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Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis.

De Simone V, Ronchetti G, Franzè E, Colantoni A, Ortenzi A, Fantini MC, Rizzo A, Sica GS, Sileri P, Rossi P, MacDonald TT, Pallone F, Monteleone G, Stolfi C - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus

IL-21 deficiency significantly reduces colon tumorigenesis in Apcmin/+ miceA. Experimental protocol used to assess the effect of IL-21 ablation on colon tumorigenesis in Apcmin/+ mice. B. Representative western blotting showing IL-21 expression in colon tissues taken from Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of five representative experiments is shown. NT, non-tumor area, T, tumor area. Right inset. Quantitative analysis of IL-21/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice killed on day 56 as measured by densitometry scanning of western blots. Values are expressed in arbitrary units (a.u.) and indicate the mean ± SEM of all experiments (n=5). C. Representative endoscopic pictures of colon tumors developed in Apcmin/+ mice and IL-21 KO-Apcmin/+ mice. Graphs show the number of lesions and the endoscopic scoring of tumors. Data indicate mean ± SEM of four independent experiments in which at least four mice per group were considered. D. Representative images showing PCNA immunostaining in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. The scale bars are 20μm. One of four representative experiments in which similar results were obtained is shown.
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Figure 2: IL-21 deficiency significantly reduces colon tumorigenesis in Apcmin/+ miceA. Experimental protocol used to assess the effect of IL-21 ablation on colon tumorigenesis in Apcmin/+ mice. B. Representative western blotting showing IL-21 expression in colon tissues taken from Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of five representative experiments is shown. NT, non-tumor area, T, tumor area. Right inset. Quantitative analysis of IL-21/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice killed on day 56 as measured by densitometry scanning of western blots. Values are expressed in arbitrary units (a.u.) and indicate the mean ± SEM of all experiments (n=5). C. Representative endoscopic pictures of colon tumors developed in Apcmin/+ mice and IL-21 KO-Apcmin/+ mice. Graphs show the number of lesions and the endoscopic scoring of tumors. Data indicate mean ± SEM of four independent experiments in which at least four mice per group were considered. D. Representative images showing PCNA immunostaining in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. The scale bars are 20μm. One of four representative experiments in which similar results were obtained is shown.

Mentions: To further evaluate the role of IL-21 in sporadic CRC in vivo we used Apcmin/+ mice. IL-21 was overexpressed in the colonic lesions of Apcmin/+ mice treated with AOM and killed on day 56 (Figure 2A) as compared to the non-tumor areas (Figure 2B). Both Apcmin/+ (control) and IL-21-knockout (IL-21 KO)-Apcmin/+ mice were injected with AOM and monitored for tumor formation. Four Apcmin/+ mice had to be killed before the end of the scheduled treatment, because of intestinal occlusion caused by large colonic tumors, whereas all the IL-21-KO-Apcmin/+ mice survived until the end of the study.


Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis.

De Simone V, Ronchetti G, Franzè E, Colantoni A, Ortenzi A, Fantini MC, Rizzo A, Sica GS, Sileri P, Rossi P, MacDonald TT, Pallone F, Monteleone G, Stolfi C - Oncotarget (2015)

IL-21 deficiency significantly reduces colon tumorigenesis in Apcmin/+ miceA. Experimental protocol used to assess the effect of IL-21 ablation on colon tumorigenesis in Apcmin/+ mice. B. Representative western blotting showing IL-21 expression in colon tissues taken from Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of five representative experiments is shown. NT, non-tumor area, T, tumor area. Right inset. Quantitative analysis of IL-21/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice killed on day 56 as measured by densitometry scanning of western blots. Values are expressed in arbitrary units (a.u.) and indicate the mean ± SEM of all experiments (n=5). C. Representative endoscopic pictures of colon tumors developed in Apcmin/+ mice and IL-21 KO-Apcmin/+ mice. Graphs show the number of lesions and the endoscopic scoring of tumors. Data indicate mean ± SEM of four independent experiments in which at least four mice per group were considered. D. Representative images showing PCNA immunostaining in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. The scale bars are 20μm. One of four representative experiments in which similar results were obtained is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496406&req=5

Figure 2: IL-21 deficiency significantly reduces colon tumorigenesis in Apcmin/+ miceA. Experimental protocol used to assess the effect of IL-21 ablation on colon tumorigenesis in Apcmin/+ mice. B. Representative western blotting showing IL-21 expression in colon tissues taken from Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of five representative experiments is shown. NT, non-tumor area, T, tumor area. Right inset. Quantitative analysis of IL-21/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice killed on day 56 as measured by densitometry scanning of western blots. Values are expressed in arbitrary units (a.u.) and indicate the mean ± SEM of all experiments (n=5). C. Representative endoscopic pictures of colon tumors developed in Apcmin/+ mice and IL-21 KO-Apcmin/+ mice. Graphs show the number of lesions and the endoscopic scoring of tumors. Data indicate mean ± SEM of four independent experiments in which at least four mice per group were considered. D. Representative images showing PCNA immunostaining in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. The scale bars are 20μm. One of four representative experiments in which similar results were obtained is shown.
Mentions: To further evaluate the role of IL-21 in sporadic CRC in vivo we used Apcmin/+ mice. IL-21 was overexpressed in the colonic lesions of Apcmin/+ mice treated with AOM and killed on day 56 (Figure 2A) as compared to the non-tumor areas (Figure 2B). Both Apcmin/+ (control) and IL-21-knockout (IL-21 KO)-Apcmin/+ mice were injected with AOM and monitored for tumor formation. Four Apcmin/+ mice had to be killed before the end of the scheduled treatment, because of intestinal occlusion caused by large colonic tumors, whereas all the IL-21-KO-Apcmin/+ mice survived until the end of the study.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus