Trefoil Factor 1 Stimulates Both Pancreatic Cancer and Stellate Cells and Increases Metastasis

Abstract

Objectives Trefoil factor 1 (TFF1) is a stable secretory protein expressed widely in the gastrointestinal mucosa that is also expressed in pancreatic ductal adenocarcinoma (PDAC). In the current study, we documented the extent and timing of TFF1 expression and investigated the effects of TFF1 on PDAC cells and stellate cells, the primary cells of the PDAC stroma. Methods Trefoil factor 1 expression in pancreatic cancer tissues and cell lines was analyzed using microarray, quantitative reverse transcriptase–polymerase chain reaction, and immunohistochemistry. The effects of recombinant TFF1 on cell growth, migration, and invasion of pancreatic cancer cell lines and immortalized human pancreatic stellate cells (HPSCs) were analyzed using MTS and Matrigel-coated invasion chambers. In vivo studies were also conducted in which Mpanc-96 cells stably expressing TFF1 were implanted orthotopically into nude mice. Results Trefoil factor 1 was highly increased in preneoplastic lesions. Recombinant TFF1 stimulated motility of both cancer and HPSCs. In contrast, only HPSC cell growth was increased by TFF1. In vivo studies showed that overexpression of TFF1 in PDAC cells did not affect primary tumor growth but greatly increased metastasis. Conclusions The present data demonstrate that TFF1 influences both PDAC cells and stellate cells and stimulates metastasis.

Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer

“…However, seemingly contradictory to its proposed role as a tumor suppressor, TFF1 is frequently ectopically expressed or overexpressed in many human cancers, including oesophagus, lung, breast, pancreas, biliary tract, large bowel, mucinous-subtype ovarian tumors, bladder and prostate as well as their associated metastases [68][69][70][71]. In all TFF1-positive cancers, the protein is expressed in the cytoplasm of the tumor epithelial cells, as it is in normal gastric mucosal cells [10,25,72] (Fig.…”

Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features

“…27 TFF1 is normally expressed in gastric mucosa and in the adenocarcinoma of many organs, including pancreatic adenocarcinoma. 28 AGR2 is a secreted protein and a potential member of the endoplasmic reticulum-associated protein disulfide isomerase family, as evidenced by its structural similarity to other protein disulfide isomerase proteins. 29 AGR2 promotes the initiation and progression of pancreatic intraepithelial neoplasia.…”

Pancreatic Stellate Cells

“…There is evidence that increased ECM synthesis by PSCs in response to cancer cells is likely mediated by TGFβ1 and fibroblast growth factor 2 (FGF2) [136]. Factors implicated in cancer cell-induced PSC proliferation include PDGF, COX-2 [137], and trefoil factor 1 (TFF1) [138] (a stable secretory protein that is upregulated in pancreatic cancer but not expressed in the normal pancreas), with ERK1/2 identified as the responsible signaling pathway [138]. Factors mediating the effects of PSCs on cancer cells have not yet been characterized, although there is evidence that PSCinduced proliferation of cancer cells may be mediated, at least in part, by PDGF [139].…”