Genetic heterogeneity of colorectal cancer and the microbiome

Table 1 Features of some bacteria associated with colorectal cancer

Virulence factors, clinical and experimental data	CRC pathways
B. fragilis
- Contains B. fragilis toxin (BFT) that is zinc-dependent metalloprotease toxin[185,186]; -Associated with colitis[186], low-grade dysplasia, tubular adenomas, and serrated polyps[163], Lynch syndrome and familial adenomatous polyposis[187]; - More often associated with left-sided CRC[163]; - Characterized by biofilms formation[38]; - Associated with unfavorable CRC prognosis[123]; - Potentiates oncogenesis in the distal colon in mice[188]	-Induction of stepwise cleavage of E-cadherin and stimulates cell proliferation[185]; - Synthesis of cytokines, incl. IL-17↑[26,123,163,188]; - Activation of the WNT/β-catenin pathway → c-Myc transcription and translation↑ → cell proliferation↑[189]; - STAT3 activation in the mucosal immune cells → mucosal permeability↑[163,186,188]; - NF-κB activation →Th17с↑[163]; - STAT3 and NF-κB activation→ COX-2 and MMP-9 expression↑[123,163]; - BRAF and KRAS mutations, expression of MLH1↓[123]; - APC mutations[187]
E. coli
- Contains Colibactin and Cytotoxic necrotizing factor 1 (CNF1)[190]; - Can carry the pathogenicity island pks (pks + E. coli), which encodes a set of enzymes that synthesize Сolibactin[191]; - Associated with inflammatory bowel disease and CRC[192]; - More frequently found in CRC biopsies than in healthy mucosa[191]; - More common in advanced stages of CRC[193,194]; - Potentiates induction of invasive cancer in mice[192]; – Differences in the frequency of pks + E. coli in patients with CRC, adenomas and in healthy people were not detected[195]	- Induction of DNA double-strand breaks[196]; - DNA alkylation[190]; - Decrease of tumor-infiltrating T lymphocytes (CD3+ and CD8 T cells) and increases colonic inflammation[197]; - Activation of angiogenesis[198] and epithelial-mesenchymal transition[199]; - Modulates activity Rho GTPases (signaling G-proteins of Ras subfamily), thereby affecting the actin cytoskeleton, that contributes to the disruption of cell adhesion (due to the reorganization of the expression of E-cadherin, β-catenin, zonula occludens-1 (ZO-1) and caveolin- 1), the reduction of phagocytosis and improve epithelial cell motility[200,201]; - Induction of cell proliferation[191]; - Depletion of host mismatch repair proteins via bacterially secreted EspF effector protein[142]
F. nucleatum
- Contains adhesion protein FadA, Fap2 и RadD[96]; - Synthesis of toxic metabolites: Secondary bile acids, trimethylamine N-oxide, hydrogen sulfide, heme, nitrosamines, heterocyclic amines and polyaromatic hydrocarbons[96]; - Characterized by biofilms formation[38]; - Often detected in adenomas[38,202], tumor samples with high grade dysplasia[203], carcinoma tissue[44,202,204], distant CRC metastases[125]; - More frequently found in CRC biopsies than in healthy mucosa[205]; - Associated with proximal tumor localization[161,204,206,207], higher depth of invasion[206], higher clinical stage[206,207], low tumor differentiation[206,207], lymph node metastases and low survival rate[204]; - Promotes CRC induction in a traditional experimental model in mice[202]	- Associated with MLH1 methylation[206,207]; MSI-H[161,206-208]; CIMP-H[161,207]; BRAF mutation[206,207]; - FadA-dependent activation of the E-cadherin/β-catenin pathway → cell proliferation↑ and expression of E-cadherin↑[96]; - Activation of p38 MAPK and NF-κB signaling pathways → synthesis IL-6, IL-8 and IL-18↑[204]; - Inhibition of NK cell cytotoxicity by the Fap2 protein and an increase in the number of myeloid suppressor cells[96,204,208]; - Regulates miR21 expression via the TLR4/MYD88/NFκB[96,202,208,209]
Streptococcus gallolyticus (Sg)
- More frequently found in CRC biopsies than in healthy mucosa[210,211]; - Circulation of Sg in the blood in patients with CRC is most likely associated with dysfunction of the epithelial barrier[212]; - In a mouse xenograft model of CRC, Sg promotes tumor growth[211]	- Induction of cell proliferation through WNT/β-catenin pathway[211] and modulation of extracellular matrix[213]; - Increase in expression of c-Myc and cyclin D1 proteins[211]; - Stimulation of proliferation of the intestinal epithelium by some Sg strains which is associated with their ability to adhere to the intestinal epithelium and the genetic characteristics of the host cells[211,214]
Enterococcus faecalis (Ef)
- Contains superoxide[215]- Promotes CRC induction in Il10 -/- mice experimental model[215]	- Promotes chromosome instability[215]; - Ef polarize colon macrophages to produce endogenous mutagens → initiation CIN → expression of progenitor and tumor stem cell markers[216]; - Induces gene mutation and endogenous transformation through microbiome-induced bystander effects[217]; - Activation of the WNT/β-catenin pathway[217]; - Activation of transcription factors c-Myc, Klf4, Oct4 and Sox2[217]

APC: Adenomatous polyposis coli; BFT: B. fragilis toxin; BRAF: B-Raf proto-oncogene; CIMP: CpG island methylator phenotype; CIN: Initiate chromosomal instability; CNF: Cytotoxic necrotizing factor 1; COX2: Cyclooxygenase 2; FadA: Fatty acid desaturase A; KRAS: Kirsten ras; MAPK: Mitogen-activated protein kinase; MLH1: MutL homolog 1; MPP-9: Metalloproteinase-9; MSI: Microsatellite instability; MYD88: Myeloid differentiation primary response 88; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NK: Natural killer; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SMAD4: Small mothers against decapentaplegic 4; TLR: Toll-like receptor; TP53: Tumor protein 53; ZO-1: Zonula occludens-1.