Table 1.

Immune Signaling Pathways Involved in the Development of CAC

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.