Abstract 719: Pathobiological implications of Trefoil Factors in the progression and metastasis of pancreatic cancer
Authors: Jahan Rahat , Kaur Sukhwinder , Macha Muzafar A. , Sheinin Yuri , Smith Lynette , Meza Jane , Batra Surinder K. 
Published: July 2017

Background: Pancreatic cancer (PC) is a highly lethal malignancy and the disastrous statistics warrants an urgent need to develop new diagnostic and prognostic marker(s) and therapeutic target(s) for its better management. Trefoil factors (TFF 1/2/3) are a family of small, stable molecules observed to co-express with mucin and secreted by mucus-producing cells that facilitate mucosal repair after injury. Recent studies have shown that TFF1 and TFF3 can differentiate between molecular subtypes of PC. Based on this, we hypothesized that differential expression of TFF1 and TFF3 could predict pancreatic intraepithelial neoplasia (PanIN) as well as the early stage of PC. The present study explores the diagnostic and functional significance of TFF in PC.

Material and Methods: Immunohistochemistry was used to determine the expression status of TFF1 and TFF3 in PC tissue microarray containing normal pancreatic (n=40), pancreatic intraepithelial lesion 1, 2, 3 (PanIN 1- 3, n=13) and well, moderately and poorly differentiated PC tissues (n=149). Sandwich ELISA was used to detect TFF1 levels in serum. The diagnostic significance of TFF1 was evaluated in the sample set (n=331) comprising of benign control (BC, n=104), chronic pancreatitis (CP, n=47), early stage PC (EPC, Stage 1 and 2, n=78) and late PC (LPC, Stage 2-3, n=69). RT-PCR and ELISA were carried out to profile levels of TFF1 and TFF3 in PC cell lines and cell supernatants respectively. Recombinant treatment with TFF3 was performed to observe the impact on of transmembrane (MUC4) and secreted mucins (MUC5AC) stability and expression.

Results: Differential expression of TFF3 was observed in PanIN precursor lesion, pancreatic cancer tissue in comparison to normal pancreatic tissue (p &lt; 0.0003). Furthermore, the TFF3 expression was significantly higher for well-differentiated tumor in comparison to poorly differentiated cases (p = 0.006). For TFF1, expression was significantly higher in PanIN lesions compared to normal pancreas (p &lt; 0.0001), and PC versus normal pancreatic tissue (p &lt; 0.0001). In serum, significantly increased expression of TFF1 was observed in EPC serum samples compared to BC (p-value = 0.035) and CP (p-value=0.0058) cases. RT-PCR analysis revealed positive expression of TFF1 and TFF3 in the majority of the PC cell lines. Treatment of PC cells with recombinant TFF3 lead to differential expression of MUC4 and MUC5AC.

Conclusion: Overall, both tissue and serum based studies show that TFF1 and TFF3 are differentially expressed in early PanIN lesions as well early stage of PC tissues compared to normal pancreas. Overall, these results suggest a potential implication of TFF1 and TFF3 in PC pathogenesis and provide a basis for functional impact of TFF 1 and 3 on mucins stability and downstream signaling in PC pathogenesis.

Citation Format: Rahat Jahan, Sukhwinder Kaur, Muzafar A. Macha, Yuri Sheinin, Lynette Smith, Jane Meza, Surinder K. Batra. Pathobiological implications of Trefoil Factors in the progression and metastasis of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 719. doi:10.1158/1538-7445.AM2017-719