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applications [110,111] .

Finally, other integrins, such as very late antigen 4 and VLA5, are important homing factors, being able to
bind endothelial VCAM-1 and bone matrix fibronectin, thus partaking in cancer cell homing to bone, at
[112]
least in multiple myeloma .

Another class of adhesion molecules, i.e., the cadherins, which mediate homophilic interactions between
cells, can also mediate homing to bone. In particular, cadherin 11, (also referred to as osteoblast cadherin)
can also be expressed by prostate cancer cells and promote their homing to the endosteal niche.
Consistently, cadherin 11 is not expressed by normal prostate tissue, but its expression emerges when the
normal tissue becomes cancerous . This molecule may also be considered an example of osteo-mimicry.
[113]
[114]
Similar findings were also observed in breast cancer cells , and, after homing, cadherin 11 overexpressing
cells were able to increase osteoclastogenesis, thus propelling the osteolytic vicious cycle.

EXTRACELLULAR VESICLES: AN IMPORTANT TOOL TO SHUTTLE THE PRO-
METASTATIC MESSAGE
The role of extracellular vesicles (EVs) as crucial mediators of intercellular communication is well
established. EVs are structures surrounded by a lipidic bilayer, naturally released by non-apoptotic cells in
both physiological and pathological conditions . According to their origin and size, the scientific
[115]
community has classically distinguished two major populations of EVs: microvesicles with a diameter of
100-1000 nm, which are directly shed by the plasma membrane, and exosomes, which 30-150 nm vesicles
originating from the endo-lysosomal compartment after fusion of multivesicular bodies with the plasma
membrane [116,117] . Although this classification is falling out of use [118,119] , for the purpose of this review, it is
adopted to describe the works published using this nomenclature.

EVs can be found in all biological fluids, such as blood, urine, saliva, and cerebrospinal and seminal fluid,
and they often mirror the molecular setup of the cell of origin, which makes them very attractive as
diagnostic tools . EVs serve as cargo for a wide range of molecules, including DNA, proteins, lipids, and
[117]
[120]
different types of RNA (mRNAs and miRNAs) . Based on these characteristics, EVs represent an optimal
means for tumor cells’ colonization of distant organs. Tumor cells release significantly higher levels of EVs
compared to normal cells, and this is also true for tumor cells that preferentially metastasize the bone, such
[123]
as prostate [121,122] and breast cancer .

EVs released by primary tumor cells actively participate in the initiation of the PMN . As a paradigm of
[73]
this role, a few years ago, Hoshino et al. identified a specific cluster of integrins expressed on the surface
[124]
of tumor-derived exosomes, which allows their adhesion to a specific cell type or extracellular matrix
molecule present in a distant organ, thus driving the organotropism of tumor cells. In particular, they found
that exosomes expressing integrin αvβ5 specifically bind to Kupffer cells, promoting liver tropism, while
exosomal integrins α6β4 and α6β1 bind to lung-resident fibroblasts, thus mediating lung metastases.
Therefore, the authors proposed the exosomal integrin expression profile as a potential predictor of patient
organ-specific metastasis . Consistent with these results, in a colon cancer in vivo model, Ji et al.
[124]
[125]
demonstrated that the primary tumor releases integrin beta-like 1 (ITGBL1)-enriched EVs to convert lung
fibroblasts and hepatic stellate cells to a cancer-activated phenotype, which in turn promotes PMN
establishment by secreting proinflammatory cytokines. Moreover, the EVs enrichment in ITGBL1 is driven
by the RUNX2 transcription factor. Similarly, Costa-Silva et al. found that pancreatic cancer-derived EVs
[126]
contribute to the PMN formation in the liver by shuttling macrophage migration inhibitory factor.