Extracellular vesicles - biomarkers and effectors of the cellular interactome in cancer

Abstract

In multicellular organisms both health and disease are defined by patterns of communication between the constituent cells. In addition to networks of soluble mediators, cells are also programed to exchange complex messages pre-assembled as multimolecular cargo of membraneous structures known extracellular vesicles (EV). Several biogenetic pathways produce EVs with different properties, and known as exosomes, ectosomes, and apoptotic bodies. In cancer, EVs carry molecular signatures and effectors of the disease, such as mutant oncoproteins, oncogenic transcripts, microRNA, and DNA sequences. Intercellular trafficking of such EVs (oncosomes) may contribute to horizontal cellular transformation, phenotypic reprograming, and functional re-education of recipient cells, both locally and systemically. The EV-mediated, reciprocal molecular exchange also includes tumor suppressors, phosphoproteins, proteases, growth factors, and bioactive lipids, all of which participate in the functional integration of multiple cells and their collective involvement in tumor angiogenesis, inflammation, immunity, coagulopathy, mobilization of bone marrow-derived effectors, metastasis, drug resistance, or cellular stemness. In cases where the EV role is rate limiting their production and uptake may represent and unexplored anticancer therapy target. Moreover, oncosomes circulating in biofluids of cancer patients offer an unprecedented, remote, and non-invasive access to crucial molecular information about cancer cells, including their driver mutations, classifiers, molecular subtypes, therapeutic targets, and biomarkers of drug resistance. New nanotechnologies are being developed to exploit this unique biomarker platform. Indeed, embracing the notion that human cancers are defined not only by processes occurring within cancer cells, but also between them, and amidst the altered tumor and systemic microenvironment may open new diagnostic and therapeutic opportunities.

Keywords: cancer; cellular interactions; exosomes; extracellular vesicles; oncogenes.

Figure 1

Implications of the vesiculation process in cancer. Heterogeneous populations of cancer and host cells remain functionally interconnected. This process is, at least in part, mediated by extracellular vesicles (EVs) that shuttle molecules between different populations of cancer cells and between them and the non-transformed host stromal and blood cells. Cancer cells may include stem cell-like compartment (e.g., cells expressing CD133), or cells that express other surface molecules (MET, EGFR, EPCAM – see text) with important functions. Some of the more notable EV-mediated molecular exchanges described recently in the literature include: (i) transfer of oncogenes (ONC) from cancer cells to normal cells, a possible horizontal transformation of these cells resulting in changes in phenotype, as well as (in some cases) acquisition of tumorigenic properties; (ii) transfer of tumor suppressors (TSG), such as PTEN between cells, with a possible impact on negative control of cellular transformation; (iii) transfer of MET receptors from metastatic cancer cells to myeloid cells (CD11b+) to modulate metastatic niche effects; (iv) contribution of platelet-derived EVs (CD41+) to the metastatic phenotype of cancer cells, and several other effects; (v) shedding of EVs by activated endothelium (CD31+). While tumor-derived EVs constitute a minority within the pool of particles circulating in plasma, they can be detected for diagnostic purposes. The diagnostic and therapeutic opportunities, and challenges associated with studies on cellular vesiculation are described in the text in detail.