The Role of Small Extracellular Vesicles in the Progression of Colorectal Cancer and Its Clinical Applications

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide and a longstanding critical challenge for public health. Screening has been suggested to effectively reduce both the incidence and mortality of CRC. However, the drawback of the current screening modalities, both stool-based tests and colonoscopies, is limited screening adherence, which reduces the effectiveness of CRC screening. Blood tests are more acceptable than stool tests or colonoscopy as a first-line screening approach. Therefore, identifying blood biomarkers for detecting CRC and its precancerous neoplasms is urgently needed to fulfill the unmet clinical need. Currently, many kinds of blood contents, such as circulating tumor cells, circulating tumor nucleic acids, and extracellular vesicles, have been investigated as biomarkers for CRC detection. Among these, small extracellular vesicles (sEVs) have been demonstrated to detect CRC effectively in recent reports. sEVs enable intercellular shuttling-for instance, trafficking between recipient cancer cells and stromal cells-which can affect tumor initiation, proliferation, angiogenesis, immune regulation; metastasis, the cancer-specific molecules, such as proteins, microRNAs, long noncoding RNAs, and circular RNAs, loaded into cancer-derived sEVs may serve as biomarkers for the detection of cancers, including CRC. Indeed, accumulating evidence has shown that nucleic acids and proteins contained in CRC-derived sEVs are effective as blood biomarkers for CRC detection. However, investigations of the performance of sEVs for diagnosing CRC in clinical trials remains limited. Thus, the effectiveness of sEV biomarkers for diagnosing CRC needs further validation in clinical trials.

Keywords: biomarker; blood test; colorectal cancer; small extracellular vesicle.

Figure 1

Proposed role of small EVs in the metastatic cascade of CRC Premetastatic niches (PMNs) possess six characteristics: vascular leakiness and angiogenesis, lymphangiogenesis, inflammation, immunosuppression, genetic reprogramming, and organotropism. sEVs play a vital role in each part of the above characteristics. CRC-derived sEVs containing miR-25-3p contribute to the induction of vascular leakiness and angiogenesis. Furthermore, sEVs containing miR-25-3p may impair the junctions of the endothelial cell layer. CRC-derived sEVs containing IRF-2 have been postulated to stimulate VEGF-C (vascular endothelial growth factor C) secretion, resulting in lymphangiogenesis and metastasis. sEVs containing miR-21 help polarize liver macrophages into an IL-6-secreting phenotype, contributing to the inflammatory environment. Tumor-derived sEVs express specific integrins to initiate the formation of PMNs in a particular tissue. Integrin α6/integrin β4/integrin β1 and integrin β5/integrin αv are enriched in sEVs with lung and liver tropism, respectively. (The figure was created at Biorender.com on 9 January 2022).