The biology and function of exosomes in cancer

Abstract

Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40-150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes can be used as liquid biopsies and noninvasive biomarkers for early detection, diagnosis, and treatment of cancer patients.

Figure 1. Exosome biology and heterogeneity is a reflection of the origin and status of the originating tissue or cell at the time of exosome generation.

(A) In culture, the same cell type can produce exosomes with distinct nucleic acids and proteins above the baseline of some common protein markers. Exosome production can be dynamic, with the same cell shedding exosomes with different compositions based on their health status. (B) It has been assumed that exosomes are cellular trash bags for elimination of excess proteins, but many studies have shown that exosomes often exhibit certain specific markers, irrespective of the organ or cellular source. This suggests that certain proteins are transported to the exosomes with some degree of specificity. Additionally, distinct differences have been identified in the RNA and protein species present in exosomes, likely reflecting cellular and organ specificity. This second layer of complexity is dynamic and can change with the evolving status of the organ and cells within. Here, the pancreas is provided as an example, but this dynamism in exosomal contents presumably holds true for all organs. Therefore, exosome heterogeneity is a much more complex phenomenon than cellular heterogeneity and can be fleeting depending on stimuli and the functional status of the organ.

Figure 2. Tumor-associated and circulating cancer-derived exosomes are a heterogeneous population that generates a unique tumor nanoenvironment (TNE).

Tumors are a composite of cancer cells (CCs) with different genetics and phenotypes, stromal cells (including immune cells), mesenchymal cells (such as mesenchymal stem cells [MSCs] and fibroblasts), ECs, and stromal elements (such as ECM components). Immune cell subtypes can be found in the tumors and include DCs, B cells, Teffs, Tregs, NK cells, and macrophages. All of these cells shed exosomes, contributing to TNE diversity. These exosomes likely participate in cell-to-cell communications within the tumor microenvironment and contribute to the heterogeneity of circulating exosomes. Exosomes derived from the serum or plasma can yield DNA for whole genome sequencing (WGS) and the identification of gene mutations and deletions. Additionally, exosomes allow for the analysis of mRNA; noncoding RNA (ncRNA), including miR and lncRNA; proteins; lipids; and metabolites.

Figure 3. Sequencing of exosomal DNA and RNA can identify all driver and passenger mutations and deletions, providing information on actionable genetic defects associated with cancer.

Tumors contain a heterogeneous mix of cancer cells. Clonal heterogeneity emerges when different sets of mutations and deletions drive different cancer cell clones, generating zones within tumors that contain unique sets of cancer cells with defined genetics. Therefore, tumor biopsies or portions cannot provide a view of the entire landscape of cancer-associated genetic defects. Analysis of cancer exosomes from the patient’s blood can potentially overcome this limitation and offer genetic information reflecting the status of all the cancer cells in the tumor in order to account for tumor heterogeneity.