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Maurizi et al. J Cancer Metastasis Treat 2021;7:35 https://dx.doi.org/10.20517/2394-4722.2021.74 Page 11 of 19

however, cannot be strictly considered as bone metastases. It has been shown that multiple myeloma-
derived exosomes, as well as exosomes isolated from multiple myeloma patients, are internalized by
osteoclast precursors, eventually leading to an enhancement of pre-osteoclast migration and osteoclast
[136]
differentiation and functions, thus greatly contributing to the development of osteolytic lesions . Later on,
a mechanism of action was proposed by Raimondo et al. , who found an enrichment of amphiregulin
[137]
(AREG) content, a molecule overexpressed in several types of cancers, in multiple myeloma-derived
exosomes, which in turn activated the EGF pathway, eventually leading to an increase of osteoclast
[138]
formation and activity. Similarly, Taverna et al. showed that exosomes from non-small cell lung cancer
carry AREG, which again activated osteoclast differentiation by a RANKL-dependent mechanism through
the EGF pathway, eventually leading to bone metastases development.

Among other bone-related malignancies, we should also mention melanoma, which rarely metastasizes to
bone; however, when this happens, both prognosis and quality of life of patients dramatically worsen. One
of the first studies on this topic revealed that melanoma cells are able to educate bone marrow progenitor
cells towards a prometastatic phenotype by upregulating the oncoprotein MET . Consistently, recent
[139]
studies point out a crucial role for EVs in influencing the migration and invasiveness of melanoma cells
towards the bone . Melanoma-derived EVs induce immune suppression and, in turn, defective dendritic
[140]
[140]
cell functions . They also promote PMN to distant organs by delivering a cargo of factors that increase the
[141]
release of immunosuppressive cytokines, as well as angiogenic factors and matrix metalloproteinases .
[142]
With regards to the specific role of melanoma EVs on osteotropism, Mannavola et al. found that bone
conditioned medium significantly increased CXCR4, CXCR7 and PTHrP expression in osteotropic
melanoma cells, while their exosomes were able to reprogram non-osteotropic melanoma cells by reverting
their original poor bone tropism towards an osteotropic phenotype. This effect is accomplished through the
upregulation of membrane CXCR7 by melanoma cells, which is required to promote their chemotaxis
toward SDF1 gradient, eventually leading to bone colonization. A summary of the main proposed roles of
EVs in the PMN establishment is presented in Figure 2.

CLINICAL RELEVANCE OF PRE-METASTATIC NICHE-TARGETING IN THE BONE
METASTASES
The concept of the PMN represents a paradigm shift in the way we look at metastasis prevention and
therapy. Indeed, new therapeutic approaches have been developed to target not only cancer cells but also
the microenvironment, to prevent the tumor from homing to bone and/or developing into overt metastases.

With specific regards to the bone PMN, it could be targeted at different levels: (1) inhibiting the production
of tumor-derived factors that allow the establishment of PMN; (2) blocking the interaction of the CTCs with
the reprogrammed stromal cells or counteracting their reprogramming; and (3) reverting the
immunosuppressive niche . While the former option would probably be a very effective approach, thus
[10]
far, no attempt has been made in clinical trials to the best of our knowledge. LOX would be an attractive
therapeutic target in this regard, especially considering that a recent report showed that LOX inhibition is
[143]
able to overcome chemotherapy resistance in triple negative breast cancer (TNBC) subtypes. This would
allow preventing PMN formation, while making the primary tumor easier to treat, even in its most
aggressive form, i.e., chemotherapy resistant TNBC. An oral pan-LOX inhibitor has been developed by
Pharmaxis for the treatment of myelofibrosis, which recently passed a phase I clinical trial and seemed to be
well tolerated. Therefore, we have the tools and the knowledge to exploit this pathway. As for the latter
point, i.e., blocking the interaction of CTCs with the reprogrammed stromal cells, or counteracting their
reprogramming, this is surely the issue where most of the efforts have been put thus far. In fact, anti-
resorptive drugs such as bisphosphonates (BPs) and denosumab have been tested in clinical trials as