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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 13 of 19

bone metastases, although its adoption is hindered by low cost-effectiveness compared to other similar
[147]
therapies . However, where Radium-233 could really shine is the adjuvant setting: by accumulating in the
bone tissue before bone metastases are detected, radium could target micrometastases, especially dormant
tumor cells, more effectively than any other known agent, since they do not need actively cycling cells to
perform their cytotoxic activity . This could address one of the most significant issues in cancer
[148]
nowadays, and several clinical trials are in progress with radium-233, alone or in combination with other
drugs such as nivolumab, both in overtly metastatic breast and in prostate cancer, as well as oligometastatic
or non-metastatic prostate cancer (www.clincaltrials.gov; keywords: prostate cancer, radium).

As for Point (3), conventional chemotherapy, alone or in combination with anti-angiogenetic molecules
such as anti-ANG2, subverts the immunosuppressing niche, inducing an anti-tumor immune response
along with a reduction of the inflammatory and angiogenetic processes in the secondary site . Moreover,
[149]
anti-angiogenic agents such as the TSU68 have been demonstrated to be a valid approach to target both the
primary tumor and the PMN .
[150]

Extracellular vesicles could also represent attractive therapeutic targets to prevent PMN establishment, but
to date there is no therapy available that would allow the targeting of these particles without significant side
effects for the host. However, an early feasibility study aimed at removing EVs from the host’s blood to
prevent the establishment of EV-induced immune-suppressive PMNs in squamous cell carcinoma of the
head and neck is in progress (NCT04453046). This trial features treatment with pembrolizumab (anti-PD-1
mAb) and treatment of patients’ blood with a Hemopurifier, an extracorporeal circulation device that uses a
lectin affinity matrix cartridge, originally designed to clear viruses from the bloodstream. This device is also
able to clear cancer-derived EVs, which have a similar glycosylation status and size to those viruses. This
approach could potentially be applied to all cancers, including those that metastasize to bone, thus this is a
trial worth following. The field is young, and many exosome-release inhibitors are being developed,
targeting the Ras-related proteins RAB27A/RAB27B or sphingomyelinase, as well as indirect inhibitors such
as cannabidiol, ketotifene, and, interestingly, proton pump inhibitors (PPIs) . The latter mechanism of
[151]
action is based largely on the fact that cancer cells secrete more EVs when their microenvironment is acidic,
which is mainly achieved through tumoral and microenvironmental V-ATPases. As we recently
demonstrated , omeprazole is able to reduce bone pain and, at least at later stages, osteolysis. Therefore,
[152]
this could be an interesting treatment which could inhibit osteoclastic acidification, hence influencing PMN
formation, reduce acidity-induced pain, and inhibit tumor EVs secretion. PPIs are used worldwide and have
few side effects; therefore, although we cannot realistically imagine a single-agent adjuvant therapy based on
PPIs for cancer, these could be an interesting addition to a standard therapy which would be worth
exploring. In addition to this, efforts are in place to exploit EVs as diagnostic tools that would on the one
hand help diagnose primary tumors of unknown origin, and on the other hand monitor treatment response,
[153]
onset of drug resistance, and propensity to metastasize .

CONCLUSIONS
In this review, we discuss the specific hallmarks of the bone/bone marrow PMN, focusing on key
microenvironmental players (i.e., osteoblasts, osteoclasts, osteocytes, bone marrow adipocytes, endothelial
cells, and immune cells), as well as the molecular pathways involved in its establishment. We then give an
overview of the homing process, which is the next step in metastasis, where CTCs becoming DTCs in the
bone microenvironment, using specific molecular cues and proteins to their advantage. This process
includes proteins that can fall into the concepts of osteo- or HSC-mimicry, where cancer cells can express
bone microenvironmental factors to persuade, at the molecular level, that they belong in that milieu.
Extracellular vesicles are also very important in PMN establishment. These nano-scale molecular carriers