Highly skewed distribution of miRNAs and proteins between colorectal cancer cells and their exosomes following Cetuximab treatment: biomolecular, genetic and translational implications
Marco Ragusa1,*, Luisa Statello1,*, Marco Maugeri1,*, Cristina Barbagallo1, Roberta Passanisi1, Mohamed S. Alhamdani2, Giovanni Li Destri3, Alessandro Cappellani4, Davide Barbagallo1, Marina Scalia1, Hadi Valadi5, Jörg D. Hoheisel2,**, Cinzia Di Pietro1,**, Michele Purrello1,**
1 Molecular, Systems and Genome BioMedicine Unit, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy, EU
2 Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany, EU
3 Dipartimento di Scienze Chirurgiche, Trapianti d’Organo e Tecnologie Avanzate, Università di Catania, Catania, Italy, EU
4 Dipartimento di Chirurgia, Università di Catania, Catania, Italy, EU
5 University of Gothenburg, Department of Rheumatology and Inflammation Research, Gothenburg, Sweden, EU
* Equal Contribution.
** Senior Corresponding Authors.
Michele Purrello, email:
Keywords: Cetuximab, Colon Cancer, Exosomes, miRNAs, Proteins
Received: February 24, 2014 Accepted: March 14, 2014 Published: March 16, 2014
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.