Anti-Metastatic Effects of Plant Sap-Derived Extracellular Vesicles in a 3D Microfluidic Cancer Metastasis Model

Abstract

<jats:p>Natural medicinal plants have attracted considerable research attention for their potential as effective drugs. The roots, leaves and stems of the plant, Dendropanax morbifera, which is endemic to southern regions of Asia, have long been used as a folk medicine to treat variety of diseases. However, the sap of this plant has not been widely studied and its bioactive properties have yet to be clearly elucidated. Here, we isolated extracellular vesicles from D. morbifera sap with the goal of improving the intracellular delivery efficiency and clinical effectiveness of bioactive compounds in D. morbifera sap. We further investigated the anti-metastatic effects of D. morbifera sap-derived extracellular vesicles (DMS-EVs) using a cancer metastasis model based on 3D microfluidic system that closely mimics the in vivo tumor environment. We found that DMS-EVs exerted a concentration-dependent suppressive effect on cancer-associated fibroblasts (CAFs), which are important mediators of cancer metastasis. DMS-EVs also altered expression level of genes, especially growth factor and extracellular matrix (ECM)-related genes, including integrin and collagen. Our findings suggest that DMS-EVs can act as anti-CAF agents to reduce CAFs in the tumor microenvironment. They further indicate the utility of our 3D microfluidic model for various drug-screening assays as a potential alternative to animal testing for use in validating therapeutic effects on cancer metastasis.</jats:p>

Plant-derived nanovesicles: Current understanding and applications for cancer therapy

“…Importantly, the combination of these two types of vesicles produced synergistic cytotoxic activities against tumor cells and minimized the side effects [ 99 ]. The same research group also demonstrated that Dendropanax morbifera PELNs exerted suppressive effects on cancer-associated fibroblasts in a tumor microenvironment, suggesting potential antimetastatic activity [ 98 ]. PEGylated nanovesicles from Asparagus cochinchinensis effectively inhibited liver cancer cell proliferation without inducing systemic toxic effects in xenograft models.…”

Extracellular Vesicles from Plants: Current Knowledge and Open Questions

“…Moreover, DM-EVs-treated CAFs showed a gene expression panel different from that of untreated cells. Among the genes with different expressions, there were cell migration related-genes (TFG-β2, PDGFC, ILK, and AK) and extracellular matrix (ECM)-related genes (CD44, PLAU, COL3A1, COL4A6, ITGA11, and ITGA6) [46]. Recently, Potestà et al studied the properties of microvesicles (MVs) isolated from Moringa oleifera seed aqueous extract (MOES) [19]; in previous work, the same authors demonstrated that MOES contains miRNAs which could be responsible for its anti-proliferative and pro-apoptotic effects on cancer cells, and not on healthy cells [16].…”

Stability of Plant Leaf-Derived Extracellular Vesicles According to Preservative and Storage Temperature

“…Dendropanax morbifera, which is endemic to southern parts of Asia, has historically been used in traditional medicine and the commercial production of golden varnish. Dendropanax morbifera extracts have been shown to have anticancer [33,34], antioxidant [35], antidiabetic [36], anti-inflammatory [37], and anti-melanogenic effects [5]. We previously developed a technology to isolate plant-derived EVs and used it to isolate EVs from Dendropanax morbifera [5].…”