Table 1.
Pathway | Molecule | Function | Preclinical data | Evidence in human disease | References |
---|---|---|---|---|---|
OS | 8-OH-dG | Marker for OS | Increased 8-OH-dG in inflamed and dysplastic tissue samples of UC patients | 20 | |
NO | Marker for OS | Increased NO concentrations in active and inactive IBD | 21 | ||
DDR | γH2A.X | Marker for DDR activation | Increased in IBD tissue | 24 | |
Aag | Enzyme involved in base excision repair | Aag deficiency: increased number of DNA base lesions and tumors in the AOM-DSS model | 27 | ||
Nrf2 | Transcription factor involved in the regulation of redox mechanisms | Nrf2 deficiency: Increased number of tumors in the AOM-DSS model | 28 | ||
Glutathione peroxidase GPX3 | Redox enzyme | GPX3 deficiency: increased tumors in the AOM-DSS model, even tumor development after DSS treatment without AOM | 29 | ||
TNFα/NF-κB signaling | NF-κB | Proinflammatory transcription factor | Deletion of IKK-β in myeloid cells: reduced tumor size and deletion of IKK-β in intestinal epithelial cells decreased tumor number in AOM-DSS model. Overexpression of constitutively active IKK-β in APC-deficient mice increased tumor development, DNA damage, and DDR |
Increased activity of NF-κB in IBD tissue, no evidence in human CAC | 34, 35, 39, 40 |
TNF2 | Proinflammatory cytokine involved in NF-κB activation | Anti-TNFα treatment protective in AOM-DSS model, TNFR1 signaling in myeloid cells promotes proinflammatory microenvironment, TNFR2 signaling in intestinal epithelial cells promotes tumor cell survival | Increased TNFα signaling and anti-TNF therapy in IBD patients. No distinct proof for functional role of TNFα in human CAC | 45, 47, 50 | |
IL6/IL11/STAT3 signaling | IL6 | Proinflammatory cytokine | Mice with deficient IL6 signaling or treatment with anti-IL6 antibodies reduces tumor growth in AOM-DSS model | IL6 promotes growth of human colorectal cancer cell lines | 51, 52, 53, 54, 91 |
IL11 | Proinflammatory cytokine, member of IL6 family | IL11-receptor a1 deficiency: protection against tumor development in the AOM-DSS model | 60 | ||
STAT3 | Transcription factor mediating effects of IL6-receptor activation | Conditional deletion of STAT3 in intestinal epithelial cells protects against, whereas constitutive activation of STAT3 promotes tumor development in the AOM-DSS model | 56 | ||
miR-34 | miR-34 induced by the tumor-suppressor gene p53 | miR-34 deficiency: increased IL6/STAT3 signaling and tumor growth in the AOM-DSS model | 58 | ||
Th17 cells | IL17A | Th17 effector cytokines | Anti-IL17A antibody–treated and IL17A-deficient mice: protection in AOM-DSS model | 64, 65 | |
IL-21 | IL21-deficient mice: reduced tumor growth in AOM-DSS model | 66 | |||
IL-22 | IL22 induces intestinal epithelial cell proliferation via STAT3 activation. IL22 binding protein deficiency promotes tumor growth in the AOM-DSS model | Increased IL22 and IL22-receptor expression in UC and CRC tissue | 67, 68, 92 | ||
TLR signaling | TLR4 | TLR activated by LPS | TLR4 deficiency: reduced tumor growth in the AOM-DSS model | Overexpressed in human CAC tissue | 79, 80 |
TLR2 | TLR activated by bacterial cell wall components | TLR2 deficiency: increased tumor development in AOM + DSS model | 81 | ||
Myd88 | Downstream mediator of TLR activation | Role of Myd88, depending on specific model. Protective effect in AOM-DSS model; tumor-promoting effect in IL10-deficient mice treated with AOM or wild-type mice treated with AOM and oxazolone | 75, 82, 93 | ||
Inflammasome/NLR family | NLRP3 | Inflammasome components | NLRP3 deficiency: more tumors in the AOM-DSS model | 88 | |
NLRP6 | NLRP6 deficiency: increased intestinal inflammation and tumor development in AOM-DSS model | 60, 87, 90 | |||
NLRP12 | NLRP12 deficiency: increased NF-κB signaling and tumor development | 89 |
Aag, alkyladenine DNA glycosylase; 8-OH-dG, 8-oxo-7,8-dihydro-2,-deoxyguanosine; NO, nitric oxide; Nrf2, nuclear factor-erythroid 2–related factor 2; OS, oxidative stress.