Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review

Abstract

Trafficking of biological material across membranes is an evolutionary conserved mechanism and is part of any normal cell homeostasis. Such transport is composed of active, passive, export through microparticles, and vesicular transport (exosomes) that collectively maintain proper compartmentalization of important micro- and macromolecules. In pathological states, such as cancer, aberrant activity of the export machinery results in expulsion of a number of key proteins and microRNAs resulting in their misexpression. Exosome-mediated expulsion of intracellular drugs could be another barrier in the proper action of most of the commonly used therapeutics, targeted agents, and their intracellular metabolites. Over the last decade, a number of studies have revealed that exosomes cross-talk and/or influence major tumor-related pathways, such as hypoxia-driven epithelial-to-mesenchymal transition, cancer stemness, angiogenesis, and metastasis involving many cell types within the tumor microenvironment. Emerging evidence suggests that exosome-secreted proteins can also propel fibroblast growth, resulting in desmoplastic reaction, a major barrier in effective cancer drug delivery. This comprehensive review highlights the advancements in the understanding of the biology of exosomes secretions and the consequence on cancer drug resistance. We propose that the successful combination of cancer treatments to tackle exosome-mediated drug resistance requires an interdisciplinary understanding of these cellular exclusion mechanisms, and how secreted biomolecules are involved in cellular cross-talk within the tumor microenvironment.

Figure-1. Biogenesis and release of Exosomes

Diagram depicting the well accepted model for exosome biogenesis and release. Primarily, the exosomes are derived from the multi-vesicular bodies (MVBs) which are known as late endosomes (originally derived from lysosomes). Exosome generation can be triggered by many factor including extracellular stimuli (e.g., microbial attack) and other stresses. The exosomes can be released into the extracellular environment by fusion of MVBs with the cell surface that is supported by a number of specialized proteins called SNAREs.

Figure-2. Exosome Structure

Exosomes are capable of hosting a wide array of molecules including viruses, nucleic acid material (RNAs, DNA), and microRNAs depending on a variety of factors including the cell type or origin. Other factors influencing exosome content include pathological state of the host organism. The contents of exosomes can be transferred from the cell of origin to their target cells in local microenvironment or even at distant site that can possibly give rise to an exponential intercellular communication networks.

Figure-3. Role of Exosomes in Sustaining Cancer Resistance Networks

Exosome mediated export of biological material can induce a microenvironment favorable for resistance. Exosome released factor can promote (a) EMT cell morphology, resulting in stemness; (b) promote fibroblast like cell formation that causes desmoplatic reaction (stromal reaction); (c) promote immune escape mechanisms and (d) promote angiogenesis and metastasis. The miRNAs expelled by exosomes can regulate multiple signaling pathways that cumulatively promote resistant phenotype of most tumors.

Figure-4. Drug Exclusion Mechanisms of Exosomes (hypothesis)

Diagram showing intracellular exosomal packaging of chemical drugs and or their breakdown products (active forms). Such exosome residing drugs can be expelled by cells, resulting in diminished drug efficacy and this is a distinctly separate from other drug transport mechanism.