The Cancer Microbiota: EMT and Inflammation as Shared Molecular Mechanisms Associated with Plasticity and Progression

Abstract

With the advent of novel molecular platforms for high-throughput/next-generation sequencing, the communities of commensal and pathogenic microorganisms that inhabit the human body have been defined in depth. In the last decade, the role of microbiota-host interactions in driving human cancer plasticity and malignant progression has been well documented. Germ-free preclinical models provided an invaluable tool to demonstrate that the human microbiota can confer susceptibility to various types of cancer and can also modulate the host response to therapeutic treatments. Of interest, besides the detrimental effects of dysbiosis on cancer etiopathogenesis, specific microorganisms have been shown to exert protective activities against cancer growth. This has strong clinical implications, as restoration of the physiologic microbiota is being rapidly implemented as a novel anticancer therapeutic strategy. Here, we reviewed past and recent literature depicting the role of microbiota-host interactions in modulating key molecular mechanisms that drive human cancer plasticity and lead to malignant progression. We analyzed microbiota-host interactions occurring in the gut as well as in other anatomic sites, such as oral and nasal cavities, lungs, breast, esophagus, stomach, reproductive tract, and skin. We revealed a common ground of biological alterations and pathways modulated by a dysbiotic microbiota and potentially involved in the control of cancer progression. The molecular mechanisms most frequently affected by the pathogenic microorganisms to induce malignant progression involve epithelial-mesenchymal transition- (EMT-) dependent barrier alterations and tumor-promoting inflammation. This evidence may pave the way to better stratify high-risk cancer patients based on unique microenvironmental/microbial signatures and to develop novel, personalized, biological therapies.

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

“…The underlying molecular mechanism involved in IS effects on tumor progression is the reversal of the epithelial-to-mesenchymal transition, similar to other metabolites [ 16 , 17 , 40 , 41 , 44 , 45 , 47 ]. Reverting or inhibiting EMT slows cell movement, diapedesis, and metastasis formation, as was observed in our study.…”

“…Breast cancer oncobiosis modulates the immune system, including lymphocytes and mast cells [ 16 , 25 , 32 , 39 , 40 , 41 , 42 , 43 ]. Furthermore, oncobiosis supports epithelial-to-mesenchymal transition (EMT) [ 16 , 17 , 40 , 44 ], migration and invasion [ 17 , 40 ], the reduction of oxidative stress [ 40 , 45 ], the proportions of ALDH1+ cancer stem cells [ 17 , 40 ], and widespread metabolic alterations [ 16 , 17 , 40 ] in cancers cells. These elementary steps are translated into enhanced tumor growth [ 16 , 17 ], aggressive tumor infiltration to the surrounding tissues [ 16 , 17 ], and enhanced metastasis formation [ 16 , 17 , 41 , 46 , 47 ].…”

Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma

“…Bacterial metabolites modulate the redox balance of cancer cells [24,34], as well as cancer cell metabolism [22,23]. These processes culminate in cytostasis, a reprogramming of the epithelial-mesenchymal transition leading to decreased cancer stem cells [22][23][24][25]29,34,35,45]. These basic events are the pillars for the inhibition of cancer cell growth, movement, and metastasis formation [46][47][48].…”

Dysbiosis of Oral Microbiota and Its Effect on Epithelial-Mesenchymal Transition: a Review

“…Certain species, such as Fusobacterium nucleatum, Porphyromonas gingivalis, and Prevotella sp., have been co-related with OSCC. Recent findings indicate prolonged infection of P. gingivalis promotes the migratory and invasive properties in epithelial cells, increasing the expression of matrix metalloproteinase and induction of EMT transcription factors (TF), such as snail, slug, and ZEB1 [83].…”