Abstract
Exchange of molecules via exosomes is a means of eukaryotic intercellular communication, especially within tumour microenvironments. However, no data are available on alterations of exosomal molecular cargo by environmental cues (eg, pharmacological treatments). To approach this issue, we compared the abundance of 754 miRNAs and 741 cancer-related proteins in exosomes secreted by Caco-2 (Cetuximab-responsive) and HCT- 116 (Cetuximab-resistant) CRC cells, before and after Cetuximab treatment, with that in their source cells. Cetuximab significantly altered the cargo of Caco-2 exosomes: it increased abundance of miRNAs and proteins activating proliferation and inflammation and reduced miRNAs and proteins related to immune suppression. These alterations did not precisely mirror those in source cells, suggesting a Cetuximab-linked effect. Analogous alterations were detected in HCT-116. Transfection of exosomes from Cetuximab-treated Caco-2 into HCT-116 significantly increased HCT-116 viability; conversely, no viability alteration was detected in Caco-2 transfected with exosomes from Cetuximab-treated HCT-116. Analysis of networks, comprising targets of differentially expressed (DE) exosomal miRNAs and DE exosomal proteins, demonstrates a significant involvement of processes related to proliferation, inflammation, immune response, apoptosis. Our data extend existing knowledge on molecular mechanisms of eukaryotic intercellular communication, especially in oncological processes. Their translation to clinical settings may add new weapons to existing therapeutic repertoires against cancer.
Highlights
Exosomes are nanosized vesicles (50-120 nm in diameter), which derive from endosomal compartment invaginations called Multivesicular Bodies (MBVs)
The data reported in this paper demonstrate that Cetuximab significantly alters the miRNAs and proteins cargo of exosomes released by colorectal cancer (CRC) cells
Profiling of exosomal miRNAs after Cetuximab treatment showed changes for 25 and 20 miRNAs in Caco2 exosomes and source cells, respectively (Table 2 and 3); in comparison, we detected 9 and 12 miRNAs whose levels had been altered by Cetuximab in HCT-116 exosomes and source cells, respectively (Table 4)
Summary
Exosomes are nanosized vesicles (50-120 nm in diameter), which derive from endosomal compartment invaginations called Multivesicular Bodies (MBVs). High levels of exosomes in plasma of colorectal cancer (CRC) patients were secreted by poorly differentiated tumours and were associated with decreased overall survival [29]. Despite these scientific advances, the biologic and pathologic significance of exosomes is still not fully understood. The biologic and pathologic significance of exosomes is still not fully understood Based on these premises, we sought to analyze the alterations of exosomal miRNAs and proteins cargo profiles from CRC cells following Cetuximab treatment. We show that transfection of steady-state or Cetuximab-treated HCT-116 (Cetuximab unresponsive) with exosomes from Cetuximab-treated Caco-2 (Cetuximab sensitive) significantly increases HCT116 viability and alters their Cetuximab responsiveness
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