Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

Abstract

Exosomes, the extracellular vesicles produced in the endosomal compartments, facilitate the transportation of proteins as well as nucleic acids. Epigenetic modifications are now considered important for fine-tuning the response of cancer cells to various therapies, and the acquired resistance against targeted therapies often involves dysregulated epigenetic modifications. Depending on the constitution of their cargo, exosomes can affect several epigenetic events, thus impacting post-transcriptional regulations. Thus, a role of exosomes as facilitators of epigenetic modifications has come under increased scrutiny in recent years. Exosomes can deliver methyltransferases to recipient cells and, more importantly, non-coding RNAs, particularly microRNAs (miRNAs), represent an important exosome cargo that can affect the expression of several oncogenes and tumor suppressors, with a resulting impact on cancer therapy resistance. Exosomes often harbor other non-coding RNAs, such as long non-coding RNAs and circular RNAs that support resistance. The exosome-mediated transfer of all this cargo between cancer cells and their surrounding cells, especially tumor-associated macrophages and cancer-associated fibroblasts, has a profound effect on the sensitivity of cancer cells to several chemotherapeutics. This review focuses on the exosome-induced modulation of epigenetic events with resulting impact on sensitivity of cancer cells to various therapies, such as, tamoxifen, cisplatin, gemcitabine and tyrosine kinase inhibitors. A better understanding of the mechanisms by which exosomes can modulate response to therapy in cancer cells is critical for the development of novel therapeutic strategies to target cancer drug resistance.

LncRNA SNHG6 sponges miR-101 and induces tamoxifen resistance in breast cancer cells through induction of EMT

“…Various non-coding RNAs, ranging from microRNAs (miRNAs) to long non-coding RNAs (lncRNAs) have been reported to mechanistically and functionally affect the tamoxifen resistance. Our own earlier work demonstrated a role of miR-10b in the tamoxifen resistance of ER-positive breast cancers (8) and such role of miRNAs in tamoxifen resistance has been investigated by several other researchers as well (6,7,9). Further, lncRNAs are novel molecules of interest in terms of their possible role in the modulation of response to tamoxifen in ER-positive breast cancers (10).…”

Therapeutic Applications of Stem Cell-Derived Exosomes

“…This can lead to the activation of signaling pathways such as the mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and PI3K/Protein kinase B (Akt) pathways, which play crucial roles in cell survival, proliferation, and differentiation [ 72 , 73 ]. Furthermore, the delivery of miRNAs by exosomes can modulate gene expression in recipient cells by affecting mRNA stability and translation, an example being the regulation of PTEN expression by exosomal miR-21, which activates the PI3K/Akt pathway [ 74 ]. The bioactive molecules present in exosomes thus impact target cells through various means, including the transfer of activated receptors and the induction of epigenetic changes, underlining the complexity and specificity of exosome-mediated communication [ 75 ].…”

Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs

“…Exosomes were once thought to be the only way for cells to excrete waste products, but subsequent researches have demonstrated that exosomes function as transporters of substances, transmitters of information and biomarkers in the physiological and pathological processes of the organism ( 86 – 88 ). Exosomes are extremely significant to tumor growth, metastasis, angiogenesis and immune regulation, metabolism, and drug resistance by delivering a variety of biomolecules that mediate signal transduction ( 89 , 90 ). Exosomes, as effective biomarkers of diseases, especially cancer, have become a new research field.…”