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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 3 of 19

It is widely demonstrated that chronic inflammatory processes play a pivotal role in tumor progression and
metastasis [14,15] , and that they are related to physiological phenomena such as aging [16,17] . In the context of the
bone/bone marrow PMN, inflammation plays at least a two-faced role: on the one hand, it promotes
[18]
osteoclast differentiation , which fuels bone loss and tumor cells homing and engraftment, while, on the
other hand, it increases vascular leakiness, favoring tumor extravasation . The increase of vascular
[19]
permeability and angiogenesis is a crucial event for bone metastasis development. Key molecules involved
in this event include vascular endothelial growth factor (VEGF), angiopoietin-2, mesenchymal epithelial
transition factor (c-MET), and matrix metalloproteinases [10,20-24] . Although not focused on the bone/bone
marrow pre-metastatic niche per se, a recent study demonstrated that, in breast cancer-bearing mice, bone
marrow-derived suppressor cells can migrate to the lungs through C5a signaling and cause an angiogenic
[25]
switch and vascular leakiness in the lungs, favoring the establishment of a PMN before tumor arrival .
Moreover, recent cutting-edge studies revealed that extracellular vesicles released by tumor cells in the
primary site influence the vascular permeability in the PMN to promote the extravasation of the CTCs, as
discussed in further detail in the following paragraphs.

BONE/BONE MARROW CELLS AND TUMOR-DERIVED FACTORS SHAPING THE BONE
PRE-METASTATIC NICHE
[10]
Tumor cells are able to recruit and reprogram normal resident cells to promote tumor dissemination .
Therefore, different cell types in the bone/bone marrow microenvironment, including osteoblasts,
osteoclasts, osteocytes, endothelial cells, bone marrow macrophages, and adipocytes [Figure 1 and Table 1],
have a role to play in the establishment of the PMN, as discussed in the following paragraphs.

Osteoblasts and osteoclasts
Two of the most crucial players in the establishment of overt bone metastases are osteoblasts, the bone-
forming cells, and osteoclasts, the bone-resorbing cells. Their role, albeit less well-described, seems to also
be pivotal in the establishment of the PMN in the bone/bone marrow compartment. Osteoblasts have been
shown to respond to primary tumor-secreted factors such as PTHrP, which activates their RANKL
production and increases osteoclast differentiation, thus starting a classic cancer-bone “vicious cycle” at a
[8]
distance . This activation of osteoclastic bone resorption triggers the release of factors such as insulin-like
growth factor-1, bone morphogenic proteins, and platelet-derived growth factor from the bone matrix,
which may help establish a pre-metastatic microenvironment. Another important action of the PTHrP
secreted by the primary tumor site is the induction of the (C-C motif) ligand 2 chemokine expression by
osteoblasts, which in turns recruits and activates M2 macrophages. The latter may partake in the PMN and
foment tumor growth [26,27] once they migrate to the bone microenvironment. Other primary tumor-secreted
factors that act similarly to PTHrP are heparanase (HPSE), its derived soluble factor Syndecan-1, and IL-8.
HPSE is a matrix-remodeling enzyme that cleaves heparan sulfate, but it also has signaling roles in multiple
pathways that are important for cell growth, including proto-oncogene tyrosine-protein kinase Src,
extracellular signal-regulated kinase (ERK), hepatocyte/insulin-like/epidermal-growth factors (HGF, IGF,
and EGF, respectively), signal transducer and activator of transcription (STAT), and protein kinase B
(PKB) . HPSE has been shown to promote bone resorption in breast cancer-inoculated mice, in absence of
[24]
detectable bone metastases . This is accomplished through the shedding of syndecan-1 and IL-8 from the
[25]
primary site, which activate osteoclastogenesis directly , and possibly through osteoblastic RANKL
[26]
[27]
upregulation, at least in multiple myeloma . HPSE is considered an oncogene, since it is also able to
promote primary tumor growth and angiogenesis, but, intriguingly, a close homolog of HPSE, called
heparanase-2 (Hpa2) but lacking any heparanase activity, has been shown to have oncosuppressor
activity , indicating that the catalytic activity is crucial for the oncogenic function and that this pathway is
[24]
worthy of more investigation as a therapeutic target, despite clinical trials so far having been