Erica Dugnani1, Valeria Sordi1, Silvia Pellegrini1, Raniero Chimienti1, Ilaria Marzinotto2, Valentina Pasquale1, Daniela Liberati2, Gianpaolo Balzano3, Claudio Doglioni4, Michele Reni5, Alessandra Gandolfi1, Massimo Falconi6, Vito Lampasona2, Lorenzo Piemonti7. 1. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. 2. Division of Genetics and Cell Biology, Genomic Unit for the Diagnosis of Human Pathologies, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. 3. Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. 4. Department of Pathology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. 5. Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. 6. Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. 7. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: piemonti.lorenzo@hsr.it.
Abstract
BACKGROUND: Despite the recent introduction of new drugs and the development of innovative multi-target treatments, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. Even when PDAC is resectable, the rate of local or widespread disease recurrence remains particularly high. Currently, reliable prognostic biomarkers of recurrence are lacking. We decided to explore the potential usefulness of pancreatic developmental regulators as biomarkers of PDAC relapse. METHODS: We analyzed by quantitative real-time PCR the mRNA of selected factors involved either in pancreatic organogenesis (ISL1, NEUROD1, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1 and PTF1α) or associated with terminally committed pancreatic cells (CHGA, CHGB, GAD2, GCG, HNF6α, INS, KRT19, SYP) in 17 PDAC cell lines and in frozen tumor samples from 41 PDAC patients. RESULTS: High baseline levels of the ISL1, KRT19, PAX6 and PDX1 mRNAs in PDAC cell lines, were risk factors for time-dependent xenograft appearance after subcutaneous injection in CD1-Nude mice. Consistently, in human PDAC samples, high levels of KRT19 mRNA were associated with reduced overall survival and earlier recurrence. Higher levels of PDX1 or PAX6 mRNAs were instead associated with a higher frequency of local recurrence. CONCLUSIONS: Our findings suggest that selected factors associated with pancreas development or its terminal differentiation might be implicated in mechanisms of PDAC progression and/or metastatic spread and that the measurement of their mRNA in tumors might be potentially used to improve patient prognostic stratification and prediction of the relapse site.
BACKGROUND: Despite the recent introduction of new drugs and the development of innovative multi-target treatments, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. Even when PDAC is resectable, the rate of local or widespread disease recurrence remains particularly high. Currently, reliable prognostic biomarkers of recurrence are lacking. We decided to explore the potential usefulness of pancreatic developmental regulators as biomarkers of PDAC relapse. METHODS: We analyzed by quantitative real-time PCR the mRNA of selected factors involved either in pancreatic organogenesis (ISL1, NEUROD1, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1 and PTF1α) or associated with terminally committed pancreatic cells (CHGA, CHGB, GAD2, GCG, HNF6α, INS, KRT19, SYP) in 17 PDAC cell lines and in frozen tumor samples from 41 PDACpatients. RESULTS: High baseline levels of the ISL1, KRT19, PAX6 and PDX1 mRNAs in PDAC cell lines, were risk factors for time-dependent xenograft appearance after subcutaneous injection in CD1-Nude mice. Consistently, in humanPDAC samples, high levels of KRT19 mRNA were associated with reduced overall survival and earlier recurrence. Higher levels of PDX1 or PAX6 mRNAs were instead associated with a higher frequency of local recurrence. CONCLUSIONS: Our findings suggest that selected factors associated with pancreas development or its terminal differentiation might be implicated in mechanisms of PDAC progression and/or metastatic spread and that the measurement of their mRNA in tumors might be potentially used to improve patient prognostic stratification and prediction of the relapse site.
Authors: Liya G Kondratyeva; Dina R Safina; Igor P Chernov; Eugene P Kopantzev; Sergey V Kostrov; Eugene D Sverdlov Journal: Cancer Manag Res Date: 2019-07-26 Impact factor: 3.989