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Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.

De Simone V, Franzè E, Ronchetti G, Colantoni A, Fantini MC, Di Fusco D, Sica GS, Sileri P, MacDonald TT, Pallone F, Monteleone G, Stolfi C - Oncogene (2014)

Bottom Line: Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α 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-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.

ABSTRACT
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-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α 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-α, 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-α 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.

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Orally administered BP-1-102 reduces colonic tumorigenesis in Apcmin/+ mice. (a) Experimental protocol used to assess the effect of BP-1-102 treatment on colonic tumorigenesis in Apcmin/+ mice. (b) Upper panels show representative endoscopic pictures of colon tumors developed in mice treated with either dimethyl sulfoxide (DMSO) (CTR) or BP-1-102. Graphs show the number of lesions and the endoscopic scoring of tumors developed in mice treated with either DMSO (CTR) or BP-1-102. Data indicate mean±s.e.m. of three independent experiments in which at least four mice per group were considered. Differences were calculated using the two-tailed Student's t-test. (c) Representative images showing proliferating cell nuclear antigen (PCNA) immunostaining in colonic sections taken from Apcmin/+ mice treated with either DMSO (CTR) or BP-1-102. The scale bars are 20 μm. One of six representative experiments in which similar results were obtained is shown. NT, non-tumor area; T, tumor area.
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fig5: Orally administered BP-1-102 reduces colonic tumorigenesis in Apcmin/+ mice. (a) Experimental protocol used to assess the effect of BP-1-102 treatment on colonic tumorigenesis in Apcmin/+ mice. (b) Upper panels show representative endoscopic pictures of colon tumors developed in mice treated with either dimethyl sulfoxide (DMSO) (CTR) or BP-1-102. Graphs show the number of lesions and the endoscopic scoring of tumors developed in mice treated with either DMSO (CTR) or BP-1-102. Data indicate mean±s.e.m. of three independent experiments in which at least four mice per group were considered. Differences were calculated using the two-tailed Student's t-test. (c) Representative images showing proliferating cell nuclear antigen (PCNA) immunostaining in colonic sections taken from Apcmin/+ mice treated with either DMSO (CTR) or BP-1-102. The scale bars are 20 μm. One of six representative experiments in which similar results were obtained is shown. NT, non-tumor area; T, tumor area.

Mentions: Next, we tested whether BP-1-102 could inhibit intestinal tumorigenesis in Apcmin/+ mice. Mice were treated intraperitoneally with AOM (10 mg/kg) once a week for 2 weeks. Two weeks after the last AOM injection, mice were randomly divided into two groups and given either BP-1-102 (in 1% dimethyl sulfoxide (DMSO) in phosphate-buffered saline (PBS)) or 1% DMSO in PBS (control) three times a week by oral gavage until being killed (day 56) (Figure 5a). Three control mice had to be killed before the end of the scheduled treatment, because of intestinal occlusion caused by large colonic tumors, whereas all mice treated with BP-1-102 survived until the end of the study.


Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.

De Simone V, Franzè E, Ronchetti G, Colantoni A, Fantini MC, Di Fusco D, Sica GS, Sileri P, MacDonald TT, Pallone F, Monteleone G, Stolfi C - Oncogene (2014)

Orally administered BP-1-102 reduces colonic tumorigenesis in Apcmin/+ mice. (a) Experimental protocol used to assess the effect of BP-1-102 treatment on colonic tumorigenesis in Apcmin/+ mice. (b) Upper panels show representative endoscopic pictures of colon tumors developed in mice treated with either dimethyl sulfoxide (DMSO) (CTR) or BP-1-102. Graphs show the number of lesions and the endoscopic scoring of tumors developed in mice treated with either DMSO (CTR) or BP-1-102. Data indicate mean±s.e.m. of three independent experiments in which at least four mice per group were considered. Differences were calculated using the two-tailed Student's t-test. (c) Representative images showing proliferating cell nuclear antigen (PCNA) immunostaining in colonic sections taken from Apcmin/+ mice treated with either DMSO (CTR) or BP-1-102. The scale bars are 20 μm. One of six representative experiments in which similar results were obtained is shown. NT, non-tumor area; T, tumor area.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493653&req=5

fig5: Orally administered BP-1-102 reduces colonic tumorigenesis in Apcmin/+ mice. (a) Experimental protocol used to assess the effect of BP-1-102 treatment on colonic tumorigenesis in Apcmin/+ mice. (b) Upper panels show representative endoscopic pictures of colon tumors developed in mice treated with either dimethyl sulfoxide (DMSO) (CTR) or BP-1-102. Graphs show the number of lesions and the endoscopic scoring of tumors developed in mice treated with either DMSO (CTR) or BP-1-102. Data indicate mean±s.e.m. of three independent experiments in which at least four mice per group were considered. Differences were calculated using the two-tailed Student's t-test. (c) Representative images showing proliferating cell nuclear antigen (PCNA) immunostaining in colonic sections taken from Apcmin/+ mice treated with either DMSO (CTR) or BP-1-102. The scale bars are 20 μm. One of six representative experiments in which similar results were obtained is shown. NT, non-tumor area; T, tumor area.
Mentions: Next, we tested whether BP-1-102 could inhibit intestinal tumorigenesis in Apcmin/+ mice. Mice were treated intraperitoneally with AOM (10 mg/kg) once a week for 2 weeks. Two weeks after the last AOM injection, mice were randomly divided into two groups and given either BP-1-102 (in 1% dimethyl sulfoxide (DMSO) in phosphate-buffered saline (PBS)) or 1% DMSO in PBS (control) three times a week by oral gavage until being killed (day 56) (Figure 5a). Three control mice had to be killed before the end of the scheduled treatment, because of intestinal occlusion caused by large colonic tumors, whereas all mice treated with BP-1-102 survived until the end of the study.

Bottom Line: Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α 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-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.

ABSTRACT
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-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α 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-α, 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-α 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.

Show MeSH
Related in: MedlinePlus