Exosomes are responsible for intercellular communication between tumor cells and others in the tumor microenvironment. These microvesicles promote oncogensis and can support towards metastasis by promoting a pro-tumorogenic environment. Modifying the exosomal content and exosome delivery are emerging novel cancer therapies. However, the clinical translation is limited due to feasibility of isolating and delivery of treated exosomes as well as an associated immune response in patients.
In this study, Northeastern University researchers provide proof-of-concept for a novel treatment approach for manipulating exosomal content by genetic transfection of tumor cells using dual-targeted hyaluronic acid-based nanoparticles. Following transfection with plasmid DNA encoding for wild-type p53 (wt-p53) and microRNA-125b (miR-125b), they evaluated the transgene expression in the SK-LU-1 cells and in the secreted exosomes. Furthermore, along with modulation of wt-p53 and miR-125b expression, they also show that the exosomes (i.e., wt-p53/exo, miR-125b/exo and combination/exo) have a reprogramed global miRNA profile. The miRNAs in the exosomes were mainly related to the activation of genes associated with apoptosis as well as p53 signaling. More importantly, these altered miRNA levels in the exosomes could mediate macrophage repolarization towards a more pro-inflammatory/antitumor M1 phenotype. However, further studies, especially in vivo studies, are warranted to assess the direct influence of such macrophage reprogramming on cancer cells and oncogenesis post-treatment.
Characteristics of exosomes secreted from SK-LU-1 cells
(a) Transmission electron microscopy images of the exosomes isolated from non-transfected SK-LU-1 cells. The upper image was acquired at lower magnification, while the lower image is with higher magnification. (b,c) Venn diagram to illustrate miRNAs distribution between SK-LU-1 cells (SK/cells) and exosomes (SK/exo) secreted from non-transfected cells above the nonspecific background internal controls (red line in (c)). (d) Comparative distribution of miRNA expression profile in SK-LU-1 cells (SK/cells) and in exosomes (SK/exo).
The current study provides a novel platform enabling the development of therapeutic strategies affecting not only the cancer cells but also the tumor microenvironment by utilizing the ‘bystander effect’ through genetic transfer with secreted exosomes. Such modification could also support antitumor environment leading to decreased oncogenesis.