Abstract
The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies.
Highlights
Colorectal cancer is the second and third most common malignant disease in women and men, respectively [1]
Altered genes or polymorphisms that are repeatedly found in colorectal cancer (CRC) often affect the KRAS, MYC, Wnt, mitogen-activated protein kinase (MAPK), or TGF-β/bone morphogenetic protein (BMP)signaling pathways, lamina structural proteins or components of the DNA repair machinery [reviewed in Ref. [2, 5]]
Several factors have received increased attention that are distinct from tumor cells and that substantially contribute to cancer progression
Summary
Colorectal cancer is the second and third most common malignant disease in women and men, respectively [1]. Resistance to CAC in Il21−/− mice was associated with reduced CD4+ T cell infiltration and decreased production of IL-6 and IL-17A in the intestinal mucosa [159] This suggests a pro-tumorigenic role of IL-21 in the setting of AOM/DSS-induced CAC. Our data suggest that IL-33 does not directly affect the proliferation of tumor cells, but rather decreases the barrier function of the intestine This in turn allows for increased translocation of bacterial products to normally sterile tissues and induces the production of pro-tumorigenic cytokines, such as IL-6, by immune cells [194]. Cytokines, such as IL-6, may activate STAT3 to promote tumor growth. TGF-β may for instance promote IL-11 secretion by CAFs [7], which in turn activates STAT3 and drives the proliferation of tumor cells [97]
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