Abstract
Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to “switch homes” and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of “vicious cycle” and “osteolytic” vs. “osteosclerotic” bone metastases; as well as on novel concepts, such as cellular dormancy and extracellular vesicles. At the molecular level, we will focus on hypoxia-associated factors and angiogenesis, the Wnt pathway, parathyroid hormone-related peptide (PTHrP) and chemokines. At the supramolecular/cellular level, we will discuss tumour dormancy, id est the mechanisms through which a small contingent of tumour cells coming from the primary site may be kept dormant in the endosteal niche for many years. Finally, we will present a potential role for the multimolecular mediators known as extracellular vesicles in determining bone-tropism and establishing a premetastatic niche by influencing the bone microenvironment.
Highlights
Metastatic bone disease is currently considered incurable [1]
We found that osteotropic breast cancer cells (MDA-MB-231) can reprogram osteoblasts so that they produce a higher amount of RANKL-Extracellular vesicles (EVs), which contributes to the vicious cycle by inducing osteoclastogenesis
We presented an overview of key topics related to bone metastasis, focusing our attention on classical concepts related to bone marrow metastasis, as well as aspects that have emerged in the very last few years, such as the cellular dormancy and extracellular vesicles
Summary
Metastatic bone disease is currently considered incurable [1]. Bone metastases (BM) are extremely common, and patients report unbearable pain in late stages, which makes palliative therapy with analgesics of the highest grade of the World Health Organisation analgesic ladder, i.e., strong opioids, a necessity [2]. When the program to follow the latter option is activated, osteoblasts depose bone matrix around themselves, until the point where they are encased in it, becoming bona fide osteocytes [15,16,17] This cell type vastly outnumbers the other bone-resident ones, and its main function is sensing mechanical variations in the microenvironment through a complex network of interconnected canaliculi, able to perceive shear stress by means of the primary cilium, which requires a protein complex composed by the cilium and the cilia-associated proteins Polycystin 1 and 2 [18,19,20]. Osteomacs have been shown to produce BMPs, controlling osteoblast activity in vitro and in vivo [37,38] They represent almost 20% of the bone marrow cells, and together with BMMs can become tumour-associated macrophages, eventually supporting tumour growth and immune escape, which is important in the bone marrow, as it has been suggested in prostate cancer [39]. BMAs are thought to be part of the endosteal niche, limited or no evidence is present to date about their role in cancer or HSC dormancy/reactivation [57]
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