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Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis.

Yin SY, Jian FY, Chen YH, Chien SC, Hsieh MC, Hsiao PW, Lee WH, Kuo YH, Yang NS - Nat Commun (2016)

Bottom Line: Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression.Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel.Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

View Article: PubMed Central - PubMed

Affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.

ABSTRACT
Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

No MeSH data available.


Related in: MedlinePlus

In vivo neutralization of IL-25 activity can effectively invalidate the anti-metastatic activity of Q2-3.(a) Representative bioluminescent images of tumour-resected mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1; 3 injections per week), anti-mouse IL-25 Ab (100 μg per mice; 2 injections per week), Q2-3+IL-25 Ab, or Q2-3+isotype IgG, at 3 weeks post tumour resection. The label ‘D' in the photograph denotes the mice died before 3 weeks post tumour resection. (b) Quantification of tumour metastasis by measuring luciferase activity photons s−1 cm−2 sr−1 in mice, as revealed along the indicated time course (12 weeks). (c) Survival of test mice after different treatments. NS, no significant difference between the ‘Q2-3' and ‘Q2-3+Anti-IgG' groups. **P<0.01, was obtained between the ‘Q2-3' and ‘Q2-3+Anti-IL-25' groups (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two independent experiments.
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f5: In vivo neutralization of IL-25 activity can effectively invalidate the anti-metastatic activity of Q2-3.(a) Representative bioluminescent images of tumour-resected mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1; 3 injections per week), anti-mouse IL-25 Ab (100 μg per mice; 2 injections per week), Q2-3+IL-25 Ab, or Q2-3+isotype IgG, at 3 weeks post tumour resection. The label ‘D' in the photograph denotes the mice died before 3 weeks post tumour resection. (b) Quantification of tumour metastasis by measuring luciferase activity photons s−1 cm−2 sr−1 in mice, as revealed along the indicated time course (12 weeks). (c) Survival of test mice after different treatments. NS, no significant difference between the ‘Q2-3' and ‘Q2-3+Anti-IgG' groups. **P<0.01, was obtained between the ‘Q2-3' and ‘Q2-3+Anti-IL-25' groups (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two independent experiments.

Mentions: To address whether IL-25 expression plays a key role in the anti-metastatic activity of Q2-3 on mammary tumour cells, we further employed an antibody-neutralization approach to deplete the in vivo IL-25 activity in the same 4T1 tumour resection model. Again by detecting the luminescent activity derived from transgenic 4T1-Luc2 cells in test mice, co-treatment of mice with Q2-3 (100 μg kg−1) and anti-mouse IL-25 antibody (100 μg per injection per mice), unlike the anti-metastatic effect detected for the ‘Q2-3 treatment only' group, resulted in full metastatic activity as observed for the control (PBS) group. In contrast, by using an irrelevant anti-IgG antibody preparation for this antibody-depletion test, the Q2-3 effect on anti-metastasis was sustained virtually in total (Fig. 5a,b). These results show that IL-25 obviously plays a central role in anti-metastatic activity of Q2-3. Consistently, the mice in the co-treatment group (Q2-3+Anti-IL-25) also exhibited a survival rate that was decreased to a similar level to that of the control (PBS) group, as compared with the mice of the Q2-3-treated group (Fig. 5c). Interestingly, even in vivo administration of anti-mouse IL-25 antibody was repeatedly found to detectably promote 4T1 metastasis, as compared with that of the control tumour-resected mice (Fig. 5a,b). This finding suggests that the presence or expression of endogenous IL-25 caused weak suppression of tumour metastasis in the untreated, tumour-resected mice. Altogether, these results suggest that the in vivo anti-metastatic effect of Q2-3 is mediated by endogenous IL-25 activity.


Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis.

Yin SY, Jian FY, Chen YH, Chien SC, Hsieh MC, Hsiao PW, Lee WH, Kuo YH, Yang NS - Nat Commun (2016)

In vivo neutralization of IL-25 activity can effectively invalidate the anti-metastatic activity of Q2-3.(a) Representative bioluminescent images of tumour-resected mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1; 3 injections per week), anti-mouse IL-25 Ab (100 μg per mice; 2 injections per week), Q2-3+IL-25 Ab, or Q2-3+isotype IgG, at 3 weeks post tumour resection. The label ‘D' in the photograph denotes the mice died before 3 weeks post tumour resection. (b) Quantification of tumour metastasis by measuring luciferase activity photons s−1 cm−2 sr−1 in mice, as revealed along the indicated time course (12 weeks). (c) Survival of test mice after different treatments. NS, no significant difference between the ‘Q2-3' and ‘Q2-3+Anti-IgG' groups. **P<0.01, was obtained between the ‘Q2-3' and ‘Q2-3+Anti-IL-25' groups (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4837478&req=5

f5: In vivo neutralization of IL-25 activity can effectively invalidate the anti-metastatic activity of Q2-3.(a) Representative bioluminescent images of tumour-resected mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1; 3 injections per week), anti-mouse IL-25 Ab (100 μg per mice; 2 injections per week), Q2-3+IL-25 Ab, or Q2-3+isotype IgG, at 3 weeks post tumour resection. The label ‘D' in the photograph denotes the mice died before 3 weeks post tumour resection. (b) Quantification of tumour metastasis by measuring luciferase activity photons s−1 cm−2 sr−1 in mice, as revealed along the indicated time course (12 weeks). (c) Survival of test mice after different treatments. NS, no significant difference between the ‘Q2-3' and ‘Q2-3+Anti-IgG' groups. **P<0.01, was obtained between the ‘Q2-3' and ‘Q2-3+Anti-IL-25' groups (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two independent experiments.
Mentions: To address whether IL-25 expression plays a key role in the anti-metastatic activity of Q2-3 on mammary tumour cells, we further employed an antibody-neutralization approach to deplete the in vivo IL-25 activity in the same 4T1 tumour resection model. Again by detecting the luminescent activity derived from transgenic 4T1-Luc2 cells in test mice, co-treatment of mice with Q2-3 (100 μg kg−1) and anti-mouse IL-25 antibody (100 μg per injection per mice), unlike the anti-metastatic effect detected for the ‘Q2-3 treatment only' group, resulted in full metastatic activity as observed for the control (PBS) group. In contrast, by using an irrelevant anti-IgG antibody preparation for this antibody-depletion test, the Q2-3 effect on anti-metastasis was sustained virtually in total (Fig. 5a,b). These results show that IL-25 obviously plays a central role in anti-metastatic activity of Q2-3. Consistently, the mice in the co-treatment group (Q2-3+Anti-IL-25) also exhibited a survival rate that was decreased to a similar level to that of the control (PBS) group, as compared with the mice of the Q2-3-treated group (Fig. 5c). Interestingly, even in vivo administration of anti-mouse IL-25 antibody was repeatedly found to detectably promote 4T1 metastasis, as compared with that of the control tumour-resected mice (Fig. 5a,b). This finding suggests that the presence or expression of endogenous IL-25 caused weak suppression of tumour metastasis in the untreated, tumour-resected mice. Altogether, these results suggest that the in vivo anti-metastatic effect of Q2-3 is mediated by endogenous IL-25 activity.

Bottom Line: Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression.Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel.Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

View Article: PubMed Central - PubMed

Affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.

ABSTRACT
Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

No MeSH data available.


Related in: MedlinePlus