Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis

Abstract

Tumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. Accordingly, EVs play an essential role in both primary tumor growth and metastatic evolution. EVs orchestrate multiple systemic pathophysiological processes, such as coagulation, vascular leakiness, and reprogramming of stromal recipient cells to support pre-metastatic niche formation and subsequent metastasis. Clinically, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.

Keywords: cancer; exosomes; extracellular vesicles; intercellular communication; metastasis; microvesicles; pre-metastatic niche.

Figure 1. Role of tumor-derived EVs on the primary tumor microenvironment

Tumor EVs cause fibroblasts to differentiate into myofibroblasts, which release MMPs and lead to extracellular matrix remodeling. The breakdown of ECM leads to the release of growth factors embedded in the ECM and promotes invasion through parenchymal cells. Tumor EVs activate tumor-associated macrophages to secrete G-CSF, VEGF, IL-6, and TNFα, which together promote angiogenesis and create an inflammatory niche. Tumor EVs affect immune system homeostasis mostly by triggering immunosuppressive changes that protect the tumor. Tumor EVs activate and expand T_regs and MDSCs, which inhibit CD8⁺ T-cell mediated targeting of the tumor. Furthermore, tumor EVs have been shown to express FasL and TRAIL on their membrane and directly induce apoptosis of CD8⁺ T-cells. Tumor EVs increase neutrophil mobilization and to be associated with increased tumor progression. Natural killer cells, which play an important role in antitumor immunity, can be either activated or suppressed by tumor EVs, depending on the tumor model studied and the EV cargo. Dendritic cells can be activated by the tumor-derived antigens delivered via tumor EVs and enforce a CD8⁺-mediated anti-tumor response. As the tumor grows, it develops metabolic demands that outgrow its blood supply and thus becomes increasingly hypoxic. In response to low oxygen concentrations, the tumor secrets angiogenic factors and EVs that promote blood vessel recruitment. EVs derived from the primary tumor can stimulate epithelial cells to release factors involved in EMT that trigger the loss of tumor cell adhesion (Fibronectin and Vimentin), ECM remodeling, and angiogenesis (MMPs), which together promote the release of tumor cells into the circulation and their spread to distant sites.

Figure 2. Tumor-derived EVs promote pre-metastatic niche formation and metastasis

EVs play a distinct role at multiple steps in PMN formation at distant sites of future metastasis. Depending on the cancer cell of origin, EVs can circulate through both blood and lymphatic vessels to reach their destination for PMN initiation. Through an unknown mechanism, tumor EVs can induce vascular leakiness and interact with the resident cells of distant organs. Depending on their membrane composition, such as specific exosomal integrin combinations (exosomal α₆β₄ and α₆β₁ integrins associated with lung metastasis / exosomal α_vβ₅ integrin with liver metastasis), EVs are targeted to particular resident cell types within a particular organ. Upon their uptake by the recipient cells, EVs can induce the expression of several inflammatory mediators (e.g. S100 family proteins, TGFβ, IL-6, IL-8 and TNFα), resulting in the activation and remodeling of stromal cells and the recruitment of BMDCs to the PMN, which are critical for tumor progression. In pancreatic cancer, migration inhibitory factor (MIF)-containing exosomes are taken up by Kupffer cells promoting TGFβ secretion. TGFβ, in turn, then induces fibronectin secretion by hepatic stellate cells. The increase in fibronectin ultimately leads to the recruitment of BMDC's, which are critical for establishment of the PMN. In melanoma, exosomes can educate BMDCs through the transfer of MET and help establish a PMN in the lung. Melanoma-derived exosomes can also prepare lymph node PMN formation, by promoting recruitment of melanoma cells, extracellular matrix deposition, and vascular proliferation in the lymph nodes.