS: In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. RESULTS: In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. CONCLUSIONS: The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.
OBJECTIVES:Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs. METHODS: In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. RESULTS: In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. CONCLUSIONS: The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.
Authors: Shuichi Aoki; Koetsu Inoue; Sebastian Klein; Stefan Halvorsen; Jiang Chen; Aya Matsui; Mohammad R Nikmaneshi; Shuji Kitahara; Tai Hato; Xianfeng Chen; Kazumichi Kawakubo; Hadi T Nia; Ivy Chen; Daniel H Schanne; Emilie Mamessier; Kohei Shigeta; Hiroto Kikuchi; Rakesh R Ramjiawan; Tyge Ce Schmidt; Masaaki Iwasaki; Thomas Yau; Theodore S Hong; Alexander Quaas; Patrick S Plum; Simona Dima; Irinel Popescu; Nabeel Bardeesy; Lance L Munn; Mitesh J Borad; Slim Sassi; Rakesh K Jain; Andrew X Zhu; Dan G Duda Journal: Gut Date: 2021-01-11 Impact factor: 31.793
Authors: Vida Mashayekhi; Orsola Mocellin; Marcel H A M Fens; Gerard C Krijger; Lodewijk A A Brosens; Sabrina Oliveira Journal: Theranostics Date: 2021-08-25 Impact factor: 11.556