Microvesicles in Cancer: Small Size, Large Potential

Abstract

Extracellular vesicles (EV) are secreted by all cell types in a tumor and its microenvironment (TME), playing an essential role in intercellular communication and the establishment of a TME favorable for tumor invasion and metastasis. They encompass a variety of vesicle populations, among them the well-known endosomal-derived small exosomes (Exo), but also larger vesicles (diameter > 100 nm) that are shed directly from the plasma membrane, the so-called microvesicles (MV). Increasing evidence suggests that MV, although biologically different, share the tumor-promoting features of Exo in the TME. Due to their larger size, they can be readily harvested from patients' blood and characterized by routine methods such as conventional flow cytometry, exploiting the plethora of molecules expressed on their surface. In this review, we summarize the current knowledge about the biology and the composition of MV, as well as their role within the TME. We highlight not only the challenges and potential of MV as novel biomarkers for cancer, but also discuss their possible use for therapeutic intervention.

Keywords: biomarker; cancer; microvesicles; therapy; tumor microenvironment.

Figure 1

Microvesicles (MV) shaping the local tumor microenvironment (TME) and distant metastatic niches to promote tumor growth. On the one hand, MV shed from the plasma membrane of tumor cells act in an autologous way on other tumor cells by transferring oncogenic cargo and stimulating pro-tumorigenic signaling. On the other hand, MV are able to mediate heterologous cell–cell communication by acting on cells present within the TME, such as macrophages, T cells, fibroblasts, or endothelial cells. As a result, these cells become activated and change their phenotype to enhance tumor growth. Once the tumor has gained access to the circulation, tumor MV can be distributed throughout the body and mediate cargo transfer and cell–cell communication at distant sites. This induces the formation of pre-metastatic niches that offer a favorable environment for subsequent seeding of tumor cells in secondary organs.

Figure 2

The microvesiculome in blood. The growth of a tumor is accompanied by secretion of circulating tumor cells (CTCs) as well as of tumor-derived soluble factors and MV. When encountering any of these components, benign blood cells can become activated and react by shedding their own, altered MV. Taken together, this results in changes in the composition as well as expression pattern of MV in the blood of cancer patients. Liquid biopsy-based MV sampling should therefore not only be focused on the detection of tumor MV, but also on alterations in non-tumor blood MV.

Figure 3

MV in cancer therapy. The figure summarizes the roles of MV in cancer therapy. Once a tumor has gained access to the circulation, circulating tumor MV in blood can be used as biomarkers in liquid biopsies. Moreover, they can mediate therapy resistance by capturing or exporting the administered anti-cancer drugs. Due to their role in therapy resistance and tumor microenvironment crosstalk resulting in pre-metastatic niche formation, they should be regarded as a novel therapeutic target. However, MV can also have a beneficial role in cancer therapy as they represent promising novel drug delivery systems with the benefits of high biocompatibility as well as opportunities for specific targeting and crossing of biological barriers. Vesicular functions, which have only been reported for endosomal-derived small exosomes (Exo) and lack experimental proof for MV, are highlighted in grey.