Inflammation-driven carcinogenesis in ulcerative colitis: Molecular and immunological pathways

Table 1 Gut microbiota and inflammatory bowel disease

Intestinal Bacteria	Bacterial loaded	Involved or altered metabolic pathway	Associated inflammatory disease	Immuno-modulatory effect	Ref
Faecalibacterium prausnitzii	↓	Butyrate synthesis. Mucus production promotion	CD; UC	Induces IL10RA-dependent claudin-2 suppression and promotes the differentiation of regulatory T cells	[126]
Prevotella (p. Ej. P. Copri)	Depending on the species	Fiber fermenter	↑ incidence and complications of IBS and IBD	Inhibits the autoimmune response and maintains the intestinal barrier	[127]
		SCFA		Associated with systemic inflammation, altering the production of cytokines and regulatory T cells
		Producer (propionate and acetate)
Bacteroides fragilis enterotoxigénic	↑	Beneficial gut bacteria that feed complex carbohydrates	UC	It disrupts the immune response by promoting or exacerbating inflammation	[128]
		Toxicogenic strain, pro-inflammatory signaling, and disruption of the intestinal barrier	Active IBD
			CRC risk
Veillonella parvula	↑	Lactate-fermenting opportunistic pathogenic commensal bacterium	Active UC	Increases the permeability of epithelial cells in the colon by activating macrophages and producing pro-inflammatory factors	[129]
Tyzzerella nexilis	↑	Commensal bacterium involved in the fermentation of indigestible carbohydrates and the synthesis SCFA	Intestinal inflammation	Mobile genetic elements confer pathogenic properties and promote neuroinflammation	[130]
Rothia mucilaginosa	↑	-	IBD	Increases levels of circulating lymphocytes and correlates with the inflammatory marker calprotectin	[131]
Blautia hansenii	↓ in active disease	Synthesis SCFA helps maintain the function of colonic mucus	↓ in active disease	Prevent the adhesion of pathogenic bacteria	[132]
				Suppression of pro-inflammatory response
Akkermansia muciniphila	↓	Degrade the glycoprotein mucin as a source of carbon and nitrogen	IBD	Reduces the levels of infiltrating macrophages in the colon and cytotoxic T cells	[133]
Bifidobacterium spp.	↓	Fermentation of complex carbohydrates (fiber)	CD; UC	Regulates intestinal inflammation, promotes T-cell response, and strengthens the intestinal barrier	[134]
Lactobacillus spp.	↓	Lactate synthesis, immune modulators, and intestinal barrier repair	IBD	It regulates cytokine production and reduces the effects of TNF-α. It induces the production of B cells, NK cells, and Treg cells	[135,136]
Enterococcus faecalis	↑	Biofilm formation, pro-inflammatory cytokines, and glucosamine metabolism	IBD complicated	Pathobiont behavior activates NF-κB and TLR inflammatory pathways	[137]

↑: Increased; ↓: Decreased; CD: Crohn disease; UC: Ulcerative colitis; IBS: Intestinal bowel syndrome; IBD: Inflammatory bowel disease; SCFA: Short chain fatty acids; CRC: Colorectal cancer; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; NK: Natural killer; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; TLR: Toll-like receptor.

Table 2 A summary of tissue-based biomarkers identified in ulcerative colitis-colorectal cancer and their clinical relevance for screening

Biomarker	Clinical relevance	Advantages/limitations	Ref.
TP53	71% in low-grade dysplasia, 83% in high-grade dysplasia, 100% in adenocarcinoma; absent in uninvolved mucosa	Adjunctive biomarker to identify high-risk patients before histologic changes occur, predicting risk of evolution toward malignancy	[88,138-140]
p14ARF hypermethylation	100% in dysplastic tissue vs 26% in non-dysplastic biopsies	Predictor of future dysplasia during surveillance	[141,142]
1-8U gene (interferon-inducible) (IFITM3)	High expression in cancer and severely inflamed and cancerous UC mucosa; absent in normal tissue	Discrimination of high-risk areas before visible dysplasia	[143,144]
Telomere shortening + clonal expansions	100% sensitivity, 80% specificity distinguishing progressors from non-progressors (early-onset UC)	Risk stratification in young patients with extensive disease	[145,146]
		Associated with proximity to dysplasia
Aneuploidy (flow cytometry ploidy)	5/6 patients with aneuploidy developed dysplasia in 1-2.5 years vs 0/19 without aneuploidy	Not routinely implemented by insufficient prospective validation, and the growing emphasis on gene-specific genomic alterations	[88,146-148]
	Adjunctive marker in biopsies indefinite for dysplasia
Copy number variants (lpWGS-derived CNA score)	Cumulative chromosomal alterations before advanced neoplasia	Scalable, cost-effective tool to predict progression from low-grade dysplasia	[88,149,150]
		Lack of prospective multicenter validation, standardized analytical pipelines and cut-off values, and generalizability beyond low-grade dysplasia cohorts
miR-9 methylation	Increases with age, disease duration, proximity to cancer	High-accuracy discrimination in rectal mucosa Lack of independent prospective validation and evidence supporting its use only within multi-marker methylation panels	[88,151,152]
Methylation panel (SFRP2, SFRP4, WIF1, APC1A, APC2)	Detects pre-cancerous and invasive neoplasia	Validated multiplex panel from a multicenter study (ENDCAP-C) Limited by the need for colonic biopsy, only moderate prediction of neoplastic progression in non-neoplastic mucosa, and the transition toward genome-wide biomarkers (e.g., CNA profiling and lpWGS)	[153,154]
Stool microbiome (16 rRNA sequencing)	Mucosal microbiota (Firmicutes/Bacteroidetes ratio) exhibit persistent dysbiosis UC-CRC	Positive association between Fermicutes and Proteobacteria Bacteroidetes and inflammatory markers with incidence of CRC	[155,156]
TP53-nuclear (IHC) + cytokeratin 7	TP53 strong nuclear overexpression correlates with neoplastic progression	Useful adjunct when histology is ambiguous (indefinite for dysplasia)	[157-159]
	CK7 not expressed in normal colonic mucosa. Expressed in all cases of epithelial dysplasia, with no difference between moderate and severe dysplasia
miR-21, miR126, miR146b-5p and miR-223	Upregulation in active UC	Non-invasive disease monitoring	[160]
miR-142-3p, miR-144-3p, and miR-193a-5p	Overexpression in adenomas but down-regulated in CRC	Biomarker pre-cancer	[161]
miR-31, miR-135b and miR-106a	Tracking of malignant progression via expression profiling	Mucosal miRNAs that not only accurately discriminate dysplasia from normal mucosa but also indicate a higher risk of CRC and are expressed in UC-CRC	[162,163]
ctDNA, circulating tumor cells, exosomes, tumor-educated platelets	Reflect real-time molecular heterogeneity	Minimally invasive surveillance complementary to colonoscopy	[164]
		Requires validation
KRAS mutations	Occur later, often co-occurring with TP53 Frequency of KRAS mutations increases continuously from non-dysplastic IBD colon to UC-CRC, and they are observed to be mutually exclusive with BRAF mutations	Limited clinical utility as a standalone biomarker	[165]
	Invisible lesions in patients without IBD exhibit fewer KRAS and APC mutations compared with polypoid lesions, but show a higher frequency of BRAF mutations	KRAS mutations were enriched in non-dysplastic UC colon at approximately 14%	[166]

TP53: Tumor suppressor factor p53; p14ARF: Protein 14 encoded by the alternative reading frame; miR: MicroRNAs; SFRP2: Secreted frizzled-related protein 2; SFRP4: Secreted frizzled-related protein 4; WIF1: Wnt inhibitory factor 1; APC1A: Promoter 1A of the APC gene; APC2: APC regulator of wnt signaling pathway 2; KRAS: Kirsten rat sarcoma viral oncogene homolog; CNA: Copy number alteration; UC-CRC: Ulcerative colitis-associated colorectal cancer; CK7: Cytokeratin-7; ctDNA: Circulating tumor DNA; IHC: Immunohistochemistry; lpWGS: Low-pass whole genome sequencing; UC: Ulcerative colitis; CRC: Colorectal cancer; IBD: Inflammatory bowel disease; ENDCAP-C: Enhanced neoplasia detection and cancer prevention in chronic colitis; APC: Adenomatous polyposis coli; BRAF: B-Raf proto-oncogene.

Table 3 Main drugs used in the treatment of ulcerative colitis: Doses, mechanisms of action, and therapeutic response

Treatment		Dose scheme	Mechanism	Response	Ref.
5-ASA	Mesalazine	Induction: 2.4-4.8 g/day	Anti-inflammatory by activating PPAR-y receptors	UC: Clinical and endoscopic remission	[10,89,167,168]
		Maintenance: 1.5-2.0 g/day		CD: Poor response
Glucocorticoids	Betamethasone	Induction: 5 mg/day	Immunosuppressors by reduced expression of IL-1, IL-1β and IL-8, TGF-β3 and IL-10	UC: Clinical and endoscopic remission	[167,169,170]
	Budesonide MMX	Induction and maintenance: 9 mg/day
	Hydrocortisone	Induction: 356 mg/day		CD: Clinical remission
	Prednisolone	Induction: ≥ 30 mg/day
Thiopurines	Azathioprine	Induction and maintenance: 1.5 to 2.5 mg/kg/day	Immunosupressor. Targets Rac1 activation and inhibits gut T cells	UC: Poor response in active disease. Used for remission maintenance	[171-174]
				CD: Clinical remission
	6-mercaptopurine	Induction and maintenance: 1-1.5 mg/kg/day	Immunosuppressor. Inhibits purine synthesis	UC: Remission maintenance	[175,176]
				CD: Clinical remission or significant improvement
	Methotrexate	Induction and maintenance: 25 mg/week	Immunosupressor inhibits purine synthesis	UC: Poor response	[177-179]
			Decrease in production of cytokines and eicosanoids	CD: Clinical remission and maintenance

5-ASA: 5-aminosalicylic acids; UC: Ulcerative colitis; CD: Crohn disease; PPAR: Peroxisome proliferator-activated receptors; MMX: Multi-matrix system; IL: Interleukin; TGF-β3: Transforming growth factor-beta 3.

Table 4 Biologic strategies for inflammatory bowel disease

Biologic effect	Treatment	Dose scheme	Mechanism	Response	Ref.
TNF-α inhibitor	Infliximab	Induction: Intravenously 5 mg/kg, 2 weeks and 6 weeks	Monoclonal antibody against TNF-α	Clinical remission, reduced fistulous disease in UC	[91,180,181]
		Maintenance: Every 8 weeks thereafter
	Adalimumab	Induction: 160 mg followed by 80 mg after two weeks	Fully humanized IgG1 monoclonal antibody against TNF-α	Induction and maintenance of remission in CD	[91,182,183]
		Maintenance: 40 mg every two weeks		Some patients do not respond
	Ustekinumab	Induction: 130 mg fixed dose or 6 mg/kg for 8-12 weeks	IgG1 monoclonal antibody that binds to p40 subunit of pro-inflammatory IL 12 and 23	Clinical remission in UC	[90,91,180,184]
		Maintenance: 90 mg every 8-12 weeks
	Risankizumab	Induction: 600 mg for12 weeks, or 1200 mg at 0 weeks, 4 weeks, and 8 weeks	Antibody binds to p19 subunit of IL-23	Improved clinical remission rate with short-term efficacy and safety in moderate-to-severe UC	[91,185]
		Maintenance: 180 mg or 360 mg every 8 weeks
Anti-adhesion molecule inhibitors	Vedolizumab	Induction: 300 mg at initial, 2 weeks and 6 weeks	Monoclonal IgG1 antibody against α4-β7 integrin, and disruption of lymphocyte trafficking	Clinical and safety outcomes at 6-10 weeks in moderately to severe CD	[91,186]
		Maintenance: Same dose every 8 weeks
JAK inhibitors	Upadacitinib	Induction: 45 mg/day for 12 weeks	Immunosuppression by targeting JAK1	Clinical remission and endoscopic response in CD	[91,187,188]
		Maintenance: 15-30 mg/day for 52 weeks		Improvement of fecal calprotectin and C-reactive protein levels
	Tofacitinib	Induction: 10 mg twice a day for 8 weeks	Inhibition of JAK1 and JAK3, JAK2 and TYK2, blocking signaling for IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, and IFN-γ cytokines	Clinical response improvement and reduce of inflammatory markers in UC	[90,91,189-191]
		Maintenance: 5-10 mg twice a day for 26 weeks

UC: Ulcerative colitis; CD: Crohn disease; IL: Interleukin; IgG1: Immunoglobulin G1; TNF-α: Tumor necrosis factor alpha; JAK: Janus kinase; IFN-γ: Interferon-gamma; TYK: Tyrosine kinase.