Association of the Microbiota and Pancreatic Cancer: Opportunities and Limitations

Abstract

The human body is thoroughly colonized by a wide variety of microorganisms, termed microbiota. Pancreatic cancer, one of the most aggressive forms of cancer, is no exception. The microbiota of pancreatic cancer largely influences and even dominates the occurrence, development and outcome of pancreatic cancer in many ways. Studies have shown that microbiota could change the malignant phenotype and prognosis of pancreatic cancer by stimulating persistent inflammation, regulating the antitumor immune system, changing the tumor microenvironment and affecting cellular metabolism. This is why the association of the microbiota with pancreatic cancer is an emerging area of research that warrants further exploration. Herein, we investigated the potential microbial markers of pancreatic cancer, related research models, the mechanism of action of microbiota in pancreatic cancer, and pancreatic cancer-microbiota-related treatment.

Keywords: biomarkers; microbiota; molecular mechanism; pancreatic cancer; targeted therapy.

Figure 1

The pathways the microbiota migrates to the pancreatic tissue. Transduodenal papillary reflux pathway: The pancreas is connected to the oral cavity, esophagus, and stomach upward through the pancreatic duct, downward to the duodenum, and adjacent to the common bile duct. These features suggest the possibility of microbiota reflux into the pancreatic duct and then into the pancreatic parenchyma through the large/little papillae. Translymphatic circulation pathway: The microbiota distant from the pancreas (such as in the colon) enters the MLN by chance and is phagocytized by mononuclear phagocytes (e.g. CX3CR1⁺ cells) or DCs, and instead of being lysed, these opportunistic pathogens are fortunately transferred to the pancreatic tissue for reproduction via the lymphatic system. Transcirculatory pathway: The microbiota far away from the pancreas (such as in the colon) enters the blood under pathological conditions (such as damage to the intestinal barrier caused by colitis), and colonizes other organs, including pancreatic tissue, along with the blood circulation.

Figure 2

Potential microbial markers associated with PC. Oral microbial markers: Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans; Gastric microbial markers: Helicobacter pylori; Duodenal microbiota markers: Acinetobacter, Aquabacterium, Oceanobacillus, Rahnella, Massilia, Delftia, Deinococcus and Sphingobium; Common bile duct microbial markers: Enterococcus, Streptococcus, Shigella, Veroella and Enterobacter; Colonic microbial markers: Proteobacteria, Synergistetes, Euryarchaeota, Ascomycota and Basidiomycota; Pancreatic microbial markers: Helicobacter pylori, Proteobacteria, Bacteroidetes, Firmicutes, Ascomycota, Basidiomycota and Malassezia.

Figure 3

Cytotoxicity and pro-inflammatory effects of microbiota. Bacteria can act directly on host cells and produce toxic effects. For example, Helicobacter pylori binds to gastric epithelial cells through the adhesin HopQ and CEACAM, and the virulence factor CagA is directly injected into epithelial cells through T4SS. Colibactin secreted by Pathogenic Escherichia coli in the host cellinduces cross-links between DNA strands and double-strand DNA breaks. Host cells secrete chemokines and recruit immune cells, such as neutrophils, macrophage and T cells. These immune cells are activated by LPS to produce ROS/RNS, inflammatory cytokines and chemokines, increase damage to host cells. Damaged host cells may be transformed, self-limiting, apoptosis or necrosis, while necrotic pancreatic cells release endogenous digestive enzymes, further damaging other pancreatic cells.

Figure 4

The pathogenic molecular mechanisms of microbial metabolites in PC. Microbial lysates such as LPS in the pancreatic TME, upregulates PD-L1 through the TLR4/MyD88/AKT/NF-κB signaling pathway, and induces TILs depletion and apoptosis. The activation of TLRs can cause a variety of tumor suppressor proteins, such as p16, p21, p27, p53, pRb, PTEN and MAP2K4, disorder, which induce STAT3 activation, promote migration and EMT.

Figure 5

Microbiota regulates tumor immune microenvironment. The microbiota in the TME can activate the immune system and recruit immune cells. Immune cells are induced by microbiota to differentiate into different subtypes of immune cells, which secrete the appropriate factors that play pro- or anti-neoplastic roles in tumorigenesis and progression. For example, immune cells with antitumor effects, M1 macrophages (secreting IL-1β/IL-6/TNF), CD8⁺ T cells, and Th1 (differentiated from CD4⁺ T cells and secreting IFNγ) may be reduced by the presence of microbiota. In contrast, immune cells with pro-tumor effects, M2 macrophages (secreting TGF/IL-10/CCL18), B cells, MDSC, and CD4⁺ differentiated into Th2 (secreting TGF/IL-6), Th17 (secreting IL-17), and Treg (secreting IL-10) are increased.