Abstract A55: A role of bone morphogenetic protein signaling in pancreatic cancer
Authors: Miyabayashi Koji , Ijichi Hideaki , Takahashi Ryota , Yamamoto Keisuke , Asaoka Yoshinari , Tateishi Keisuke , Nakai Yousuke , Isayama Hiroyuki , Moses Harold L. , Koike Kazuhiko 
Published: October 2015

TGF-beta signaling has a crucial role in pancreatic tumorigenesis, and almost all of pancreatic cancers carry at least one genetic alteration of TGF-beta related genes, such as SMAD4, TGFBR2, SMAD3, and BMPR2. However, the role of BMP signaling in pancreatic cancer remains unclear. Previous studies reported the depletion of BMP signaling resulted in the aggressive phenotype of cancer, and some reported BMP signaling played an important role in tumor progression and metastasis.

We have already established pancreas-specific Tgbr2 knockout mice in the context of Kras activation, which clinically and histopathologically recapitulate human PDAC. With regard to PDAC, Smad4 mutation or deletion is more commonly observed, however the Smad4 knockout mice with activating Kras mutation was reported to show cystic type tumor of pancreas. Therefore, our Kras+Tgfbr2KO might be the closest approximation of the human PDAC in terms of histology. We examined the effect of BMP signaling on the tumorigenesis and progression of PDAC using this mouse model.

We performed immunohistochemistry of murine PDAC to evaluate whether BMP signaling was related to the PDAC progression. We examined the effect of Bmp4 and Bmp7 on the proliferation, invasion and adhesion using murine PDAC and PanIN cells in vitro. We have already established the murine PDAC cell lines from Pancreas-specific Kras+Tgfbr2KO mice and murine PanIN cells from Pancreas-specific activating Kras mutation mice. Bmpr2 was knocked down in PanIN cell lines using shRNA, and we examined whether the effect of BMP signaling was canceled by Bmpr2 knockdown. In vivo, we evaluated the effect of BMP signaling on tumor growth and tumor-stromal interaction using the xenograft mouse model of Bmpr2-negative PanIN cells.

The immunohistochemistry of murine pancreas tissues demonstrated that Smad1/5/8 was more strongly phosphorylated in PDAC compared to PanIN lesion. We also observed that Smad1/5/8 was phosphorylated in stromal cells surrounding tumor areas, which was likely to suggest the importance of BMP signaling in PDAC progression and tumor-stromal interaction. In vitro, both Bmp4 and Bmp7 did not affect the proliferation and invasion of PDAC and PanIN cells, but they increased the adhesion of PDAC and PanIN cells, and knockdown of Bmpr2 canceled the effect of Bmps. In vivo, we evaluated the growth of subcutaneous tumor allograft and the tumors of Bmpr2-negative PanIN cells showed slower tumor growth than tumors of the control, differently from the results in vitro. These results suggested that BMP signaling was associated with the tumor-stromal interaction and played important role in tumor progression.

In this study we evaluated the role of BMP signaling in pancreatic cancer using pancreas-specific Kras+Tgfbr2KO mice, and demonstrated that BMP signaling played important role in the adhesion and progression of pancreatic cancer, which was due to the tumor-stromal interaction.

Citation Format: Koji Miyabayashi, Hideaki Ijichi, Ryota Takahashi, Keisuke Yamamoto, Yoshinari Asaoka, Keisuke Tateishi, Yousuke Nakai, Hiroyuki Isayama, Harold L. Moses, Kazuhiko Koike. A role of bone morphogenetic protein signaling in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A55.