Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers

Abstract

Recent advances in the study of tumor-derived microvesicles reveal new insights into the cellular basis of disease progression and the potential to translate this knowledge into innovative approaches for cancer diagnostics and personalized therapy. Tumor-derived microvesicles are heterogeneous membrane-bound sacs that are shed from the surfaces of tumor cells into the extracellular environment. They have been thought to deposit paracrine information and create paths of least resistance, as well as be taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. The complexity of their bioactive cargo-which includes proteins, RNA, microRNA, and DNA-suggests multipronged mechanisms by which microvesicles can condition the extracellular milieu to facilitate disease progression. The formation of these shed vesicles likely involves both a redistribution of surface lipids and the vertical trafficking of cargo to sites of microvesicle biogenesis at the cell surface. Current research also suggests that molecular profiling of these structures could unleash their potential as circulating biomarkers as well as platforms for personalized medicine. Thus, new and improved strategies for microvesicle identification, isolation, and capture will have marked implications in point-of-care diagnostics for cancer patients.

Figure 1.

Types of membrane vesicles released extracellularly by tumor cells. (1) Exosomes are formed and sequestered in preformed MVBs and released upon fusion of the MVB-limiting membrane with the plasma membrane. (2) Apoptotic bodies are formed by the random blebbing of the plasma membrane. Fragmented DNA and cytoplasmic organelles are packaged indiscriminately into these blebs. (3) TMVs contain selectively sorted cargo and form by the outward blebbing and fission of the plasma membrane. Nascent microvesicles at the cell surface may be a convergence point for multiple membrane trafficking pathways, including ARF6-regulated early endosome recycling, which directs specialized cargo to these sites of biogenesis.

Figure 2.

TMV-mediated modulation of the tumor microenvironment. Accruing literature suggests that shed TMVs can condition the stromal microenvironment to promote angiogenesis, evasion of the immune response, tumor invasion, and, potentially, metastasis. TMVs released from tumor cells (brown) can be taken up by cells in the tumor microenvironment, such as carcinoma-associated fibroblasts (blue), with consequences for target cell behavior. They can also interact with the extracellular matrix by depositing paracrine information or facilitating matrix degradation, thereby creating paths of least resistance.