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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 7 of 19

mediated by the Notch pathway. This leads to the disruption of the bone remodeling compartment thus
inducing osteolytic lesions [68,69] .

Bone marrow adipocytes and vascular leakiness
It is well-established that bone marrow adipocytes (BMAs) increase in number with age, as well as in
response to lifestyle changes and other external factors [70-72] , and it is becoming clear that their number is
inversely correlated with bone mineral density and directly correlated with osteoclast activation. This makes
BMAs crucial in bone metastasis development and growth, but it is not the only function exerted by these
cells in the tumoral context. In fact, BMAs seem to play a key role in establishing vascular leakiness, which
allows tumor cells to escape circulation and engraft in the bone marrow. This action is exerted through
several factors, including the inflammatory cytokines IL-6, IL-1β, and TNFα and novel players such as
angiopoietin-like 2 (ANGPTL2) and ANGPTL4, visfatin, and stromal cell-derived factor 1 (SDF1). This,
together with the fact that bone marrow sinusoids are by nature permissive for intra- and extravasation of
[73]
CTCs, can create an ideal condition for tumor engraftment in the bone marrow . Furthermore, SDF1 is
one of the most widely recognized homing factors for CTCs, as described above. Another important action
BMAs exert in the context of the PMN establishment is the secretion and promotion of expression of
LOX . As stated above, this protein creates a stiffer matrix that more readily receives circulating tumor
[74]
[74]
cells . Finally, the SDF1/CXCR4 pathway increases adhesion molecules expression in bone marrow
endothelial cells, key examples being vascular cell adhesion molecule-1 (VCAM-1) and integrins α4β1,
which enhance multiple myeloma, prostate, and lung cancer homing to bone [75,76] .

Immune cells
The bone/bone marrow PMN needs to be an immune-privileged area since cancer cells need to escape
immune surveillance to engraft and survive in such an immune cells-rich environment. This process is
achieved by the recruitment of immune-suppressive cells such as Treg, macrophages, and myeloid-derived
suppressor cells [11,12,77,78] in the PMN. Consistent with this idea, increasing number of the immunosuppressive
Treg in the bone marrow has been associated with metastatic dissemination of different neoplasias [79,80] .
Conversely, CD8+ T-cells, NK cells, and other immune cells expressing specific markers such as caveolin-1
and IL-1β have been reported to prevent the formation of the PMN or to keep the cancer cells in a dormant
[84]
state [81-83] . Recently, Monteran et al. demonstrated that 4T1 mouse breast cancer cells induce systemic
immune suppression, associated with an increase of granulocytes and myeloid cells along with a decrease of
NK cells and lymphocytes in the early steps of bone marrow pre-metastatic niche formation . Intriguingly,
[84]
Monteiro and Bonomo also recently found that cancer cells can exploit immune cells in a completely
[85]
different way, which still results in the priming of the bone/bone marrow microenvironment for metastasis.
In fact, after coming in contact with the primary tumor, primed CD4+ T-cells can migrate to the bone
marrow and activate osteoclastogenesis by means of RANKL and IL-17F, which results in bone loss, before
the tumor can be detected in bone. This bone loss of course primes the microenvironment for metastatic
engraftment. Intriguingly, in this case, dendritic cells are used as osteoclast precursors. Finally, primary
tumor-derived molecules such as S100A8/9, serum amyloid A1, serum amyloid A3, toll-like receptor 4, IL-6,
and TNFα have been linked with the recruitment of immune and regulatory cells in the PMN, as well as
osteoclastogenesis, thus inducing a microenvironmental remodeling that creates a PMN and may promote
metastasis [73,86,87] .

TAKING ADVANTAGE OF THE PRE-METASTATIC NICHE: HOW CANCER CELLS HOME TO
BONE
After the establishment of the PMN, the bone/bone marrow microenvironment becomes a better “soil” for
the cancerous “seed”. The next step for the CTCs is to extravasate into the bone/bone marrow milieu and