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.