Ulcerative colitis and colorectal cancer: Pathogenic insights and precision strategies for prevention and treatment

Table 1 Summary of key molecular and cellular pathways in colitis-associated colorectal cancer

Pathway/cell type	Key mediators	Biological role	Impact on tumorigenesis
IL-6/JAK/STAT3 pathway	IL-6, JAK, STAT3	Promotes epithelial proliferation and inhibits apoptosis	Facilitates CI and epithelial transformation
NF-κB signaling	NF-κB, TNF-α	Controls immune and inflammatory gene expression	Sustains pro-tumorigenic inflammation
TGF-β pathway	TGF-β, TGFBR2	Regulates epithelial growth; normally anti-proliferative	Loss or mutation promotes tumor progression
SOCS3 regulation	SOCS3	Inhibits STAT3-mediated signaling	Dysregulation leads to enhanced inflammation and carcinogenesis
MAPK/ASK1 signaling	ASK1	Mediates stress response and immune modulation	ASK1 deficiency exacerbates inflammation and susceptibility to cancer
CD4+ T helper cells	IL-17, IL-22, IL-9	Stimulate epithelial regeneration and immune activation	Promote dysplasia and tumor development
Macrophages (M1/M2)	IL-13, CCL17 (M2), TNF-α (M1)	M1: Antitumor; M2: Tumor-promoting via immunosuppression and cytokine release	High M2 infiltration is linked to poor prognosis and metastasis
Regulatory T cells	FOXP3, IL-10	Maintain immune tolerance and suppress inflammation	Dual role: Contextually antitumor or tumor-permissive
Tumor-infiltrating leukocytes	Various cytokines and chemokines	Orchestrate local immune response	Serve as prognostic markers; role depends on cellular composition
S100 family proteins	S100A9, S100A8	Mediate inflammation and immune cell recruitment	Correlated with tumor progression; potential therapeutic targeting

IL: Interleukin; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; CI: Chronic inflammation; NF-κB: Nuclear factor kappa B; TNF: Tumor necrosis factor; TGF-β: Tumor growth factor-beta; TGFBR2: Transforming growth factor beta receptor 2; SOCS: Suppressor of cytokine signaling; MAPK: Mitogen-activated protein kinase; ASK: Apoptosis signal-regulating kinase; CCL: Chemokine ligand; FOXP3: Forkhead box P3.

Table 2 Chemopreventive drugs in colitis-associated colorectal cancer

Compound	Reported effect	Recommendation	Ref.
5-ASA	Protective effect for patients with long-standing extensive colitis. Lower risk of developing CRC/dysplasia in UC patients	Mesalamine compounds have a recognized protective role against CRC in UC patients	[99-101]
Thiopurines	Protective against HGD and CRC risk in IBD patients	No recommendations due to their carcinogenic effects (i.e., lymphoma, urinary tract cancer, non-melanoma skin cancer)	[102-104]
Biologic drugs	Chemopreventive effects of anti-TNF-α treatment in IBD patients	No recommendations	[101,105-107]
Statins and folic acid	Controversial chemopreventive role of statins on CRC in IBD patients. Protective effects of folate supplementation against CRC development	No recommendations	[108-110]
UDCA	Decrease in colonic dysplasia in patients with UC and PSC. Chemopreventive effects on risk of advanced CRC and HGD	No recommendations	[111]
NSAIDs and aspirin	No significant chemoprotective role in CRC risk	No recommendations	[112]

ASA: Aminosalicylic acid; CRC: Colorectal cancer; UC: Ulcerative colitis; IBD: Inflammatory bowel disease; HGD: High-grade dysplasia; TNF: Tumor necrosis factor; UDCA: Ursodeoxycholic acid; PSC: Primary sclerosing cholangitis; NSAIDs: Nonsteroidal anti-inflammatory drugs.

Table 3 Endoscopic surveillance strategies in inflammatory bowel disease

	Frequency of surveillance
ECCO 2017	Every year (high risk)	PSC or stricture or dysplasia detected within past 5 years or extensive colitis with severe active inflammation or family history of CRC in FDR age < 50
	Every 2-3 years	Extensive colitis with mild or moderate active inflammation or post-inflammatory polyps or family history of CRC in FDR age > 50
	Every 5 years	Absence of intermediate or high-risk features
ACG 2019	Every year	PSC
	Every 1-3 years	UC of any extent beyond the rectum
	Adjust intervals	Based on previous colonoscopies and combined risk factors: Duration of disease, younger age at diagnosis, greater extent of inflammation, FDR with CRC
AGA 2021	Every year	Moderate or severe inflammation (any extent), PSC, family history of CRC in FDR age < 50, dense pseudopolyposis, history of higher-risk visible dysplasia < 5 years ago
	Every 2-3 years	Mild inflammation (any extent), strong family history of CRC (but no FDR age < 50), features of prior severe colitis (moderate pseudopolyps, extensive mucosal scarring), history of invisible dysplasia or higher-risk visible dysplasia > 5 years ago, history of lower risk visible dysplasia < 5 years ago
	Every 5 years	Continuous disease remission since last colonoscopy with mucosal healing on current exam, plus either of: ≥ 2 consecutive exams without dysplasia, minimal historical colitis extent (ulcerative proctitis or < 1/3 of colon in CD)

ECCO: European Crohn’s and Colitis Organisation; ACG: American College of Gastroenterology; AGA: American Gastroenterological Association; PSC: Primary sclerosing cholangitis; CRC: Colorectal cancer; FDR: First degree relative; UC: Ulcerative colitis; CD: Crohn’s disease.

Table 4 Current available endoscopic procedures for colitis-associated colorectal cancer surveillance

Type of procedure	Type of biopsies	Strengths	Limitations
Standard with light endoscopy	Random biopsies	Increases dysplasia detection rate	Longer procedure times and cost
High-definition endoscopy	Targeted biopsies	Images of substantially higher resolution for dysplasia detection	Cost
Chromoendoscopy	Targeted biopsies	Best at highlighting irregularities in the architecture of the mucosa thanks to the contrasting dye	Specialized equipment and additional training required, longer procedure time
Narrow band imaging	NA	Greater contrast of the mucosal surface	Lower sensitivity in dysplasia detection
Fujinon intelligent color enhancement and I scan digital contrast	NA	Perception of subtle changes of the mucosal surface	Limited relevant data
Confocal laser endomicroscopy	NA	Real-time microscopy available in vivo during examination	Longer procedure time, extra equipment and training required
Full-spectrum endoscopy	NA	Better visualization of the mucosa thanks to increased visual field	Longer withdrawal and total procedure time

NA: Not available.