Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis

Abstract

Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells.

Keywords: biomarkers; cancer; cell-to-cell communication; extracellular vesicles; metastasis.

Figure 1

Extracellular vesicle production. Extracellular vesicles, and in particular exosomes, originate from multivesicular bodies (MVBs) which are formed during the inward budding of the plasma membrane. The subsequent inward budding of the MVB membrane encapsulates and packages cytosolic components resulting in the formation of EVs. EV cargo comprises selectively packaged proteins (e.g., tetraspanins, cytoplasmic proteins, and enzymes), nucleic acids (e.g., DNA, RNA, and miRNAs) and lipids, which have been shown to be cell-type dependent reflecting the metabolic status of their cells of origin. The subsequent fusion of MVBs with the plasma membrane results in the release of EVs into the tumor microenvironment.

Figure 2

The “ecosystem” of the tumor microenvironment (TME). The tumor microenvironment of solid tumors is composed of extracellular matrix (ECM) components and a multitude of different stromal cells, including macrophages, dendritic cells, neutrophils, and myeloid-derived suppressor cells, adipocytes, fibroblasts, and endothelial cells, in addition to both non-cancerous and cancerous epithelial cells.

Figure 3

Tumor-derived EVs are critical mediators in tumor-cell metastasis. Extracellular secretion by tumor cells act as nanosized intracellular messages between cancer cells and surrounding stromal cells within the tumor microenvironment. Their cargo, which is composed of proteins, lipids, DNA, mRNAs, miRNAs, and other non-coding RNAs, is tailored by their cells of origin to specifically and directly promote cancer progression and metastasis by affecting epithelial-to-mesenchymal transition, tumor cell intravasation, dissemination, extravasation, and most critically, pre-metastatic niche formation.