The Role of Interleukins in Colorectal Cancer

Abstract

Despite great progress has been made in treatment strategies, colorectal cancer (CRC) remains the predominant life-threatening malignancy with the feature of high morbidity and mortality. It has been widely acknowledged that the dysfunction of immune system, including aberrantly expressed cytokines, is strongly correlated with the pathogenesis and progression of colorectal cancer. As one of the most well-known cytokines that were discovered centuries ago, interleukins are now uncovering new insights into colorectal cancer therapy. Herein, we divide currently known interleukins into 6 families, including IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family and IL-17 family. In addition, we comprehensively reviewed the oncogenic or antitumour function of each interleukin involved in CRC pathogenesis and progression by elucidating the underlying mechanisms. Furthermore, by providing interleukins-associated clinical trials, we have further driven the profound prospect of interleukins in the treatment of colorectal cancer.

Keywords: Clinical therapy; Colorectal cancer; Interleukins; Molecular mechanism.

Figure 1

Potential role of the IL-1 family in colorectal cancer. HLA class II antigens expressed on CRC cells stimulate the resting monocytes to produce IL-1β. Complement immunity triggers neutrophils to release IL-1β, which can cause myeloid cells to produce IL-6 and increase the IL-17A response. IL-1β can act on IECs and CRC cells. IL-33 can be secreted by vascular endothelial cells and tumour cells. Tumour-secreted IL-33 can act on myeloid cells, causing them to release S100A8/9 and VEGF, thereby altering the tumour microenvironment. IL-33 can also trigger macrophage production of prostaglandin E2, alter the phenotype of Tregs and activate SEMFs and mast cells. The production of IGA in B cells is triggered by IL-33. IL-18 can stimulate epithelial restitution and activate the T cell response, thus enhancing the integrity of the intestinal barrier.

Figure 2

The diagram summarizes the major signaling pathways of IL-8 in CRC. IL-8 binds to G protein-coupled receptor CXCR1 or CXCR2, leading to the activation of PI3K, which induces the phosphorylation of Akt and ERK, respectively. The Akt signals have been reported to activate transcription factors NF-κB, which is associated with CRC cell proliferation, migration and invasion, and is particularly correlated with chemoresistance after MDR1 activation. In addition, TOPK, reported a downstream factor of Akt, mediates anti-anoikis. Another ERK induces the phosphorylation of Ets transcription factors, thus upregulating integrin αβv6 expression, which mediates CRC migration. In addition, ERK signaling also activates C/EBPα, thus promoting IL-8 expression. DUSP2 is a termination factor of ERK activation, and studies have reported its inhibitory role against ERK in CRC. Cell-free DNA activates TLR9-MyD88 signaling, thus promoting IL-8 expression in CRC. NTPase2 binds to Y2R to activate ERK signaling, especially that which leads to mediated IL-8 expression. In addition, the ADK antagonist NTPase2 functions by binding to Y2R.

Figure 3

IL-22 signaling is transduced through heterodimer receptor complexes composed of IL-10R2 and IL-22. In addition, there is an endogenous antagonist, IL-22BP. The primary downstream signaling targets of IL-22 are STAT3, STAT1 and STAT5, which are activated by the phosphorylation of Jak1 and Tyk2. The role of IL-22 in the process of tumorigenesis is attributed to DNA damage induction through its synergistic interaction with IFN-γ or Hh infection to produce nitrogen oxide intermediates (iNOS). Furthermore, STAT3 can bind to the DMBT1 promoter region, thereby promoting tumour progression. In addition, IL-22 mediates tumour stemness, which is associated with methylation of H3K79 at three core cancer stemness genes, NANOG, SOX2 and Pou5F1.

Figure 4

This picture shows the secretion, signaling pathways and cross-talk of IL-17 and IL-6. IL-6 is mainly secreted by macrophages in epithelium and colorectal cancer tissue. IL-17 is mainly secreted by Th17. IL-17 can promote the secretion of IL-6. In addition, IL-6 can activate Th17. The IL-6 secreted by macrophages can induce the secretion of tumour-derived IL-6. IL-6 exerts its effect by combining with gp130 to activate various pathways, including the IL-6/STAT3/ERK, JAK1/2-STAT3, β-catenin/Wnt, PI3K-Akt-mTOR and Shp2-Ras-ERK pathways. Through these pathways IL-6 can change the expression of tumour cell genes such as cyclin D1, c-myc, bcl-XL, survivin, etc., to great effect. IL-6 can also facilitate the secretion of mucin and promote the tumorigenesis. IL-17 consisting of IL-17R facilitates the secretion of VEGF and promotes tumorigenesis and angiogenesis. Both IL-6 and IL-17 contribute to a microenvironment that is favourable for the growth of colorectal cancer.