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New Discovery: Interleukin-25 Induced by Q2-3 to Suppress Tumour Metastasis

Recently, a joint research team led by Dr. Ning-Sun Yang from Agricultural Biotechnology Research Centre of Academia Sinica, and Dr. Yueh-Hsiung Kuo from China Medical University in Taiwan, found a natural plant product-derivative dihydrobenzofuran lignin (Q2-3), could prevent metastasis of mammary tumour cells. They discovered that Q2-3 can be easily obtained by the dimerization of methyl caffeic acid via a one-step chemical reaction, and it could also activate the secretion of an endogenous anti-tumour factor named Interleukin-25 (IL-25).

The article with the findings, titled “Induction of IL-25 Secretion from Tumour-associated Fibroblasts Suppresses Mammary Tumour Metastasis” was published in the journal Nature Communications in last April.

The relevant press release “A Natural Plant Metabolite Derivative Q2-3 Efficiently Prevents Metastasis of Mammary Tumour Cells” was featured on APBN June 2016 issue Bioboard. We followed up with Dr. Shu-Yi Yin, the first author of the article to learn more about the research. Dr. Shu-Yi Yin is a postdoctoral fellow at the Agricultural Biotechnology Research Centre, Academic Sinica.

1. Do you mind sharing what leads to the discovery of this research?

Dr. Yin: During the past five years, a spectrum of studies have shown that the tumour-associated fibroblasts (TAFs), surrounding or embedding the cancer cells in a variety of different tumour types, are actively and intrinsically involved in mechanisms affecting tumour growth and metastasis. These fibroblasts have been shown to play key roles in interplays with the regulation of tumour cell behaviours, often via differential gene expression, regulation and secretion of specific chemokines (e.g. RANTES, CXCL12 and CXCL14), cytokines (e.g. TNF-α, IL-1β, NF-κB). In the beginning of this study, we used DNA microarray and microRNA array analyses to predict the effect of Q2-3 on TAFs, as comparing with fibroblasts without co-cultivation with tumour cells. Among different predictions, the increased IL-25 expression/secretion was proved to play important role in Q2-3-mediated anti-metastatic activity.

2. Normally, the methyl caffeic acid is extracted from what plant species to produce Q2-3?

Dr. Yin: It can be found in Polygonum amplexicaule var. sinense (Chinese name: Xuesanqi) and in the fruit of Solanum torvum. To produce Q2-3 in abundance, we transform caffeic acid into caffeic acid methyl ester through one step chemical reaction.

3. Nowadays, are there any existing drugs/methods to prevent metastasis of mammary tumour cells effectively?

Dr. Yin: Although many drugs, such as docetaxel, were clinically found to cause “specific cytotoxicity” on mammary tumour cells, no drug can prevent the metastasis of mammary tumour cells for most patients.

4. Will Q2-3 be able to prevent metastasis of all kinds of cancer?

Dr. Yin: We believe Q2-3 exhibit high potential to suppress the metastasis of different tumour cell types. However, the anti-metastatic activity of Q2-3 on each cancer type should be proved case by case. Take pancreatic cancer as an example, IL-25 signalling may not be good for treatment of the cancer. Therefore, whether Q2-3 could efficiently suppress the metastasis of pancreatic cancer should be seriously considered.

5. Your research showed that when Q2-3 is used alongside the common chemotherapy drug Docetaxel, additive effect is observed to improving the effectiveness of the drug. Will Q2-3 be able to use to improve effectiveness of other drugs beside Docetaxel? Will it be able to replace Docetaxel and used in chemotherapy?

Dr. Yin: We believe Q2-3 also could improve effectiveness of other drugs with highly cytotoxicity for tumour cells, because pharmacological basis of Q2-3 is different from these traditionally used anticancer drugs. On the other hand, whether Q2-3 can replace Docetaxel and used in chemotherapy still need further clinical studies.

6. Do you foresee any potential obstacles or challenges to translate this research into clinical application?

Dr. Yin: Although we have evaluated anti-metastatic activity of Q2-3 in vivo, we still don’t know whether Q2-3 could induce IL-25 and suppress cancer metastasis in human body. Therefore the key challenge for us is to apply clinical test and confirm specific pharmacological activity of Q2-3. On the other hand, the safety concern of Q2-3 also remains unclear. We will try to evaluate if any change of physiological index is disrupted by Q2-3.

7. Seeing that Academia Sinica has already applied for an international patent for this research finding, what are some of the important applications from this research?

Dr. Yin: Most of potential applications are described above. I think the importance of this finding may not only be the evaluation of clinical potential of this compound, but also the indication of application value of many research strategy, including omics analyses, 3D cell co-culture system and in vivo model of tumour metastasis, in study of tumour microenvironment. We believe the combination and integration of these approaches are worth to be extended for other investigations of herbal medicine. These research experiences indeed could systematically evaluate more and more surprising pharmacological mechanism for potential nature products. These nature products may include wedelalactone, cytopiloyne and deoxyelephantopin, which were also exhibit anticancer activity in vivo. Our research team in Agricultural Biotechnology Research Center (ABRC) of Academia Sinica in Taiwan will aim to reveal specific pharmacological activities of these phytochemicals in tumour microenvironment.

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