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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 angiogenesis in the tumors of IL-21 KO-Apcmin/+ miceA. VEGF expression was 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 four mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing p-VEGF-R2 Tyr1175 and VEGF-R2 expression 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 in which similar results were obtained is shown. C. Representative immunohistochemical staining of CD31 in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Staining with isotype control IgG is also shown. The scale bars are 20μm. One of four representative experiments is shown. Upper left inset. Quantification of blood vessels in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data are presented as mean values of blood vessels per high power field (hpf) ± SEM of two independent experiments in which at least two sections per group were analyzed.
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Figure 8: Reduced angiogenesis in the tumors of IL-21 KO-Apcmin/+ miceA. VEGF expression was 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 four mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing p-VEGF-R2 Tyr1175 and VEGF-R2 expression 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 in which similar results were obtained is shown. C. Representative immunohistochemical staining of CD31 in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Staining with isotype control IgG is also shown. The scale bars are 20μm. One of four representative experiments is shown. Upper left inset. Quantification of blood vessels in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data are presented as mean values of blood vessels per high power field (hpf) ± SEM of two independent experiments in which at least two sections per group were analyzed.

Mentions: VEGF signaling has been identified as a key factor in the pathogenesis of sporadic colorectal tumors in mouse and man [25, 26], and both PGE2 and IL-17A are known to induce VEGF [27, 28]. Therefore, we investigated whether IL-21 controls VEGF and VEGF-related angiogenic pathways in the Apcmin/+ mouse model. Knock-down of IL-21 reduced VEGF, p-VEGF-R2 Tyr1175 and VEGF-R2 in the tumors of Apcmin/+ mice (Figure 8A and B). Consistently, a significant decrease in CD31-positive blood vessels, reflective of a diminished neo-angiogenesis, was seen in the tumors of IL-21 KO-Apcmin/+ mice compared with control tumors (Figure 8C). No significant change in VEGF, p-VEGF-R2 Tyr1175 and VEGF-R2 expression as well as in the number of blood vessels was seen in the normal colon between control and IL-21 KO-Apcmin/+ mice (Figure 8A-C).


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 angiogenesis in the tumors of IL-21 KO-Apcmin/+ miceA. VEGF expression was 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 four mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing p-VEGF-R2 Tyr1175 and VEGF-R2 expression 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 in which similar results were obtained is shown. C. Representative immunohistochemical staining of CD31 in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Staining with isotype control IgG is also shown. The scale bars are 20μm. One of four representative experiments is shown. Upper left inset. Quantification of blood vessels in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data are presented as mean values of blood vessels per high power field (hpf) ± SEM of two independent experiments in which at least two sections per group were analyzed.
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Figure 8: Reduced angiogenesis in the tumors of IL-21 KO-Apcmin/+ miceA. VEGF expression was 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 four mice per group were considered. NT, non-tumor area, T, tumor area. B. Representative western blotting showing p-VEGF-R2 Tyr1175 and VEGF-R2 expression 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 in which similar results were obtained is shown. C. Representative immunohistochemical staining of CD31 in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Staining with isotype control IgG is also shown. The scale bars are 20μm. One of four representative experiments is shown. Upper left inset. Quantification of blood vessels in colon sections taken from Apcmin/+ mice and IL-21 KO-Apcmin/+ mice killed on day 56. Data are presented as mean values of blood vessels per high power field (hpf) ± SEM of two independent experiments in which at least two sections per group were analyzed.
Mentions: VEGF signaling has been identified as a key factor in the pathogenesis of sporadic colorectal tumors in mouse and man [25, 26], and both PGE2 and IL-17A are known to induce VEGF [27, 28]. Therefore, we investigated whether IL-21 controls VEGF and VEGF-related angiogenic pathways in the Apcmin/+ mouse model. Knock-down of IL-21 reduced VEGF, p-VEGF-R2 Tyr1175 and VEGF-R2 in the tumors of Apcmin/+ mice (Figure 8A and B). Consistently, a significant decrease in CD31-positive blood vessels, reflective of a diminished neo-angiogenesis, was seen in the tumors of IL-21 KO-Apcmin/+ mice compared with control tumors (Figure 8C). No significant change in VEGF, p-VEGF-R2 Tyr1175 and VEGF-R2 expression as well as in the number of blood vessels was seen in the normal colon between control and IL-21 KO-Apcmin/+ mice (Figure 8A-C).

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