Abstract A67: TFF (Trefoil Factor Family) is a novel tumor suppressor and can be the therapeutic target for pancreatic cancer
Authors: Yamaguchi Junpei , Yokoyama Yukihiro , Kokuryo Toshio , Nagino Masato 
Published: December 2016

Purpose: TFF (Trefoil Factor Family) are secretory protein abundantly expressed in the mucosa of GI system. The key role of TFF is healing of damaged gastrointestinal mucosa by a process called restitution. Among 3 subtypes of TFF, TFF1 is expressed in normal gastric mucosa in foveolar epithelial surface cells, and TFF2 in deep antral gland mucous cells. Recent reports revealed that loss of TFF1 result in gastric tumorigenesis and that loss of TFF2 accelerates Helicobacter-pylori induced gastric dysplasia, suggesting that TFF play a role as tumor suppressor in gastric carcinogenesis. Here we aimed to clarify whether TFF can also act as tumor suppressor in pancreatic tumorigenesis, and to investigate how to utilize the tumor-suppressive function of TFF against pancreatic cancer.

Material and Methods: The expression patterns of TFF1 and TFF2 in surgically resected pancreas (Organ Donor, Pancreatitis, IPMN; Intraductal Papillary Mucinous Neoplasm and PDAC; Pancreatic Ductal Adenocarcinoma) were analyzed by immunohistochemistry. Pancreatic cancer cell lines were transfected with either siRNA against TFF1 or overexpression vector of TFF2 in order to investigate the functional role of TFF. Pancreatic cancer cell lines were treated with estradiol and/or pioglitazone to evaluate the effect of TFF in vitro.

Results: In normal and injured pancreas, TFF expression was found only in PDG (Pancreatic Duct Gland), the progenitor compartment of pancreatic ductal epithelium located in the mesenchymal cuff of pancreatic duct. Premalignant lesions of pancreas express abundant TFF; TFF1 throughout tumor cells of PanIN and IPMN, TFF2 in tumor-progenitor compartment PDG. TFF expressions are lost in invasive pancreatic cancer, indicating that TFF1 and TFF2 might act as tumor suppressor in pancreatic carcinogenesis. The suppression of TFF1 in pancreatic cancer cell lines results in the epithelial-mesenchymal transition (EMT) and accelerated invasive ability of cancer cells, while overexpression of TFF2 inhibit proliferative ability of cancer cells. These results suggest that TFF1 and TFF2 have tumor-suppressive function for pancreatic cancer in a different manner. Estradiol has been known to upregulate TFF1, and pioglitazone was found to upregulate TFF2 expression. Either of these drugs has mild tumor suppressive effect; however, combined use of them showed enhanced suppression of cancer cell proliferation in vitro.

Conclusion: TFF1 and TFF2 act as tumor suppressor in pancreatic carcinogenesis in a different manner, and they can be a novel therapeutic target for PDAC.

Citation Format: Junpei Yamaguchi, Yukihiro Yokoyama, Toshio Kokuryo, Masato Nagino.{Authors}. TFF (Trefoil Factor Family) is a novel tumor suppressor and can be the therapeutic target for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A67.