Functional links between the microbiome and the molecular pathways of colorectal carcinogenesis

Abstract

Colorectal cancer (CRC) is a common cancer, with a concerning rise in early-onset CRC cases, signalling a shift in disease epidemiology. Whilst our understanding of the molecular underpinnings of CRC has expanded, the complexities underlying its initiation remain elusive, with emerging evidence implicating the microbiome in CRC pathogenesis. This review synthesizes current knowledge on the intricate interplay between the microbiome, tumour microenvironment (TME), and molecular pathways driving CRC carcinogenesis. Recent studies have reported how the microbiome may modulate the TME and tumour immune responses, consequently influencing cancer progression, and whilst specific bacteria have been linked with CRC, the underlying mechanisms remains poorly understood. By elucidating the functional links between microbial landscapes and carcinogenesis pathways, this review offers insights into how bacteria orchestrate diverse pathways of CRC development, shedding light on potential therapeutic targets and personalized intervention strategies.

Keywords: Colorectal cancer; Molecular pathways; Tumour microenvironment.

Fig. 1

Pathways of colorectal carcinogenesis. Image created with Biorender[83] © 2022, adapted from Keum and Giovannucci 2019

Fig. 2

Bacterial mechanisms promoting colorectal carcinogenesis. Bacteria and their known mechanisms of promoting colorectal cancer within the tumour microenvironment. Fusobacterium spp. induce myeloid cell infiltration; LPS causes M2 macrophage polarisation and induces a proinflammatory TME promoting CMS1 type tumour development. Formate, a metabolite of Fusobacterium spp., induces AhR signalling to promote cellular proliferation and migration. P. asaccharolytica LPS attenuates the immunomodulatory effects of other LPS molecules promoting CMS1 characteristics. E. coli PKS + via colibactin, induces double strand DNA breaks and CIN promoting CMS3 and adenoma-carcinoma pathway characteristics. C. jejuni, E. coli, H. ducreyi and H. hepaticus produce CDT which causes cell cycle inhibition and double strand DNA breaks promoting characteristics of the adenoma-carcinoma pathway. ETBF promotes IL-8 secretion and promotes angiogenesis and cellular migration, characteristics observed in CMS2 CRC. ETBF increases WNT signalling and promotes EMT promoting adenoma-carcinoma pathway and CMS4 characteristics. Through BFT, ETBF promotes H₂O₂ production inducing double strand DNA breaks seen in tumours arising from the adenoma-carcinoma pathway. C. perfringens through CPE increases YAP activation promoting EMT as observed in CMS4 tumours. LPS, lipopolysaccharide; TME, tumour microenvironment; CIN, chromosomal instability; CDT, cytolethal distending toxin; ETBF, enterotoxigenic Bacteroides fragilis; CRC, colorectal cancer; BFT, Bacteroides fragilis toxin; CPE, Clostridium perfringens enterotoxin; EMT, epithelial mesenchymal transition. Image created with Biorender © 2022