中研院新發現 植物衍生物抑制乳癌細胞 更新： 2016年05月04日【記者徐翠玲／綜合報導】中研院農業生物科技研究中心特聘研究員楊寧蓀與中國醫藥大學教授郭悅雄研究團隊，日前利用植物萃取物咖啡酸合成衍生物Q2-3，並且證實注入小鼠靜脈後，可促進體內抑制腫瘤因子IL-25分泌，達到減緩乳癌細胞轉移，若Q2-3與紫杉醇一起使用更具加乘效果。楊寧蓀3日表示，這項利用「細胞與細胞對話」的新方法，未來或許可以提供新的醫療策略，現正申請國際專利，未來將朝向開發臨床用藥目標前進。而此研究論文已刊登於國際專業期刊《自然通訊》（Nature communications)。研究團隊以小鼠模式，證實乳癌細胞周邊的「纖維母細胞」（非乳癌細胞）可以被誘導產生抑制乳癌因子IL-25。同時，研究團隊以一種名為methyl caffeic acid的植物化學物為原料，只透過一個步驟的化學反應步驟，成功合成植物衍生物Q2-3，靜脈注射於小鼠後，證實能夠有效促進小鼠乳癌細胞周邊的纖維母細胞合成IL-25，達到抑制乳癌細胞移轉的可能。研究團隊更進一步發現，若將Q2-3與已知的臨床抗癌藥物「紫杉醇」（docetaxel）合併使用，則具有加乘的效果，可抑制特定人類乳癌細胞的轉移。楊寧蓀表示，咖啡酸在蔬菜、水果、中草藥等植物上都可發現，他們將咖啡酸合成Q2-3抑制癌細胞轉移，目前小鼠實驗成功，保守估計發展成藥物約需10年。由於很多植物含有咖啡酸，合成0.1公克的Q2-3成本大約只要62元。
Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis/ Nature Communications 7, Article number: 11311. 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. Breast cancer is the most common malignancy in women worldwide and the second leading cause of cancer mortality1. In these patients, it is not the primary tumour, but its metastases to distant sites that are the main cause of death. Clinical surgery via resection of the malignant primary tumour is still the routine primary treatment for breast cancer patients2. Increasing evidence suggests that tumour cells are conditioned by their tissue-microenvironments at primary and secondary sites for growth and metastasis. The challenge now is therefore to prevent or suppress metastasis of cancer cells from the tumour-associated microenvironment into target tissues3. The tumour microenvironment has been described as a tumour stroma or premetastatic/metastatic niche that can promote metastasis and therapy resistance3, 4, 5. On the other hand, tumour-associated stromal cells can also produce tumour suppressor factors, such as nucleoside diphosphate kinase A (NME1)6, Kangai 1 (KAI1/CD82)7, 8 and IL-25 (ref. 9), in the tumour microenvironment, and this can restrict the development or metastasis of breast cancers. Research into molecular agents that can confer a strong stimulatory effect on the expression of potent metastasis suppressor molecules is one direction that may lead to new cancer therapies10, 11, 12. Lignans, as widespread plant natural products, have a broad variety of chemical structures and exhibit a large range of biological activities13. A series of synthetic dihydrobenzofuran lignans, obtained by biomimetic oxidative dimerization of caffeic and/or ferulic acid methyl ester followed by derivatization reactions have been shown to exhibit potent antiangiogenic activity14. Among these synthetic compounds, methyl(E)-3-[2-(3,4-dihydroxyphenyl) -7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]-prop-2-enoate (Q2-3) has been shown to exhibit a significant anti-proliferation effect on various human cancer cell lines, including Jurkat, K562 and MCF-7 cells15. Although in vitro study has indicated a specific effect of Q2-3 on cytotoxicity or G2/M cell cycle arrest in Jurkat cells15, the anti-metastatic effect of this synthetic compound in vivo has not been addressed in previous study. In this study, we first investigated whether Q2-3 and some other selected lignans could interfere with mammary tumour metastasis in a tumour resection mouse model. As compared with other tested lignans, Q2-3 conferred a significant anti-metastatic effect on test mammary tumours. In particular, we investigated whether specific cellular mechanisms of Q2-3 action, including tumour-associated fibroblast (TAF) activities in the tumour microenvironment, are associated with such bioactivity. We thus mimicked an in vitro mammary tumour microenvironment by using a three-dimensional (3D) cell co-culture system to assess the regulatory effect of Q2-3 on the expression of specific cytokines and innate immune cell activities in both human and mouse TAFs. Interleukin-25 (IL-25/IL-17E) was recently reported to confer high anticancer activity, with little or no effect on non-malignant cells9. The apoptotic activity of IL-25 was shown to be mediated by differential expression of its receptor, IL-25R, which was found to be expressed at high levels in tumours from patients with poor prognoses, but at low levels in non-malignant breast tissues9. This finding suggests that targeting the IL-25 signalling pathway may offer a novel therapeutic approach for advanced breast cancers. In this study, our findings also indicate that the stromal fibroblasts in the mammary tumour microenvironment can express IL-25 which can in turn mediate an anti-metastatic effect on the companion tumour cells. In addition, Q2-3 can greatly enhance such endogenous activity of TAFs and result in a potent anti-metastatic effect against the surrounding mammary carcinoma cells. The possible implications and application of our findings, in terms of the mechanistic regulation of tumour microenvironments and potential clinical inference with tumour metastasis using specific phytochemicals as IL-25 agonist, are discussed.
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