Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion.

Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.

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

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.

Cytotoxic Effects of Plant Sap-Derived Extracellular Vesicles on Various Tumor Cell Types.

Edible plants have been widely used in traditional therapeutics because of the biological activities of their natural ingredients, including anticancer, antioxidant, and anti-inflammatory properties. Plant sap contains such medicinal substances and their secondary metabolites provide unique chemical structures that contribute to their therapeutic efficacy. Plant extracts are known to contain a variety of extracellular vesicles (EVs) but the effects of such EVs on various cancers have not been investigated. Here, we extracted EVs from four plants-Dendropanax morbifera, Pinus densiflora, Thuja occidentalis, and Chamaecyparis obtusa-that are known to have cytotoxic effects. We evaluated the cytotoxic effects of these EVs by assessing their ability to selectively reduce the viability of various tumor cell types compared with normal cells and low metastatic cells. EVs from D. morbifera and P. densiflora sap showed strong cytotoxic effects on tumor cells, whereas those from T. occidentalis and C. obtusa had no significant effect on any tumor cell types. We also identified synergistic effect of EVs from D. morbifera and P. densiflora saps on breast and skin tumor cells and established optimized treatment concentrations. Our findings suggest these EVs from plant sap as new candidates for cancer treatment.

Wearable Lymphedema Massaging Modules: Proof of Concept using Origami-inspired Soft Fabric Pneumatic Actuators.

Lymphedema is a non-curative chronic swelling caused by impairment of the lymphatic system, affecting up to 250 million patients worldwide. The patients suffer from low quality of life because of discomfort and reduced range of motion due to the swelling. Severe swellings can be immediately mediated with special massaging technique known as the Manual Lymphatic Drainage (MLD). Limitations of MLD involves long travel distances, the cost of regular treatment sessions, and the lack of lymphedema specialists. Since MLD is performed very gently, described as caressing a baby's head, soft wearable robotics with its inherent compliance and safety is the perfect solution to creating a light and safe wearable lymphedema massaging device. In this paper, origami-inspired soft fabric pneumatic actuator is developed that creates not only normal force, but also shear force which is essential in the performance of MLD. The shear is created by the unfolding of the Z-shaped fold-lines as the actuator is inflated. One Z-folded actuator module of 30 x 60 mm dimension with a single fold of 15 mm fold height creates maximum shear force of about 1.5 N and stroke displacement of about 30 mm when subjected to compression loading of 5 N. The range of forces exerted can be tuned by varying the tension of the compressive clothing covering the actuators, and the stroke displacement can be varied by changing the parameter of the actuator module itself, such as the fold height and the number of the folds. The modules can also be repeatedly actuated under compressive clothing, and therefore, the developed actuator modules have high potential as a wearable massaging device.