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Page 6 of 19 Maurizi et al. J Cancer Metastasis Treat 2021;7:35 https://dx.doi.org/10.20517/2394-4722.2021.74

[32]
vivo and in vitro assays, Ardura et al. showed that MINDIN was able to increase prostate cancer cells
adhesion to bone and osteoblasts, thus strengthening the idea that this could be an important factor in the
PMN establishment and prostate cancer cells homing.

The expression of several matrix proteins produced by osteoblasts have also proved important in homing to
bone, and thus could be considered PMN factors. However, direct proof of this is currently lacking. An
emerging topic in PMN establishment is represented by tumor-derived extracellular vesicles (EVs), which
we and others found to be influencing the bone microenvironment in a way that favors tumor growth,
affecting osteoblasts, osteoclasts, and endothelial cells [35,36] . The role of EVs is discussed in detail in the
following paragraphs.

Osteocytes
Osteocytes represent 90%-95% of bone-resident cells [37-40] . They arise from osteoblasts, which depose matrix
around themselves and remain trapped in the mineralized matrix, eventually differentiating into mature
[42]
[41]
osteocytes . These cells regulate bone physiology acting on both osteoblast and osteoclast activities . It
has in fact been demonstrated that they negatively regulate osteoblast differentiation and function by
releasing DKK1 and sclerostin [42-44] . These molecules act as antagonist of WNT pathway by preventing the
binding of WNT ligands to the Frizzled or LRP 5 and 6 receptors. Osteocytes are also the main source of
RANKL, the most important osteoclast differentiation- and survival-inducing factor [45-49] . In addition to
RANKL, osteocytes produce other factors involved in osteoclasts differentiation, such as OPG, MCSF,
tumor necrosis factor (TNF), IL-6 and IL-11 [50,51] . Moreover, in specific circumstances, osteocytes can even
depose or resorb their neighboring bone matrix to respond to the needs of the organism . Osteocytes also
[52]
regulate other cell types within the bone/bone marrow niche. Indeed, osteocyte-derived VEGF stimulates
[53]
angiogenesis by activating the MAPK-ERK pathway in endothelial cells . Other angiogenetic factors
produced by osteocytes are sclerostin, BMP7, and RANKL [47,54] . Osteocytes also regulate skeletal muscle by
secreting myogenic factors such as sclerostin, prostaglandin E2 (PGE2), and Wnt3 [55-58] . Moreover, recent
observations demonstrated that connexin 43, a key component of gap junctions that are abundant in
osteocytic processes, may also play a role in the bone-skeletal muscle crosstalk affecting muscle formation
and function . Finally, osteocytes are also endocrine cells, able to regulate phosphate homeostasis by
[59]
fibroblast growth factor 23 (FGF23) secretion. This is a bona fide hormone, able to target renal proximal
tubular cells and reduce their expression of the sodium-phosphate transporters type IIa, thus increasing
phosphate excretion. FGF23 also reduces renal production of 1,25(OH) D, which in turn reduces gut and
2
bone absorption of phosphate .
[60]
As with other bone cells, osteocytes also play an important role in the development of bone metastases .
[61]
Indeed, they produce several factors involved in homing and proliferation of cancer cells in the bone
microenvironment. These include CCL12, IL-6, hepatocyte growth factor (HGF), and hypoxia inducible
[61]
factor 1 (HIF-1) . Recent studies demonstrated that osteocyte-derived conditioned medium increases
proliferation of human breast and prostate cancer cell lines . Moreover, skeletal loading and changes in the
[62]
mechanical forces in bone microenvironment affect cancer cells behavior through direct or indirect
osteocytes stimulation [63-66] .

Looking at the other side of the coin, tumor cells are able to impact osteocytes too, enhancing their pro-
tumoral behavior. Indeed, it has been reported that prostate cancer cells stimulate osteocytes to produce
growth-derived factor 15 (GDF15), which in turn enhances prostate cancer cells invasion and growth
through an early growth response 1 (EGR1) transcription factor-mediated mechanism . Finally, osteocytes
[67]
are also able to establish a bidirectional communication with myeloma cells by cell-cell interaction,