From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Abstract

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

Keywords: Cytokines; Inflammation; Microbiota; Neuroendocrine tumors; Tumor microenvironment.

Fig. 1

Gut microorganisms can alter the resistance to cell death, and proliferative signalling, by affecting genomic stability, damaging the DNA, and through a microbial competition with others microorganisms. These mechanisms can contribute to carcinogenesis through the increase in mutational events

Fig. 2

An important target of cancer-associated microbes is the β-catenin signalling. The microbes bind E-cadherin on colonic epithelial cells within a disrupted barrier, and trigger β-catenin activation, resulting in dysregulated cell growth

Fig. 3

The loss of boundaries between host and microbe and the activation of chronic inflammation via NF-kB and STAT3 signalling promote carcinogenesis

Fig. 4

Helicobacter pylori–associated atrophic gastritis. A complete loss of oxyntic glands is evident (a) (haematoxylin eosin, 200x magnification) with a linear (short arrow) and nodular (long arrow) ECL cell neuroendocrine hyperplasia (b) (immunohistochemistry Chromogranin A, 200x magnification, in an adjacent section of A)

Fig. 5

Common cellular signalling pathways involved in GEP NENs and perturbated after HP colonization