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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

Q2-3 administration can confer a complementary anti-metastatic effect on human cancer cells (MDA-MB-231), when used in combination with docetaxel.(a) Representative bioluminescent images of MDA-MB-231 tumour-bearing nude mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1), docetaxel (5 mg kg−1) or co-treatment with docetaxel and Q2-3 for 3 weeks, after resection of the orthotopic primary tumours. In PBS-treated (control) and docetaxel-treated groups, one mice was died before 3 weeks post tumour resection. (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. (c) Survival of test mice after different treatments. P<0.05, were obtained between the docetaxel- and co-treated mice (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two or three independent experiments.
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f7: Q2-3 administration can confer a complementary anti-metastatic effect on human cancer cells (MDA-MB-231), when used in combination with docetaxel.(a) Representative bioluminescent images of MDA-MB-231 tumour-bearing nude mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1), docetaxel (5 mg kg−1) or co-treatment with docetaxel and Q2-3 for 3 weeks, after resection of the orthotopic primary tumours. In PBS-treated (control) and docetaxel-treated groups, one mice was died before 3 weeks post tumour resection. (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. (c) Survival of test mice after different treatments. P<0.05, were obtained between the docetaxel- and co-treated mice (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two or three independent experiments.

Mentions: To further evaluate whether Q2-3 can confer a complementary or additive therapeutic effect on the suppression of tumour metastasis when used in combination with other clinically used anticancer drugs, we assessed effect of Q2-3 plus docetaxel, a drug commonly used for the treatment of human breast cancer, in suppressing the metastatic activities of human MDA-MB-231-Luc2 cells in nude mice (Fig. 7). By detecting the luminescent activity of MDA-MB-231-Luc2 cells in test mice after resection of primary mammary tumour tissues in situ (Fig. 7a), we showed that combination treatment with Q2-3 (100 μg kg−1) and docetaxel (5 mg kg−1) resulted in substantially higher anti-metastatic activity than treatment with docetaxel only (Fig. 7b). Consistently, this combined treatment also further increased the survival rate of test mice in comparison with those only receiving each single treatment (Fig. 7c). Of note, treatment with low dosage of Q2-3 alone was already more effective than treatment with docetaxel, in terms of suppressing metastasis and prolonging survival; in combination with docetaxel, Q2-3 was even more effective (Fig. 7b,c). These data together suggest that in vivo administration of Q2-3 can confer strong complementary activity on the therapeutic activity of a clinically used anticancer drug, docetaxel, for suppression of metastatic tumour cell activities by regulating the tumour-associated microenvironment.


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)

Q2-3 administration can confer a complementary anti-metastatic effect on human cancer cells (MDA-MB-231), when used in combination with docetaxel.(a) Representative bioluminescent images of MDA-MB-231 tumour-bearing nude mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1), docetaxel (5 mg kg−1) or co-treatment with docetaxel and Q2-3 for 3 weeks, after resection of the orthotopic primary tumours. In PBS-treated (control) and docetaxel-treated groups, one mice was died before 3 weeks post tumour resection. (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. (c) Survival of test mice after different treatments. P<0.05, were obtained between the docetaxel- and co-treated mice (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two or three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4837478&req=5

f7: Q2-3 administration can confer a complementary anti-metastatic effect on human cancer cells (MDA-MB-231), when used in combination with docetaxel.(a) Representative bioluminescent images of MDA-MB-231 tumour-bearing nude mice (n=8 per group) after in vivo treatment with PBS (0.1% DMSO in saline), Q2-3 (100 μg kg−1), docetaxel (5 mg kg−1) or co-treatment with docetaxel and Q2-3 for 3 weeks, after resection of the orthotopic primary tumours. In PBS-treated (control) and docetaxel-treated groups, one mice was died before 3 weeks post tumour resection. (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. (c) Survival of test mice after different treatments. P<0.05, were obtained between the docetaxel- and co-treated mice (Kaplan–Meier results were analysed by log-rank test). Similar results were obtained from two or three independent experiments.
Mentions: To further evaluate whether Q2-3 can confer a complementary or additive therapeutic effect on the suppression of tumour metastasis when used in combination with other clinically used anticancer drugs, we assessed effect of Q2-3 plus docetaxel, a drug commonly used for the treatment of human breast cancer, in suppressing the metastatic activities of human MDA-MB-231-Luc2 cells in nude mice (Fig. 7). By detecting the luminescent activity of MDA-MB-231-Luc2 cells in test mice after resection of primary mammary tumour tissues in situ (Fig. 7a), we showed that combination treatment with Q2-3 (100 μg kg−1) and docetaxel (5 mg kg−1) resulted in substantially higher anti-metastatic activity than treatment with docetaxel only (Fig. 7b). Consistently, this combined treatment also further increased the survival rate of test mice in comparison with those only receiving each single treatment (Fig. 7c). Of note, treatment with low dosage of Q2-3 alone was already more effective than treatment with docetaxel, in terms of suppressing metastasis and prolonging survival; in combination with docetaxel, Q2-3 was even more effective (Fig. 7b,c). These data together suggest that in vivo administration of Q2-3 can confer strong complementary activity on the therapeutic activity of a clinically used anticancer drug, docetaxel, for suppression of metastatic tumour cell activities by regulating the tumour-associated microenvironment.

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