Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets

Abstract

Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis. Bone is a preferred site of metastasis, and bone metastasis is generally incurable and dramatically affects patient quality of life. Bone metastasis can cause devastating complications, including hypercalcemia, pathological fractures, spinal compression, and bone pain, which result in a poor prognosis. Although the mechanisms underlying bone metastasis have yet to be fully elucidated, increasing evidence suggests that EVs in the bone microenvironment significantly contribute to cancer progression and cancer bone tropism. Emerging evidence on EV functions in bone metastasis will facilitate the discovery of novel treatments. In this review, we will discuss the remarkable effects of EVs, especially on the tumor microenvironment in bone.

Keywords: bone metastasis; extracellular vesicles; tumor microenvironment.

Figure 1

The main functions of EV cargoes involved in bone remodeling. Opposing EV functions depend on their various contents, even though EVs are produced by the same type of cell. The regulation of bone remodeling by exchanging EV contents is extremely complex.

Figure 2

The main functions of EV cargo derived from PCa cells in the bone tumor microenvironment. EVs secreted by PCa change the beneficial bone remodeling cycle into a vicious cycle, affecting bone cells. Recent investigations reported that EVs derived from bone cells also affect cancer cell viability. It is thought that EV functions in the bone tumor microenvironment are very complex.