Pre-metastatic Niche Formation in Different Organs Induced by Tumor Extracellular Vesicles

Abstract

Primary tumors selectively modify the microenvironment of distant organs such as the lung, liver, brain, bone marrow, and lymph nodes to facilitate metastasis. This supportive metastatic microenvironment in distant organs was termed the pre-metastatic niche (PMN) that is characterized by increased vascular permeability, extracellular matrix remodeling, bone marrow-derived cells recruitment, angiogenesis, and immunosuppression. Extracellular vesicles (EVs) are a group of cell-derived membranous structures that carry various functional molecules. EVs play a critical role in PMN formation by delivering their cargos to recipient cells in target organs. We provide an overview of the characteristics of the PMN in different organs promoted by cancer EVs and the underlying mechanisms in this review.

Keywords: bone marrow-derived cells (BMDCs); extracellular matrix (ECM); extracellular vesicles (EVs); immunosuppression; pre-metastatic niche (PMN); vascular permeability.

FIGURE 1

Formation of the pre-metastatic niche (PMN) in various organs. Extracellular vesicles (EVs) produced by tumor and stromal cells enter the circulation and arrive at distant organs such as the lung, liver, brain, bone marrow, and lymph nodes (LNs). Increased vascular permeability is an early event in PMN formation. Then, EVs cause extracellular matrix (ECM) remodeling principally by activating resident normal fibroblasts. The activated fibroblasts deposit new ECM components, such as FN, and produce matrix metalloproteinases (MMPs). Bone marrow-derived cells (BMDCs) are recruited into the target organs by EVs and involved in angiogenesis and/or immune responses. Furthermore, EVs can deliver their cargos to endothelial cells or immunocytes directly in the PMN to promote angiogenesis or create an immunosuppressive microenvironment.