The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

Keywords: cancer treatment; immune suppression; microbiota modulation; pancreatic ductal adenocarcinoma (PDAC); pancreatic microbiome; tumor microenvironment.

Figure 1

The pancreatic microbiota as a component of the tumor microenvironment. Comprehensive microbial studies support the existence of constant interactions between oral, gut, and pancreatic microbiome. Dysbiosis contributes to multiple changes associated with PDAC. Disruption of gut microbiota leads to enhanced bacterial translocation and subsequent activation of TLRs signaling pathway in the pancreatic environment. Besides, decreased SCFA metabolites negatively influence the production of pancreatic antimicrobial peptides. Microbiota-derived signals might affect pancreatic oncogenesis via NF-kB/MAPK, STAT3, or mTOR tumor-related inflammatory pathways. Moreover, immune response modulation leading to reduced Th1 CD4+ and CD8+ T cell differentiation and increased Th2 levels as well as the production of pro-tumorigenic metabolites might represent the pro-oncogenic mechanisms. Since microbiota has been recognized as an important part of the PDAC microenvironment, possible interactions with PSCs/CAFs need to be considered and further evaluated. Importantly, microbiota-dependent remodeling of tumor microenvironment towards PDAC immunosuppression has been reported, suggesting the complex interplay between all components within the tumor might affect the sensitivity to PDAC treatment. Abbreviations: CAFs, cancer-associated fibroblasts; MAPK, a mitogen-activated protein kinase; MDSCs, myeloid-derived suppressor cells; mTOR, the mammalian target of rapamycin; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PAMPs, pathogen-associated molecular patterns; PDAC, pancreatic ductal adenocarcinoma; PSCs, pancreatic stellate cells; SCFA, short-chain fatty acid; STAT3, signal transducer and activator of transcription 3; Th2 cells, T helper 2 cells; T reg cells, regulatory T cells; TLRs, Toll-like receptors.

Figure 2

The possible trend of the gut and/or tumor microbiome modulation in PDAC. Precise targeting of microbiota composition might represent a novel approach to improve the therapeutic efficacy and clinical outcome for PDAC patients. Further research and randomized control trials with careful benefit-risk assessment are warranted due to the considerable risks of infection in immunosuppressive cancer patients. Abbreviations: PDAC, pancreatic ductal adenocarcinoma.