Chronic Inflammation and Cytokines in the Tumor Microenvironment
Table 2
Significance and role of cytokines in tumorigenesis.
Cytokines
Colitis-associated cancer references
CCA references
TNF-
Tumor-promoting role in various stages of carcinogenesis. Related to RONS generation in IBD patients, promoting oxidative stress-mediated DNA damage. Stimulates TGF--induced EMT. Induces secretion of VEGF by human fibroblasts, promoting angiogenesis. Induces NF-B signaling, a decisive pathway in driving metastasis in a model of CAC [19–22].
Essential for bile duct epithelial cell proliferation. Impairs epithelial barrier function. Disrupts cholangiocyte tight-junction and influences the aggravation of bile duct cholestasis. Induces a DNA/RNA-editing enzyme AID in CCA cells, resulting in somatic mutation of several tumor-related genes and leading to cholangiogenesis. EMT induction in CCA cells in vitro [23–26].
IFN-
Increases in IFN- cells have been observed in IBD patients. Deficient mice did not develop DSS-induced colitis. Increases paracellular permeability in early IBD pathogenesis. Deficient mice developed higher numbers of tumors, suggesting an antitumor immune response of IFN-. In patients with UC-associated cancer and a group of UC patients with chronic severe inflammation, the IFN-inducible gene family 1-8U was overexpressed. Induces IL-18 and IL-18 binding protein IL-18BP in IBD, which have been also associated with inflammation and cancer [27–32].
Reduces transepithelial electrical resistance. Alters cholangiocyte tight-junction, leading to aggravation of bile duct cholestasis [24].
IL-6
Induces oxidative stress. A critical tumor promoter during early CAC tumorigenesis. TAM-derived IL-6 contributes to CAC in animal models. CRC patients present with high levels of IL-6 and VEGF [19, 33–35].
Cholangiocyte and CCA cells can be activated by proinflammatory cytokines through the NF-B-dependent pathway, leading to overproduction of bile duct epithelium growth factor, thus promoting cancer initiation and progression [36, 37].
TGF-
Induces CAC progression, promoting EMT. In later stages of carcinogenesis, it promotes tumor growth by creating an immunotolerant tumor environment [38, 39].
Promotes proliferation of bile duct epithelial cells and induces EMT-mediated tumor aggressiveness [23, 40].
IL-8
Colon cancer cell lines overexpressing IL-8 show enhanced proliferation, migration, and angiogenesis. IL-8 induced by TNF- accelerates EMT [21, 41].
Secreted by cholangiocytes in response to proinflammatory cytokines and together with MCP-1 and CCL-28 promotes leukocyte adhesion and retention in injured biliary epithelial cells. Injured cholangiocytes then release IGF-1 and VEGF, which can stimulate CCA cell growth [42, 43].
IL-10
IL-10−/− mice develop colitis and colorectal cancer, similar to IBD-associated cancer in humans [44].
CCA can activate macrophage polarization into M2 phenotype through the STAT-3 pathway, leading to IL-10, VEGF-A, TGF-, and MMP-2 production [45].
IL-17
Overexpressed in tumors from CAC patients and is associated with angiogenesis and poor prognosis markers. Secreted in tumors by macrophages/monocytes CD68+; Th17 and Treg FOXP3+IL17+ cells [46, 47].
Tumor-infiltrating lymphocytes IL-17+ are found in CCA intratumoral areas and correlate with lymph node metastasis, intrahepatic metastasis, and advanced stages [48].
IL-21
Enhanced in mucosa of IBD patients and in the CAC mouse model. Blockade of IL-21 signaling reduces tumor development and mucosal microenvironment inflammation [49].
