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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

Reduced expression of COX-2/PGE2 in the tumors of IL-21 KO-Apcmin/+ mice ACOX-2 was assessed by real-time PCR in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least two mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing COX-2 in colon tissues taken from Apcmin/+ mice and IL-21 KO Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of four representative experiments is shown. Bottom inset. Quantitative analysis of COX-2/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice and IL-21 KO-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=4). C. PGE2 levels were assessed by ELISA in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least three mice per group were considered.
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Figure 7: Reduced expression of COX-2/PGE2 in the tumors of IL-21 KO-Apcmin/+ mice ACOX-2 was assessed by real-time PCR in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least two mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing COX-2 in colon tissues taken from Apcmin/+ mice and IL-21 KO Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of four representative experiments is shown. Bottom inset. Quantitative analysis of COX-2/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice and IL-21 KO-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=4). C. PGE2 levels were assessed by ELISA in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least three mice per group were considered.

Mentions: Since induction of COX-2 and its product PGE2 by IL-6 and TNF-α positively influences colorectal tumorigenesis [22], we next examined whether IL-21 deficiency affects the COX-2/PGE2 axis in Apcmin/+ mice. In both control and IL-21 KO-Apcmin/+ mice, COX-2 RNA and protein were increased in the tumors as compared to non-tumor areas (Figure 7A and B), though induction of COX-2 was markedly diminished in the absence of IL-21 (Figure 7A and B). Consistently, lack of IL-21 markedly decreased PGE2 in the tumors of Apcmin/+ mice (Figure 7C). Our results are in line with previous reports showing that deletion of the Cox-2 gene in Apcmin/+ mice results in a significant reduction in both the number and size of lesions [23, 24].


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)

Reduced expression of COX-2/PGE2 in the tumors of IL-21 KO-Apcmin/+ mice ACOX-2 was assessed by real-time PCR in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least two mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing COX-2 in colon tissues taken from Apcmin/+ mice and IL-21 KO Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of four representative experiments is shown. Bottom inset. Quantitative analysis of COX-2/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice and IL-21 KO-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=4). C. PGE2 levels were assessed by ELISA in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least three mice per group were considered.
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Figure 7: Reduced expression of COX-2/PGE2 in the tumors of IL-21 KO-Apcmin/+ mice ACOX-2 was assessed by real-time PCR in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least two mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing COX-2 in colon tissues taken from Apcmin/+ mice and IL-21 KO Apcmin/+ mice killed on day 56. β-actin was used as loading control. One of four representative experiments is shown. Bottom inset. Quantitative analysis of COX-2/β-actin protein ratio in total extracts of T and NT colon tissues taken from Apcmin/+ mice and IL-21 KO-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=4). C. PGE2 levels were assessed by ELISA in colon tissues taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data indicate mean ± SEM of two independent experiments in which at least three mice per group were considered.
Mentions: Since induction of COX-2 and its product PGE2 by IL-6 and TNF-α positively influences colorectal tumorigenesis [22], we next examined whether IL-21 deficiency affects the COX-2/PGE2 axis in Apcmin/+ mice. In both control and IL-21 KO-Apcmin/+ mice, COX-2 RNA and protein were increased in the tumors as compared to non-tumor areas (Figure 7A and B), though induction of COX-2 was markedly diminished in the absence of IL-21 (Figure 7A and B). Consistently, lack of IL-21 markedly decreased PGE2 in the tumors of Apcmin/+ mice (Figure 7C). Our results are in line with previous reports showing that deletion of the Cox-2 gene in Apcmin/+ mice results in a significant reduction in both the number and size of lesions [23, 24].

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