Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with high morbidity and mortality rates. A number of factors including modulation of the tumor microenvironment, high metastatic capability, and resistance to treatment have been associated with CRC disease progression. Recent studies have documented that tumor-derived extracellular vesicles (EVs) play a significant role in intercellular communication in CRC via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells. This transfer influences a number of immune-related pathways leading to activation/differentiation/expression of immune cells and modulation of the tumor microenvironment that plays a significant role in CRC progression, metastasis, and drug resistance. Furthermore, tumor-derived EVs are secreted in large amounts in biological fluids of CRC patients and as such the expression analysis of EV cargoes have been associated with prognosis or response to therapy and may be a source of therapeutic targets. This review aims to provide a comprehensive insight into the role of EVs in the modulation of the tumor microenvironment and its effects on CRC progression, metastasis, and drug resistance. On the other hand, the potential role of CRC derived EVs as a source of biomarkers of response and therapeutic targets will be discussed in detail to understand the dynamic role of EVs in CRC diagnosis, treatment, and management.
Highlights
Colorectal cancer (CRC) is the third most common cancer globally, with high morbidity and mortality rates
The main aim of this review is to focus on the role of extracellular vesicles (EVs) in CRC with respect to immune modulation, drug resistance, and metastasis, as well as to review the literature regarding EVs as a potential source of therapeutic targets in CRC
In addition to these immune suppressive cells, there are a variety of other immune cell populations found in the tumor microenvironment such as dendritic cells, monocytes, neutrophils, mast cells, natural killer (NK) cells, CD4, CD8 cells, B cells that play diverse roles in promoting tumorigenesis in CRC via degranulation, release of pro-angiogenic factors, growth stimulatory factors (VEGF, FGF2, TNF-α), angiopoitin-1 and tryptase, granzyme B, perforin and upregulation of major histocompatibility complex (MHC) class 1 and co-stimulatory ligands leading to tumor progression and proliferation [61]
Summary
Colorectal cancer (CRC) is the third most common cancer globally, with high morbidity and mortality rates. In stage I, CRC cells are actively proliferating, forming small, benign polyps. The main options for CRC treatment include surgery and chemotherapy, depending mainly on the CRC stage and the location of the polyps [5]. Studies have demonstrated that tumor cells secrete membrane-bound vesicles, called extracellular vesicles (EVs), that serve as efficient mediators of intercellular communication [10] by releasing large amounts of nucleic acids, cytokines/chemokines, angiogenic factors, extracellular matrix remodeling factors as well as tumor microenvironment modulating factors during carcinogenesis [11,12,13]. In CRC, this is important as these alterations can affect the regulation of multiple cellular processes [16], lead to modulation of the tumor microenvironment and enhance tumor cell proliferation and transformation [14,15]. The main aim of this review is to focus on the role of EVs in CRC with respect to immune modulation, drug resistance, and metastasis, as well as to review the literature regarding EVs as a potential source of therapeutic targets in CRC
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