Exosomes in tumor microenvironment influence cancer progression and metastasis

Abstract

Exosomes are small membrane vesicles of endocytic origin with a size of 50-100 nm. They can contain microRNAs, mRNAs, DNA fragments, and proteins, which are shuttled from a donor cell to recipient cells. Many different cell types including immune cells, mesenchymal cells, and cancer cells release exosomes. There is emerging evidence that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with tumor environment. Here, we discuss different mechanisms associated with biogenesis, payload, and transport of exosomes. We highlight the functional relevance of exosomes in cancer, as related to tumor microenvironment, tumor immunology, angiogenesis, and metastasis. Exosomes may exert an immunosuppressive function as well as trigger an anti-tumor response by presenting tumor antigens to dendritic cells. Exosomes may serve as cancer biomarkers and aid in the treatment of cancer.

Fig. 1. Biogenesis and uptake of exosomes in target cells

(a) Early endosomes mature into late endosomes and exosomes are formed by a process of inward budding from the limiting membrane. Via this mechanism, cytoplasmic RNA molecules and functional proteins are encapsulated into exosomes. Moreover, transmembrane proteins maintain the same orientation relative to the cytoplasm and plasma membrane. In a second step, multivesicular endosomes fuse with the cellular membrane to release the exosomes into the extracellular space. Several cellular signals have been suggested: (b) juxtracrine signaling through receptor-ligand interactions, (c) fusion of exosomes with the cellular membrane of the target cell, resulting in a direct release of the cargo into the cytoplasm, (d) phagocytosis in an actin-cytoskeletal and phosphatidylinositol 3-kinase dependent manner.

Fig. 2. Functional relevance of exosomes in cancer

Tumor-derived exosomes can alter local and systemic microenvironment. By transferring oncogenic proteins and multidrug transporters, they can facilitate cancer cell proliferation and chemoresistance. Fibroblasts are converted into myofibroblasts, which are a key source of matrix remodelling proteins within the tumor microenvironment and participate in tumor angiogenesis. Endothelial cells are activated to support tumor angiogenesis. In the systemic environment, exosome-mediated signaling results in the recruitment of bone marrow-derived hematopoetic cells in order to form a pre-metastatic niche in distant organs. Tumor-derived exosomes interact with myeloid-derived cells to suppress the anti-tumor immune response.