Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular ‘debris’

Abstract

Cancer cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids. MVs are generated via diverse biological mechanisms triggered by pathways involved in oncogenic transformation, microenvironmental stimulation, cellular activation, stress, or death. Vesiculation events occur either at the plasma membrane (ectosomes, shed vesicles) or within endosomal structures (exosomes). MVs are increasingly recognized as mediators of intercellular communication due to their capacity to merge with and transfer a repertoire of bioactive molecular content (cargo) to recipient cells. Such processes may occur both locally and systemically, contributing to the formation of microenvironmental fields and niches. The bioactive cargo of MVs may include growth factors and their receptors, proteases, adhesion molecules, signalling molecules, as well as DNA, mRNA, and microRNA (miRs) sequences. Tumour cells emit large quantities of MVs containing procoagulant, growth regulatory and oncogenic cargo (oncosomes), which can be transferred throughout the cancer cell population and to non-transformed stromal cells, endothelial cells and possibly to the inflammatory infiltrates (oncogenic field effect). These events likely impact tumour invasion, angiogenesis, metastasis, drug resistance, and cancer stem cell hierarchy. Ongoing studies explore the molecular mechanisms and mediators of MV-based intercellular communication (cancer vesiculome) with the hope of using this information as a possible source of therapeutic targets and disease biomarkers in cancer.

Co-culture of human nucleus pulposus cells with multipotent mesenchymal stromal cells from human bone marrow reveals formation of tunnelling nanotubes

“…Since experiments with cytoplasm soluble dyes or fluorescent proteins exhibited a small fraction of double-stained cells, this demonstrates that these dyes are not efficiently packed into MVs or TnTs. The cellular cargo is selectively packed into the MVs of three classes: apoptotic bodies, ectosomes and exosomes (24). The TnTs are plasma membrane protrusions that connect the cytoplasms of communicating cells (12).…”

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

“…Several lines of evidence suggest that mutant oncogenes are not confined to their host cancer cells, but may also exit them and interact with distant cells [1]. Indeed, insoluble oncoproteins, such as epidermal growth factor receptor (EGFR/EGFRvIII), KRAS or MET have been found to exit cancer cells as cargo of extracellular vesicles (EVs) [2][3][4], the production of which oncogenes stimulate [2,5].…”

Time-dependent release of extracellular vesicle subpopulations in tumor CABA I cells

“…In the same manner, MVs have been widely studied in several normal cell types, including platelets, fibroblasts, neuronal, epithelial, endothelial and red (10)(11)(12)(13), and even more widely analyzed in cancer cells (6,(14)(15)(16)(17)(18) for their role in tumor progression, evasion from apoptosis, drug resistance, immune-escape, and angiogenesis (2,3,19). The non-accidental production of EVs, in pathological and physiological events, is emphasized by the fact that they are not merely miniature parental cells, showing both similarities and differences compared to the molecular composition of the cells of origin (6,20).…”