A new avenue of research for pancreatic cancer: the pancreatic microbiome

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The intestinal and pancreatic microbiotas, both linked, are thought to play a prominent role in the development of pancreatic adenocarcinoma, one of the most lethal forms of cancer. Results which have potentially major therapeutic implications.

 

Pancreatic ductal adenocarcinoma (PDA) is the most common and most serious form of pancreatic cancer, with a five-year survival rate of only 20% after surgery followed by chemotherapy. A grim statistic which could be improved by the inclusion of the intestinal and pancreatic microbiomes in the global treatment strategy for PDA, according to the results of a study by a team based in New York.

Bacterial populations as markers

According to the observations of the researchers, it appears that the pancreatic bacterial population of patients with PDA is richer in Proteobacteria. In these subjects, the intestinal microbiota is also disrupted, with a greater presence of Proteobacteria, Actinobacteria, Fusobacteria and Verrumicrobia in comparison to control stool samples. These two microbiomes are moreover linked: the study demonstrated a possible translocation of bacteria from the intestine to the pancreas, probably via the pancreatic duct which connects the two organs. Helicobacteraceae, Bacteroidales and Mogibacteriaceae were over-represented in the intestinal microbiota of mice presenting with aggressive tumors; while Elizabethkingia, Enterobacteriaceae and Mycoplasmataceae were over‑represented in mice whose tumors progressed more slowly. The level of intestinal dysbiosis could therefore serve as a marker for the likely course of the disease.

Antibiotic therapy to boost immunotherapy

Finally, the pancreatic microbiome is at the center of the pathophysiological process of the disease. The researchers discovered that certain pancreatic bacteria, in particular Bifidobacterium pseudolongum, inactivated T-cells (by binding to TLR, toll-like receptors), protecting the tumors against any immune response. Administration of a cocktail of antibiotics to mice with the condition in order to destroy their pancreatic microbiota effectively slowed the progression of their tumors. The authors consider that a preventive antibiotic treatment could be considered in some high-risk patients with a genetic susceptibility or who already present with advanced lesions, just like the use of probiotics could correct any intestinal dysbiosis. Another result this time relating to the curative aspect: elimination of pancreatic bacteria by this same antibiotic therapy improved the efficacy of checkpoint inhibitors, a recent form of immunotherapy which aims to remove immune system constraints with respect to tumor cells, and which still has very limited efficacy in pancreatic cancer. Targeting the intestinal and pancreatic bacteria in diagnosis, treatment and prevention therefore seems one of the most promising approaches to the management of PDA.

 

Sources:

S Pushalkar et al. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov. 2018 ; Apr;8(4):403-416