Regulatory role of exosomes in colorectal cancer progression and potential as biomarkers

Abstract

Colorectal cancer (CRC) remains an enormous challenge to human health worldwide. Unfortunately, the mechanism underlying CRC progression is not well understood. Mounting evidence has confirmed that exosomes play a vital role in CRC progression, which has attracted extensive attention among researchers. In addition to acting as messengers between CRC cells, exosomes also participate in the CRC immunomodulatory process and reshape immune function. As stable message carriers and liquid biopsy option under development, exosomes are promising biomarkers in the diagnosis or treatment of CRC. In this review we have described and analyzed the biogenesis and release of exosomes and current research on the role of exosomes in immune regulation and metastasis of CRC. Moreover, we have discussed candidate exosomal molecules as potential biomarkers to diagnose CRC, predict CRC progression, or determine CRC chemoresistance, and described the significance of exosomes in the immunotherapy of CRC. This review provides insight to further understand the role of exosomes in CRC progression and identify valuable biomarkers that facilitate the clinical management of CRC patients.

Keywords: Colorectal cancer; exosome; immunoregulation; immunotherapy; metastasis.

Figure 1

Biogenesis of exosomes in donor cells and absorption by recipient cells. Exosomes are involved in cell communication by carrying a variety of bioactive molecules, including DNA, proteins, enzymes, miRNAs, lncRNAs, and circRNAs. The biogenesis of exosomes is divided into three sequential stages in donor cells, which are annotated in the upper figure and mainly involve two sorting mechanisms (the ESCRT and ESCRT-independent pathways). The release of exosomes is also influenced by extracellular environmental factors, such as acidity and calcium. Exosomes can be absorbed by recipient cells through diverse mechanisms, such as a direct fusion with target cell membranes, uptake by target cells through endocytosis, and recognition of specific receptors on the cell surface.

Figure 2

Key molecules involved in exosome crosstalk between CRC and immune cells. CRC cells influence macrophage polarization as follows: releasing exosomes carrying specific molecules, such as miRNAs or lncRNAs; affecting neutrophil function or differentiation via exosomal triphosphate RNAs, circPACRGL, or KRAS; enhancing the immunosuppressive function of MDSCs via exosomal Hsp72; promoting the polarization of B cells to PDL1⁺ Breg via exosomal lncRNA HOTAIR; affecting the killing ability of NK cells via exosomal lncRNA SNHG10; suppressing T-cell function via exosomal PD-L1 or miR-29-3p; and mediating CAF activation. Furthermore, some molecules that are carried by immune cell-derived exosomes, including miR-21-5p, miR-155-5p, S100A9, miR-181b-3p, miR-345-5p, miR-135b-5p, linc00659, and WEE2-AS1, promote the migration and invasion of CRC cells.

Figure 3

Exosome biomarkers in CRC progression, diagnosis, and treatment. Because exosomes carrying a variety of bioactive molecules reflect the characteristics of the parent cells and can be detected in multiple body fluids, exosomes have great potential as biomarkers for the diagnosis, treatment, and prediction of CRC progression. In addition, exosomes can also be used as a adjunctive diagnosis for CRC patients and a dynamic observation indicator reflecting disease changes to guide personalized medicine. With low toxicity and immunogenicity, exosomes are ideal drug delivery carriers. Numerous engineered exosomes have been designed for drug delivery therapy in CRC.