Abstract
Purpose: To analyze human and bacteria proteomic profiles in bile, exposed to a tumor vs. non-tumor microenvironment, in order to identify differences between these conditions, which may contribute to a better understanding of pancreatic carcinogenesis.Patients and Methods: Using liquid chromatography and mass spectrometry, human and bacterial proteomic profiles of a total of 20 bile samples (7 from gallstone (GS) patients, and 13 from pancreatic head ductal adenocarcinoma (PDAC) patients) that were collected during surgery and taken directly from the gallbladder, were compared. g:Profiler and KEGG (Kyoto Encyclopedia of Genes and Genomes) Mapper Reconstruct Pathway were used as the main comparative platform focusing on over-represented biological pathways among human proteins and interaction pathways among bacterial proteins.Results: Three bacterial infection pathways were over-represented in the human PDAC group of proteins. IL-8 is the only human protein that coincides in the three pathways and this protein is only present in the PDAC group. Quantitative and qualitative differences in bacterial proteins suggest a dysbiotic microenvironment in the PDAC group, supported by significant participation of antibiotic biosynthesis enzymes. Prokaryotes interaction signaling pathways highlight the presence of zeatin in the GS group and surfactin in the PDAC group, the former in the metabolism of terpenoids and polyketides, and the latter in both metabolisms of terpenoids, polyketides and quorum sensing. Based on our findings, we propose a bacterial-induced carcinogenesis model for the biliary tract.Conclusion: To the best of our knowledge this is the first study with the aim of comparing human and bacterial bile proteins in a tumor vs. non-tumor microenvironment. We proposed a new carcinogenesis model for the biliary tract based on bile metaproteomic findings. Our results suggest that bacteria may be key players in biliary tract carcinogenesis, in a long-lasting dysbiotic and epithelially harmful microenvironment, in which specific bacterial species' biofilm formation is of utmost importance. Our finding should be further explored in future using in vitro and in vivo investigations.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a malignant and highly lethal neoplasm of unknown etiology and is usually diagnosed at advanced stages [1]
In this study, using a paradigm shifting metaproteomic approach, we aimed to unravel novel and meaningful biological information that may contribute to a better understanding of PDAC bacteriainduced carcinogenesis, proposing a new carcinogenesis model for the biliary tract
A total of 20 bile samples extracted from gallbladders were analyzed, seven of which were taken from patients with GS (Table 1), and 13 from patients with PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a malignant and highly lethal neoplasm of unknown etiology and is usually diagnosed at advanced stages [1]. The currently available surgical interventions and chemotherapeutic regimes are unable to provide the desired impact on disease outcomes, and there is a clear, dismal prognosis, as 70–80% of patients will succumb to this disease during the first 2 years post-diagnosis [2]. Modifiable and non-modifiable risk factors for PDAC have an unconvincing molecular association with the disease. The development of interventions that successfully reduce the incidence of this lethal malignancy and improve its outcome is limited by the scarce knowledge of the molecular factors that may play a role in the complex process of PDAC carcinogenesis [9]. Any effort to better understand PDAC carcinogenesis, or to unravel novel therapies, may be the starting point in driving future clinical interventions
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