Extracellular vesicles and particles as mediators of long-range communication in cancer: connecting biological function to clinical applications

Abstract

Over the past decade, extracellular vesicles and particles (EVPs) have emerged as critical mediators of intercellular communication, participating in numerous physiological and pathological processes. In the context of cancer, EVPs exert local effects, such as increased invasiveness, motility, and reprogramming of tumor stroma, as well as systemic effects, including pre-metastatic niche formation, determining organotropism, promoting metastasis and altering the homeostasis of various organs and systems, such as the liver, muscle, and circulatory system. This review provides an overview of the critical advances in EVP research during the past decade, highlighting the heterogeneity of EVPs, their roles in intercellular communication, cancer progression, and metastasis. Moreover, the clinical potential of systemic EVPs as useful cancer biomarkers and therapeutic agents is explored. Last but not least, the progress in EVP analysis technologies that have facilitated these discoveries is discussed, which may further propel EVP research in the future.

Keywords: Extracellular vesicles and particles; biomarkers; cancer; organotropism; pre-metastatic niche; treatment.

Figure 1

Overview of extracellular vesicles and particle (EVP)-focused fields of study in cancer research. Intercellular communication: EVPs mediate intercellular communication between cancer, stromal, and immune cells by transferring various biomolecules to nearby as well as distant organs, resulting in both local and systemic effects. Cancer-derived EVPs stimulate angiogenesis, promote tumor growth, and suppress antitumor immunity, enhancing tumor invasion and metastatic potential. Heterogeneity: EVPs are highly diverse and new populations are constantly being discovered. The classification of new EVP populations requires multifaceted evaluation, including size, composition, membrane surface markers, and origin. Technology: various methods for separating EVPs, including differential ultracentrifugation, size exclusion chromatography, immunoaffinity capture, and asymmetric flow field flow fractionation, are available and they have their own advantages and disadvantages. Furthermore, analyses at the single EVP level, such as nanoparticle tracking analysis, high-sensitivity flow cytometry, high-resolution microscopy, as well as in vivo imaging, are now introduced. Biomarkers: EVPs in bodily fluids show potential as non-invasive biomarkers for early diagnosis, treatment response, and prognosis of cancer. Their constituent proteins, nucleic acids, lipids, and metabolites can be isolated and analyzed by mass spectrometry and next-generation sequencing. Treatment: EVPs can be used therapeutically by administering EVPs isolated from specific cells, loading various biomolecules such as anticancer or molecularly targeted drugs, or by engineering EVPs to enhance function. Strategies that block the production of tumor-derived EVPs or block the interaction of EVPs with target cells are also being investigated. EMT: epithelial-mesenchymal transition; ECM: extracellular matrix; SMAP: supramolecular attack particles; ARMM: arrestin domain-containing protein 1 -mediated microvesicles; dUC: differential ultracentrifugation; SEC: size exclusion chromatography; IAC: immunoaffinity capture; AF4: asymmetric flow field flow fractionation; NTA: nanoparticle tracking analysis.

Figure 2

The systemic effects of extracellular vesicles and particles (EVPs) in cancer. EVPs can transport various biomolecules to distant organs. EVP uptake by specific cells in the microenvironment of the remote organ results in functional reprograming of target cells. For example, tumor-derived EVPs can promote angiogenesis and vascular remodeling, modify the extracellular matrix (ECM), promote lymphangiogenesis, modulate the function of immune cells to create an immunosuppressive environment, and reprogram metabolism. Moreover, EVPs induce cachexia, muscle wasting, coagulation and thrombosis, and neural reprogramming. These alterations contribute to the formation of a pre-metastatic niche (PMN) that facilitates cancer colonization and metastasis by recruiting bone marrow-derived cells (BMDCs) to modify the microenvironment, immune cells that suppress tumor immunity such as tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), and neutrophils that promote metastasis. Dysregulation can also occur in T cells, dendritic cells (DC), and natural killer cells. Thus, the PMN becomes an immunosuppressed, metastasis-supporting environment. Once metastasis has taken place, the PMN transitions to a metastatic niche where angiogenesis, ECM remodeling, and progression of an immunosuppressive environment continue. In addition to directly modifying the microenvironment, tumor cells, stromal cells, and immune cells release EVPs that facilitate bidirectional communication/interaction. CAF: cancer-associated fibroblast.

Figure 3

Extracellular vesicles and particles (EVPs) determine metastatic organotropism. Specific molecules expressed on EVPs interact with cells or the extracellular matrix of specific organs to deliver biomolecules to distant organs. This causes changes in the microenvironment, leading to pre-metastatic niche (PMN) formation and facilitating distant metastasis to specific organs. For example, tumor-derived EVPs expressing integrin αvβ5 are taken up by the liver and promote liver PMN formation. Similarly, integrin α6β1 and α6β4 expressed on tumor-derived EVPs are taken up by the lung and promote lung metastasis. Integrin α2β1 on cancer-associated fibroblast-derived EVPs also promotes lung metastasis. Integrin α5, miR-940, and miR-141-3p are involved in bone metastasis, CEMIP and miR-181c in brain metastasis, and integrin αv in lymph node metastasis, as reported. CDH11: cadherin 11; CEMIP: cell migration inducing hyaluronidase 1.