Abstract
Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.
Highlights
Accumulation of mutations in various oncogenes and tumor suppressor genes drives the development of sporadic colorectal cancer (CRC) [1], but at the same time progression of this neoplasia is tightly controlled by complex interactions between cancer cells and immune cells in the tumor microenvironment, with the latter modulating both pro- and anti-tumorigenic pathways [2]
Flow cytometry analysis revealed that IL-21 was mostly produced by CD3+CD8- T cells (Figure 1B) and minimally expressed by CD3+CD8+ T cells and natural killer (NK) T cells (CD3+CD56+ cells) (2.54±0.4 and 0.96±0.28 respectively); no IL-21 staining was seen in NK cells (CD3-CD56+ cells), macrophages (CD68+ cells) and B cells (CD19+ cells) ruling out such cells as sources of IL-21 in human CRC (Figure 1B)
These results suggest that elevated levels of IL-21 in the tumors of Apcmin/+ mice support a tumor-promoting inflammatory microenvironment characterized by enhanced production of IL-17A, IL-22, tumor necrosis factor (TNF)-α and IL-6 and hyper-activation of STAT3/NF-kB
Summary
Accumulation of mutations in various oncogenes and tumor suppressor genes drives the development of sporadic CRC [1], but at the same time progression of this neoplasia is tightly controlled by complex interactions between cancer cells and immune cells in the tumor microenvironment, with the latter modulating both pro- and anti-tumorigenic pathways [2] These phenomena have been widely documented in CRC arising in patients with inflammatory bowel disease and in mouse models of chemically induced colitis-associated CRC [39], recent studies have clearly shown that an immune/ inflammatory infiltrate is present in sporadic CRC, and immune cell-derived cytokines sustain CRC cell growth and spread [10]. Since our studies have shown high IL-21 production in the tumor areas of patients with sporadic CRC [9], we hypothesized that this cytokine can sustain the growth of sporadic CRC
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