Exosomes in cancer: small vesicular transporters for cancer progression and metastasis, biomarkers in cancer therapeutics

Abstract

Cancer progression is a polygenic procedure in which the exosomes can function as substantial roles. Exosomes are tiny, phospholipid bilayer membrane nanovesicles of endocytic derivation with a diameter of 40-100 nm. These nanovesicles can transport bioactive molecules containing mRNAs, proteins, DNA fragments, and non-coding RNAs from a donor cell to recipient cells, and cause the alteration in genetic and epigenetic factors and reprogramming of the target cells. Many diverse cell types such as mesenchymal cells, immune cells, and cancer cells can induce the release of exosomes. Increasing evidence illustrated that the exosomes derived from tumor cells might trigger the tumor initiation, tumor cell growth and progression, metastasis, and drug resistance. The secreted nanovesicles of exosomes can play significant roles in cells communicate via shuttling the nucleic acid molecules and proteins to target cells and tissues. In this review, we discussed multiple mechanisms related to biogenesis, load, and shuttle of the exosomes. Also, we illustrated the diverse roles of exosomes in several types of human cancer development, tumor immunology, angiogenesis, and metastasis. The exosomes may act as the promising biomarkers for the prognosis of various types of cancers which suggested a new pathway for anti-tumor therapeutic of these nanovesicles and promoted exosome-based cancer for clinical diagnostic and remedial procedures.

Keywords: Angiogenesis; Cancer; Exosome; Metastasis; Therapy.

Figure 1. Schematic of exosomes derived cancer cell biogenesis and secretion.

Exosomes can secrete through cells while intracellular organs called multivesicular bodies (MVBs) fuse with the plasma membrane. The MVBs formation occurs through invaginations of late endosomes, which increased molecules from the Golgi apparatus (e.g., MHC class II molecules) or the cell surface (e.g., growth factor receptors). Subsequently, exosomes could be enriched in several materials including sphingomyelin, intracellular protein, ceramide, cholesterol, transmembrane receptors, mRNA, and miRNA. The exosomes secreted from human tumor cells can affect the local tumor microenvironment, alter the extracellular matrix, and enhance the angiogenesis, thrombosis and cancer cell proliferation.

Figure 2. Exosome recruitment of bone marrow-derived cells.

Exosomes transform the tumor microenvironment (TME) and dispose of distant tissue sites for metastasis. The efficacies of exosomes at distant tumor sites necessitate that exosomes migrate through the blood or lymph. They dispose tissue sites for metastasis or transform the bone marrow (BM) environment, and making a pre-metastatic niche to enhance tumor invasion and development. Thus tumor-derived exosomes can cause recruiting bone marrow-derived cells to the tumor and pre-tumor tissue where they function as cancer development and support the multiple tumor cell expansion and development in various human cancer cells.

Figure 3. Exosomes drive pre-metastatic niche formation.

The formation of the pre-metastatic niche is required for organ-specific metastatic tropism. The exosomes can move to the distant location for increasing the formation of pre-metastatic niche. The complementation of angiogenesis and induction of stromal and epithelial cell differentiation can be associated with a pro-tumor environment. Tumor-derived exosomes provide a pre-metastatic niche, through the polarization of tissue macrophage, suppression of dendritic cell maturation, induction of CAF (cancer-associated fibroblasts) via differentiation of fibroblasts to myofibroblasts. This effect can be performed via the mediation of intercellular cross-talk and subsequent adjustment of both local and distant microenvironments in an autocrine and paracrine fashion.

Figure 4. Regulation of immune responses by extracellular vesicles.

The tumor-derived microvesicles may function as immunosuppressive effects. Exosome-mediated communication among cancer cells and the immune system is triggered recruiting pro-cancerogenic immune cells. The regulation of immune response in a procedure of prevention tumor diagnosis and anti-tumoral immune functions through impairing the function of effector T cells and natural killer cells (NK cells) can induce mobilization of neutrophils, and differentiate T-helper cells toward a T-regulatory cell phenotype.

Figure 5. Exosomes as mediators of drug resistance.

Drug resistance applies for a critical role in various cancer treatments. There are different mechanisms of drug resistance even multi-drug resistance (MDR) such as drug efflux, triggered by extracellular vesicles, which can make the defeat of the whole remedy. The tumor-derived exosomes can induce tumor cells to promote drug resistance through sending out the tumor drugs or inhibiting antibody-based drugs.

Figure 6. The main groups of exosome-based therapies.

This overview includes impairing the secretion of exosomes via cancer cells and removing cancer derived exosomes, including bioactive molecules, from the blood (or other body fluids) of cancer patients; using exosomes, naturally-equipped nanocarriers, including microRNA (miRNA), small interference RNA (siRNA), and/or anticancer drugs for targeting delivery to tumor cells; the exosomes molecular composition indicates their cells of origin, may confer special cell or tissue tropism; applying exosomes as potent cell-free peptide-based vaccine demonstrate an remarkable strategy to inhibit tumor development; exosomal miRNAs can contribute to exosome-mediated cell–cell communication and induce anticancer features.