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2015 ; 34
(27
): 3493-503
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Th17-type cytokines, IL-6 and TNF-? synergistically activate STAT3 and NF-kB to
promote colorectal cancer cell growth
#MMPMID25174402
De Simone V
; Franzč E
; Ronchetti G
; Colantoni A
; Fantini MC
; Di Fusco D
; Sica GS
; Sileri P
; MacDonald TT
; Pallone F
; Monteleone G
; Stolfi C
Oncogene
2015[Jul]; 34
(27
): 3493-503
PMID25174402
show ga
Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing
immune/inflammatory cells. The exact contribution of each immune cell subset and
cytokine in the activation of the intracellular pathways sustaining CRC cell
growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs)
and lamina propria mononuclear cells (LPMCs) from the tumor area and the
macroscopically unaffected, adjacent, colonic mucosa of patients who underwent
resection for sporadic CRC and show that the culture supernatants of TILs, but
not of LPMCs, potently enhance the growth of human CRC cell lines through the
activation of the oncogenic transcription factors signal transducer and activator
of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization
of immune cell complexity of TILs and LPMCs reveals no differences in the
percentages of T cells, natural killer T cells, natural killer (NK) cells,
macrophages and B cells. However, T cells from TILs show a functional switch
compared with those from LPMCs to produce large amounts of T helper type 17
(Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and
IL-22), tumor necrosis factor-? (TNF-?) and IL-6. Individual neutralization of
IL-17A, IL-17F, IL-21, IL-22, TNF-? or IL-6 does not change TIL-derived
supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative
effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and
TNF-?, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3
signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A,
IL-21, IL-22, TNF-? and IL-6 are also produced in excess in the early colonic
lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB
activation. Mice therapeutically given BP-1-102, an orally bioavailable compound
targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon
tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in
the neoplastic areas. These data suggest that strategies aimed at the cotargeting
of STAT3/NF-kB activation and interaction between them might represent an
attractive and novel approach to combat CRC.