Abstract
The microbiome is an emerging key co-factor in the development of esophageal cancer, the sixth leading cause of cancer death worldwide. However, there is a paucity of data delineating how the microbiome contributes to the pathobiology of the two histological subtypes of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma. This critical knowledge gap is partially due to inadequate modeling of host–microbiome interactions in the etiology of esophageal cancers. Recent advances have enabled progress in this field. Three dimensional (3D) organoids faithfully recapitulate the structure and function of the normal, preneoplastic, and neoplastic epithelia of the esophagus ex vivo and serve as a platform translatable for applications in precision medicine. Elsewhere in the gastrointestinal (GI) tract, the co-culture of 3D organoids with the bacterial microbiome has fostered insight into the pathogenic role of the microbiome in other GI cancers. Herein, we will summarize our current understanding of the relationship between the microbiome and esophageal cancer, discuss 3D organoid models of esophageal homeostasis, review analogous models of host–microbiome interactions in other GI cancers, and advocate for the application of these models to esophageal cancers. Together, we present a promising, novel approach with the potential to ameliorate the burden of esophageal cancer-related morbidity and mortality via improved prevention and therapeutic interventions.
Highlights
The gastrointestinal (GI) tract harbors a substantial portion of the human microbiome, which plays a critical role in organ development, immunity, nutrition, and maintenance of homeostasis through symbiotic interactions with the host
3D organoids are amenable to CRISPR-mediated or RNA interference (RNAi)-mediated genomic engineering and can be used for high-throughput screening in the presence of bacteria or bacterial metabolites added to the cell culture media [68]
The microbiome is an emergent co-factor in the pathobiology of esophageal neoplasia [41]
Summary
The gastrointestinal (GI) tract harbors a substantial portion of the human microbiome, which plays a critical role in organ development, immunity, nutrition, and maintenance of homeostasis through symbiotic interactions with the host. Despite its incipient role in esophageal malignancies, how the bacterial microbiome contributes to the pathogenesis of esophageal cancer is unclear This critical knowledge gap is exacerbated by the lack of tractable models of pathogen–host interactions in the esophagus. Genetic and pharmacological manipulations as well as the co-culture of 3D organoids with known pathogens have enabled progress in understanding how these interactions contribute to malignancies elsewhere in the GI tract [15,16,17]. These techniques have not been applied in analogous models of esophageal cancer initiation and development. We will briefly summarize the relationship between the microbiome and esophageal neoplasia, discuss 3D organoid models of esophageal malignancies, highlight analogous GI models of host–pathogen interactions, and underscore the value of applying such models to esophageal disease
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