Extracellular Vesicles in Tumors: A Potential Mediator of Bone Metastasis

Abstract

As one of the most common metastatic sites, bone has a unique microenvironment for the growth and prosperity of metastatic tumor cells. Bone metastasis is a common complication for tumor patients and accounts for 15-20% of systemic metastasis, which is only secondary to lung and liver metastasis. Cancers prone to bone metastasis include lung, breast, and prostate cancer. Extracellular vesicles (EVs) are lipid membrane vesicles released from different cell types. It is clear that EVs are associated with multiple biological phenomena and are crucial for intracellular communication by transporting intracellular substances. Recent studies have implicated EVs in the development of cancer. However, the potential roles of EVs in the pathological exchange of bone cells between tumors and the bone microenvironment remain an emerging area. This review is focused on the role of tumor-derived EVs in bone metastasis and possible regulatory mechanisms.

Keywords: bone metastasis; extracellular vesicles; osteoblast; osteoclast; tumor.

FIGURE 1

The components of extracellular vesicles (ideograph). EVs can be secreted by various types of cells. EVs carry a variety of proteins, lipids, DNA, mRNA, and non-coding RNAs. Moreover, EV surface proteins contain the following substances: MHC class I/II molecules, heat shock proteins (HSP70, HSP90), and four transmembrane family proteins (CD63, CD9, CD81, and CD82, etc.). miRNAs, microRNAs; lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; mRNAs, messenger RNA; tRNA, transfer RNA.

FIGURE 2

The roles and mechanisms of the bone microenvironment in tumor metastasis to bone. A complex and abnormal cycle of bone metastasis involving mutual interactions between tumor cells, bone cells (osteoclasts and osteoblasts), and the bone matrix. As shown in this figure, in situ cancer cells enter the blood vessels, causing proliferation, migration, and invasion. Then, these cells act on osteoblasts by regulating PTH-rP, which affects preosteoclasts and osteoclasts through the mediation of a related protein (such as RANKL). Osteoblasts and osteoclasts affect bone metastases by mediating the expression and secretion of factors (for example, IGFs, TGF-β, FGFs, CA²⁺). FGFs, fibroblast growth factors; IGFs, insulin-like growth factors; PTH-rP, parathyroid hormone-related protein; RANKL, receptor activator for nuclear factor-κB ligand; TGF-β, transforming growth factor-β.

FIGURE 3

The roles of tumor-derived extracellular vesicles in bone metastases and potential molecular mechanisms. EVs, secreted by PCa (cavin-1, miR-142-3p, miR-375, PLD2), BCa (VCAM1, miR-940, miR-20a-5p), LCa (AREG, miR-21), MM (cAMP), and AML tumors could carry different and abundant content and play a key role in osteoclastic and osteoblastic cycling, leading to various metastatic lesions. PCa, prostate cancer; BCa, breast cancer; LCa, lung cancer; MM, multiple myeloma; AML, acute myelocytic leukemia; TGFB2, transforming growth factor beta 2; AXL, AXL receptor tyrosine kinase; PLD2, phospholipase D2; VCAM1, vascular cell adhesion molecule 1; AREG, amphiregulin.