Intercellular Vesicular Transfer by Exosomes, Microparticles and Oncosomes - Implications for Cancer Biology and Treatments

Abstract

Intercellular communication is a normal feature of most physiological interactions between cells in healthy organisms. While cells communicate directly through intimate physiology contact, other mechanisms of communication exist, such as through the influence of soluble mediators such as growth factors, cytokines and chemokines. There is, however, yet another mechanism of intercellular communication that permits the exchange of information between cells through extracellular vesicles (EVs). EVs are microscopic (50 nm-10 μM) phospholipid bilayer enclosed entities produced by virtually all eukaryotic cells. EVs are abundant in the intracellular space and are present at a cells' normal microenvironment. Irrespective of the EV "donor" cell type, or the mechanism of EV biogenesis and production, or the size and EV composition, cancer cells have the potential to utilize EVs in a manner that enhances their survival. For example, cancer cell EV overproduction confers benefits to tumor growth, and tumor metastasis, compared with neighboring healthy cells. Herein, we summarize the current status of knowledge on different populations of EVs. We review the situations that regulate EV release, and the factors that instruct differential packaging or sorting of EV content. We then highlight the functions of cancer-cell derived EVs as they impact on cancer outcomes, promoting tumor progression, metastases, and the mechanisms by which they facilitate the creation of a pre-metastatic niche. The review finishes by focusing on the beneficial (and challenging) features of tumor-derived EVs that can be adapted and utilized for cancer treatments, including those already being investigated in human clinical trials.

Keywords: cancer; cancer immunosuppression; cancer vaccine; exosome; extracellular vesicles; microparticle; pre-metastatic niche.

Figure 1

Schematic representation of major subtypes of EVs: exosomes, microparticles and apoptotic bodies. Exosomes, the smallest EVs, originate from within a cell by fusion followed by exocytosis of multivesicular bodies (MVB) from the cell membrane into the extracellular space. MVB are formed by the accumulation of luminal vesicles within endosomes. Ectosomes are assembled at, and pinched off from, the plasma membrane by a process of budding. Ectosomes include microvesicles (or MPs) released from activated cells and/or apoptotic bodies (produced from dying cells).

Figure 2

Tumor-derived EVs in pre-metastatic niche (PMN) formation and tumorigenesis. Tumor-derived EVs express surface and cytosolic molecules originating from the primary tumor and are carried to recipient cell/organs via the circulation. The EV surface molecules and cargo confer pro-angiogenic, pro-migratory, pro-inflammatory effects, and chemotherapeutic drug interfering or immune-regulatory effects. EV movement to target organs is generally organotropic and determined by the inherent tumor cell and EV cargos. Finally, EVs contribute to the pre-conditioning of the target site via inducing extracellular matrix remodeling, changes in blood and lymphatic vessels barrier integrity, transfer of immune inhibitory or activating factors and transfer of oncogenic factors. Together these mechanisms explain EV contributions to cancer progression and the impact on cancer treatment efficacy including treatment failures.