Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells

Abstract

Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell proliferation was related to the degree of intracellular persistence, and infection of tumor cells with P. gingivalis led to enhanced growth in vivo. To the best of our knowledge, this study is the first to demonstrate the direct effect of exposure to P. gingivalis on the tumorigenic behavior of pancreatic cancer cell lines. Our findings shed light on potential mechanisms underlying the pancreatic cancer–periodontitis link.

The oralome and its dysbiosis: New insights into oral microbiome-host interactions

“…Particularly, this may increase the risk for dental caries, periodontal disease and may even be correlated to several systemic diseases, such as atherosclerosis, Alzheimer’s disease, and cancer. Specifically, P. gingivalis and/or F. nucleatum have been associated with periodontal disease [56] , [130] , [139] , head and neck cancer [130] , [158] , pancreatic cancer [159] , colorectal cancer [160] , [161] , [162] , [163] , Alzheimer’s disease [164] , [165] , [166] , [167] , atherosclerosis [168] and pre-term births [169] , [170] .…”

“…Specifically, there is an increase in the genus Brevibacterium and order Chlamydiales in pancreatic cancers compared to normal controls. Despite a lack of direct evidence of oral microbial pathogens in pancreatic cancer, P. gingivalis is able to invade and survive inside of pancreatic cancer cells, enhance pancreatic tumor growth in vivo and cause higher rates of mutation in the tumor suppressor protein p53 and Kirsten rat sarcoma viral oncogene homolog (KRAS) gene in pancreatic cancer in vitro [159] , [287] , [288] , [289] , [290] . Thus, more studies are needed to evaluate whether P. gingivalis can directly colonize pancreatic tissue in vivo .…”

Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer

“…In a mouse PDAC model, oral administration of P. gingivalis accelerated cell proliferation and epithelial–mesenchymal transition, finally promoting PDAC progression [ 197 ]. Interestingly, intracellular P. gingivalis directly promoted tumor cell growth in human pancreatic cancer cell lines [ 198 ]. These suggest that oral dysbiosis can be a direct etiology as well as a useful marker for diagnosis and prognosis in PDAC pathogenesis.…”

Research Progress of Pancreas-Related Microorganisms and Pancreatic Cancer

“…This property can be enhanced in vitro and increased by hypoxia, which is the main feature of pancreatic cancer. Increased tumor cell proliferation was related to the degree of intracellular persistence, and infection of tumor cells with P. gingivalis led to enhanced growth in vivo ( 24 ). Oral microorganisms may colonize the pancreas through the gastrointestinal tract, especially in the case of pancreatitis, the microbiota isolated from the pancreas is similar to the oral microbiota ( 25 ).…”