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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 treatment of Q2-3 significantly suppresses the metastasis of mouse (4T1) mammary tumour cells after a tumour resection process.(a) Representative bioluminescent images of tumour-bearing mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), doxorubicin (2 mg kg−1) or different dosages of Q2-3, after resection of the orthotopic primary tumours. In the PBS-treated group (vehicle), three mice died before 3 weeks post tumour resection. The red signal represents the highest level on the colorimetric scale. (b) Quantification of tumour metastasis by measuring luciferase activity in photons s−1 cm−2 sr−1 in mice revealed along the indicated time course (n=8 per group). (c) Survival of test mice after different treatments. P<0.05, were obtained between the control (DMSO) and Q2-3-treated (20 or 100 μg kg−1) groups (Kaplan–Meier results were analysed by log-rank test). (d) Effect of Q2-3 (2, 20 or 50 μg kg−1) on the population change of monocytic (CD11b+Ly6C+) and granulocytic (CD11b+Ly6G+) MDSCs in lung tissues of test mice were quantified by flow cytometry analysis, and were compared with MDSC populations in PBS group. Data are reported as mean±s.d. (n=3). *P<0.05; **P<0.01; NS, not significant (two-tailed t-test). Similar results were obtained from three independent experiments.
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f2: In vivo treatment of Q2-3 significantly suppresses the metastasis of mouse (4T1) mammary tumour cells after a tumour resection process.(a) Representative bioluminescent images of tumour-bearing mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), doxorubicin (2 mg kg−1) or different dosages of Q2-3, after resection of the orthotopic primary tumours. In the PBS-treated group (vehicle), three mice died before 3 weeks post tumour resection. The red signal represents the highest level on the colorimetric scale. (b) Quantification of tumour metastasis by measuring luciferase activity in photons s−1 cm−2 sr−1 in mice revealed along the indicated time course (n=8 per group). (c) Survival of test mice after different treatments. P<0.05, were obtained between the control (DMSO) and Q2-3-treated (20 or 100 μg kg−1) groups (Kaplan–Meier results were analysed by log-rank test). (d) Effect of Q2-3 (2, 20 or 50 μg kg−1) on the population change of monocytic (CD11b+Ly6C+) and granulocytic (CD11b+Ly6G+) MDSCs in lung tissues of test mice were quantified by flow cytometry analysis, and were compared with MDSC populations in PBS group. Data are reported as mean±s.d. (n=3). *P<0.05; **P<0.01; NS, not significant (two-tailed t-test). Similar results were obtained from three independent experiments.

Mentions: To investigate the anti-metastatic effects of Q2-3, transgenic luciferase-expressing mouse 4T1-Luc2 cells were injected into the mammary fat pad of test mice. At 15 days post tumour cell implantation, in situ 4T1 tumours were carefully removed by a surgical resection process. Tumour metastatic activity and survival time of control and Q2-3-treated mice were examined and compared over the following 8 weeks (Fig. 2a–c). By detecting the luminescent activity of 4T1-Luc2 cells as an indication of tumour metastasis, Q2-3 treatment (≥20 μg kg−1) was found to significantly suppress the metastasis of 4T1 cells to the lung (Fig. 2a). In addition, treatment with Q2-3 at a relatively low dosage (>20 μg kg−1) had much higher anti-metastatic activity than treatment with doxorubicin (2 mg kg−1) (Fig. 2b), a drug which is used clinically for the treatment of human breast cancers1617. Q2-3 treatment also consistently, significantly increased the survival rate of tumour-resected mice (Fig. 2c). These results show that in vivo administration of Q2-3 can efficiently prevent mammary tumour metastasis after a tumour resection process.


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 treatment of Q2-3 significantly suppresses the metastasis of mouse (4T1) mammary tumour cells after a tumour resection process.(a) Representative bioluminescent images of tumour-bearing mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), doxorubicin (2 mg kg−1) or different dosages of Q2-3, after resection of the orthotopic primary tumours. In the PBS-treated group (vehicle), three mice died before 3 weeks post tumour resection. The red signal represents the highest level on the colorimetric scale. (b) Quantification of tumour metastasis by measuring luciferase activity in photons s−1 cm−2 sr−1 in mice revealed along the indicated time course (n=8 per group). (c) Survival of test mice after different treatments. P<0.05, were obtained between the control (DMSO) and Q2-3-treated (20 or 100 μg kg−1) groups (Kaplan–Meier results were analysed by log-rank test). (d) Effect of Q2-3 (2, 20 or 50 μg kg−1) on the population change of monocytic (CD11b+Ly6C+) and granulocytic (CD11b+Ly6G+) MDSCs in lung tissues of test mice were quantified by flow cytometry analysis, and were compared with MDSC populations in PBS group. Data are reported as mean±s.d. (n=3). *P<0.05; **P<0.01; NS, not significant (two-tailed t-test). Similar results were obtained from three independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4837478&req=5

f2: In vivo treatment of Q2-3 significantly suppresses the metastasis of mouse (4T1) mammary tumour cells after a tumour resection process.(a) Representative bioluminescent images of tumour-bearing mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), doxorubicin (2 mg kg−1) or different dosages of Q2-3, after resection of the orthotopic primary tumours. In the PBS-treated group (vehicle), three mice died before 3 weeks post tumour resection. The red signal represents the highest level on the colorimetric scale. (b) Quantification of tumour metastasis by measuring luciferase activity in photons s−1 cm−2 sr−1 in mice revealed along the indicated time course (n=8 per group). (c) Survival of test mice after different treatments. P<0.05, were obtained between the control (DMSO) and Q2-3-treated (20 or 100 μg kg−1) groups (Kaplan–Meier results were analysed by log-rank test). (d) Effect of Q2-3 (2, 20 or 50 μg kg−1) on the population change of monocytic (CD11b+Ly6C+) and granulocytic (CD11b+Ly6G+) MDSCs in lung tissues of test mice were quantified by flow cytometry analysis, and were compared with MDSC populations in PBS group. Data are reported as mean±s.d. (n=3). *P<0.05; **P<0.01; NS, not significant (two-tailed t-test). Similar results were obtained from three independent experiments.
Mentions: To investigate the anti-metastatic effects of Q2-3, transgenic luciferase-expressing mouse 4T1-Luc2 cells were injected into the mammary fat pad of test mice. At 15 days post tumour cell implantation, in situ 4T1 tumours were carefully removed by a surgical resection process. Tumour metastatic activity and survival time of control and Q2-3-treated mice were examined and compared over the following 8 weeks (Fig. 2a–c). By detecting the luminescent activity of 4T1-Luc2 cells as an indication of tumour metastasis, Q2-3 treatment (≥20 μg kg−1) was found to significantly suppress the metastasis of 4T1 cells to the lung (Fig. 2a). In addition, treatment with Q2-3 at a relatively low dosage (>20 μg kg−1) had much higher anti-metastatic activity than treatment with doxorubicin (2 mg kg−1) (Fig. 2b), a drug which is used clinically for the treatment of human breast cancers1617. Q2-3 treatment also consistently, significantly increased the survival rate of tumour-resected mice (Fig. 2c). These results show that in vivo administration of Q2-3 can efficiently prevent mammary tumour metastasis after a tumour resection process.

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