The Role of Extracellular Vesicles in Bone Metastasis

Abstract

Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. Despite being the focus of intense investigation, the molecular and cellular mechanisms that regulate the metastasis of disseminated tumor cells still remain largely unknown. Bone metastases severely impact quality of life since they are associated with pain, fractures, and bone marrow aplasia. In this review, we will summarize the recent discoveries on the role of extracellular vesicles (EV) in the regulation of bone remodeling activity and bone metastasis occurrence. Indeed, it was shown that extracellular vesicles, including exosomes and microvesicles, released from tumor cells can modify the bone microenvironment, allowing the formation of osteolytic, osteosclerotic, and mixed mestastases. In turn, bone-derived EV can stimulate the proliferation of tumor cells. The inhibition of EV-mediated crosstalk between cancer and bone cells could represent a new therapeutic target for bone metastasis.

Keywords: bone metastasis; exosomes; extracellular vesicles.

Figure 1

Vicious cycle of bone metastasis. Tumor cells destroy the virtuous cycle of bone remodeling stimulating osteoclast differentiation and activity by the secretion of IL-1 (Interleukin 1), IL-6 (Interleukin 6), TNFα (Tumor Necrosis Factor alpha), M-CSF (Macrophage Colony Stimulating Factor), and VEGF (Vascular Endothelial Growth Factor). TGF-β (Transforming Growth Factor beta), IGF (Insulin Growth Factor), FGF (Fibroblast Growth Factor), BMP (Bone Morphogenetic Protein), and PDGF (Platelet Derived Growth Factor) are released from the bone matrix during bone resorption and stimulate tumor cells. Bone metastastic cells influence osteoblast activity by IL-1, IL-6, PTHrP (Parathyroid hormone-related protein), PEG2 (Prostaglandin E2), TNFα, ET-1 (Endothelin-1), BMP, and various growth factors. In turn, osteoblasts secrete factors that stimulate osteoclastogenesis, including RANK-L (Receptor activator of nuclear factor kappa-B ligand), M-CSF, and IL-6.

Figure 2

Extracellular vesicles. Exosomes, microvesicles, and apoptotic bodies differ in dimensions and biogenesis. They carry several molecular components, including cytosolic and membrane proteins, receptors, and nucleic acids. Exosomes are small vesicles (50–100 nm) that are derived from multivesicular bodies (MVB), and are released by fusion of MVB with the cell membrane; microvesicles are larger vesicles (100 nm–1 µm) and are derived from budding of the plasma membrane; apoptotic vesicles have a size ranging from 1 to 5 µm, and are released by the blebbing process during apoptosis.