Abstract
Exosomes (Exos) are nano-sized extracellular vesicles constitutively released by both prokaryotic and eukaryotic cells. Their role as inter-cellular messengers involved in both physiological and pathological processes has overwhelmingly come to light in the last decade, and their contribution to cancerogenesis and tumor metastasis is under intensive investigation. Here we review the most recent information concerning Exos in colorectal cancer (CRC) and focus on their effects on tumor microenvironment and the immune system, as well as unravel their role in the formation of the pre-metastatic niche and in drug resistance. Such a recent knowledge on Exos depicts their potential translations into the clinical arena, either as an alternative tool of “liquid biopsy” or novel therapeutic approaches for CRC. However, due to the limited data available from clinical trials, they need further validations before addressing their putative application in oncology.
Highlights
The constitutive activation of the RAS-RAF mitogen-activated protein kinase (MAPK)-driven intracellular signaling, together with the angiogenic switch, have been widely described in the malignant transformation of colorectal cancer (CRC) [1]
Huber et al have shown for the first time that CRC-derived vesicles deliver different immuno-suppressive signals, such as Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL), which induce the apoptosis of CD8+ T lymphocytes [36]
Several mechanisms are involved with paradoxical activation of mTOR signaling [60] and a recent study suggested a possible effect of Exos from cetuximabresistant CRC cells to restrict the expression of PTEN, a negative regulator of PI3K [61]
Summary
The constitutive activation of the RAS-RAF mitogen-activated protein kinase (MAPK)-driven intracellular signaling, together with the angiogenic switch, have been widely described in the malignant transformation of CRC [1]. In the past few years, Exos have been widely investigated since they were discovered in many physiological and pathological processes, and accumulating evidence support their role in CRC [5] These small (50–130 nm) EVs are detectable in most body fluids, such as plasma, urine, saliva, or ascites [6]. Unlike other EVs, which directly bud-off from the cell membrane, Exos are end-products of recycling endosomal pathways since they originate from inward budding of the plasma membrane, with the subsequent formation of multivesicular bodies (MVBs) These complex structures encapsulating early Exos are actively loaded with a number of molecules including proteins, coding- and non-coding RNAs as well as DNA fragments [7, 8]. Vesicles are spread in the blood stream [9]
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