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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

Dihydrobenzofuran lignan (Q2-3) exhibits a specific cytotoxic effect on breast tumour cells.(a) Chemical reaction formula for synthesis of Q2-3 compound (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate) from two caffeic acid methyl ester molecules. (b,c) MTT assays for cytotoxic effect of Q2-3 on SKBR3 (ER−Her+ human breast cancer cell line), MDA-MB-231 (ER−Her− human breast cancer cell line), M10 (human normal epithelial cell line) and WI38 (human lung fibroblast cell line). 2 × 104 cells were seeded and compared for their growth activity after treatment with Q2-3 for 24 or 72 h. The beginning cytotoxic dosage of Q2-3 was detected at 0.3 μM, with >50% kill rate on SKBR3 and MDA-MB-231 cells. Data are reported as mean±s.d. (n=4). **P<0.01, ***P<0.001 (Two-tailed t-test). Similar results were obtained from three independent experiments.
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f1: Dihydrobenzofuran lignan (Q2-3) exhibits a specific cytotoxic effect on breast tumour cells.(a) Chemical reaction formula for synthesis of Q2-3 compound (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate) from two caffeic acid methyl ester molecules. (b,c) MTT assays for cytotoxic effect of Q2-3 on SKBR3 (ER−Her+ human breast cancer cell line), MDA-MB-231 (ER−Her− human breast cancer cell line), M10 (human normal epithelial cell line) and WI38 (human lung fibroblast cell line). 2 × 104 cells were seeded and compared for their growth activity after treatment with Q2-3 for 24 or 72 h. The beginning cytotoxic dosage of Q2-3 was detected at 0.3 μM, with >50% kill rate on SKBR3 and MDA-MB-231 cells. Data are reported as mean±s.d. (n=4). **P<0.01, ***P<0.001 (Two-tailed t-test). Similar results were obtained from three independent experiments.

Mentions: To evaluate the anticancer effect of methyl (E)-3- [2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate, denoted as Q2-3, an organic synthesis reaction was needed1314. This was achieved by the dimerization of methyl caffeic acid as catalysed in the presence of silver oxide (Fig. 1a). The yield of Q2-3 after the indicated reaction was ∼32%. We compared the cytotoxic activities of this synthetic compound on various mammary epithelial cells and fibroblasts. The compound was ∼96% pure as a single Q2-3 chemical, as determined by elemental composition analysis and HPLC (see Methods). The effects of Q2-3 on cell viability were tested on four different cell lines, M10, WI38, SKBR3 and MDA-MB-231, by treating cells with varying Q2-3 concentrations for 24 h (Fig. 1b) and 72 h (Fig. 1c). As compared with the control (0.1% dimethyl sulphoxide (DMSO)) group cells, Q2-3 effectively suppressed the growth (≥60% inhibition) of human mammary tumour cells (SKBR3 and MDA-MB-231 cells) at a relatively low concentration (≥0.5 μM). In contrast, normal human mammary epithelial (M10) and fibroblast (WI38) cell lines showed a much higher resistance to treatment with Q2-3, exhibiting≥80% viability at 2 μM (Fig. 1b,c). This result is strongly supported by data collected from more than 10 serial concentrations tested at two different time points (24 and 72 h). This result indicates a high cytotoxicity of Q2-3 on mammary tumour cells. In contrast, normal human mammary epithelial cells and fibroblasts exhibited a much higher level of tolerance for Q2-3 treatment.


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)

Dihydrobenzofuran lignan (Q2-3) exhibits a specific cytotoxic effect on breast tumour cells.(a) Chemical reaction formula for synthesis of Q2-3 compound (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate) from two caffeic acid methyl ester molecules. (b,c) MTT assays for cytotoxic effect of Q2-3 on SKBR3 (ER−Her+ human breast cancer cell line), MDA-MB-231 (ER−Her− human breast cancer cell line), M10 (human normal epithelial cell line) and WI38 (human lung fibroblast cell line). 2 × 104 cells were seeded and compared for their growth activity after treatment with Q2-3 for 24 or 72 h. The beginning cytotoxic dosage of Q2-3 was detected at 0.3 μM, with >50% kill rate on SKBR3 and MDA-MB-231 cells. Data are reported as mean±s.d. (n=4). **P<0.01, ***P<0.001 (Two-tailed t-test). Similar results were obtained from three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4837478&req=5

f1: Dihydrobenzofuran lignan (Q2-3) exhibits a specific cytotoxic effect on breast tumour cells.(a) Chemical reaction formula for synthesis of Q2-3 compound (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate) from two caffeic acid methyl ester molecules. (b,c) MTT assays for cytotoxic effect of Q2-3 on SKBR3 (ER−Her+ human breast cancer cell line), MDA-MB-231 (ER−Her− human breast cancer cell line), M10 (human normal epithelial cell line) and WI38 (human lung fibroblast cell line). 2 × 104 cells were seeded and compared for their growth activity after treatment with Q2-3 for 24 or 72 h. The beginning cytotoxic dosage of Q2-3 was detected at 0.3 μM, with >50% kill rate on SKBR3 and MDA-MB-231 cells. Data are reported as mean±s.d. (n=4). **P<0.01, ***P<0.001 (Two-tailed t-test). Similar results were obtained from three independent experiments.
Mentions: To evaluate the anticancer effect of methyl (E)-3- [2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate, denoted as Q2-3, an organic synthesis reaction was needed1314. This was achieved by the dimerization of methyl caffeic acid as catalysed in the presence of silver oxide (Fig. 1a). The yield of Q2-3 after the indicated reaction was ∼32%. We compared the cytotoxic activities of this synthetic compound on various mammary epithelial cells and fibroblasts. The compound was ∼96% pure as a single Q2-3 chemical, as determined by elemental composition analysis and HPLC (see Methods). The effects of Q2-3 on cell viability were tested on four different cell lines, M10, WI38, SKBR3 and MDA-MB-231, by treating cells with varying Q2-3 concentrations for 24 h (Fig. 1b) and 72 h (Fig. 1c). As compared with the control (0.1% dimethyl sulphoxide (DMSO)) group cells, Q2-3 effectively suppressed the growth (≥60% inhibition) of human mammary tumour cells (SKBR3 and MDA-MB-231 cells) at a relatively low concentration (≥0.5 μM). In contrast, normal human mammary epithelial (M10) and fibroblast (WI38) cell lines showed a much higher resistance to treatment with Q2-3, exhibiting≥80% viability at 2 μM (Fig. 1b,c). This result is strongly supported by data collected from more than 10 serial concentrations tested at two different time points (24 and 72 h). This result indicates a high cytotoxicity of Q2-3 on mammary tumour cells. In contrast, normal human mammary epithelial cells and fibroblasts exhibited a much higher level of tolerance for Q2-3 treatment.

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