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Page 8 of 19 Maurizi et al. J Cancer Metastasis Treat 2021;7:35 https://dx.doi.org/10.20517/2394-4722.2021.74

survive in the new microenvironment until they can develop into an overt metastasis. This process is
defined as “homing” and is regulated by very complex relationships among cancer cells, resident cells, and
the local ECM. Although we do not yet have a complete picture of how this process takes place, several
important cellular and molecular players have been identified over the years on both the CTCs and the
bone/bone marrow sides. Interestingly, to improve their ability to home to the bone/bone marrow, CTCs
can disguise themselves through complex molecular contrivances, so that resident cells consider them part
of the tissue, rather than a non-self element. This ability to “camouflage” is defined as “mimicry”, and the
two most studied cancer mimicry scenario are the so-called osteo-mimicry, where cancer cells “pretend” to
be bone cells, and the hematopoietic stem cell (HSC)-mimicry, where CTCs express typical HSC molecules
to home into their niches. Both osteo- and HSC-mimicry are important in CTCs homing. A key
osteomimetic molecule involved in CTCs bone homing is RANK, the most important receptor in osteoclast
differentiation and survival. In fact, osteoblast/osteocyte derived RANK-ligand (RANKL) creates a gradient
through which RANK-expressing tumors such as breast, prostate, and melanoma can migrate towards bone.
Another key osteomimetic homing factor is the αvβ3 integrin, which is well studied in osteoclasts, being a
key mediator of their adhesion to the bone matrix during the bone resorption process [88-90] . This molecule
can promiscuously bind to ECM components, including fibronectin, vitronectin, fibrinogen, and
[91]
osteopontin (OPN) . The latter is a key component of the bone matrix and is well-recognized as a
microenvironmental homing factor for bone metastasizing cancer cells . The αvβ3 integrin works in
[92]
concert with another important ECM receptor expressed by a subset of CTCs: CD44. The latter has been
proposed as a stemness marker in breast cancer cells, and it is also able to bind OPN, along with other ECM
components such as hyaluronan, thus co-mediating the bone homing of this subset of cancer cells. This is in
agreement with the concept that, once in the bone marrow microenvironment, CTCs may assume a stem-
cell-like phenotype and hibernate into a dormant state for months or even several years, before currently
unknown factors mediate their reactivation. This is achieved by means of HSC-mimicry. HSCs have tightly
regulated homing and quiescence-inducing mechanisms, which can be replicated and exploited by CTCs to
their advantage. Central for the homing mechanism is the SDF1-CXCR4 axis [93-95] . Indeed, SDF1 is highly
expressed in bone, and this promotes the colonization of CXCR4-positive tumors [96-100] . In line with this,
[100]
preventing the interaction between SDF1 and CXCR4 reduces bone metastasis . Annexin II is another
factor that can bind SDF1 and is used by HSCs to localize in the niche. In this case as well, cancer cells can
mimic HSCs and express this protein, thus occupying their place in the niche . In addition to the
[101]
“mimicry” molecules, other homing factors have been identified that at least partially mediate this
phenomenon. Key examples are microenvironment-derived CCL12 and CCL22, binding CCR7- and CCR4-
positive cancer cells, respectively [96,102,103] . Another interesting example is Dikkopf-related protein 1 (DKK1),
a Wnt pathway inhibitor that, according to a recent report, seems to determine bone vs. lung metastasis .
[104]
In fact, tumors with high expression of DKK1 are prone to metastasize to the bone, while DKK1-low tumors
metastasize preferentially to lungs. Although the authors did not focus specifically on dissecting the role of
DKK1 in homing, they observed a reduction in osteoblastic bone deposition in DKK1-low tumors, which
can be considered a microenvironmental reprogramming. However, whether this happens before or after
metastasis is still an open topic, which may provide valuable information for metastasis treatment. Another
important molecule in the tumor colonization of the bone is transforming growth factor β (TGFβ), which is
abundantly present in the bone matrix. TGFβ has a proliferative effect on both bone cells (osteoblasts) and
cancer cells. It has been demonstrated that the TGFβ released upon tumor-induced bone resorption is able
to increase invasion, chemotaxis, and angiogenesis [105-107] . Moreover, TGFβ stimulates tumor cells to produce
osteolytic factors that enhance osteoclast activity, eventually leading to increased bone resorption [8,18] . This
further increases the release of TGFβ from the bone matrix, fueling the so-called “vicious cycle” in the bone
microenvironment. Recently, Waning et al. demonstrated that TGFβ released from bone also contribute
[108]
to muscle weakness in an in vivo model of bone metastases. In line with this, inhibition of TGFβ and its
signaling pathway leads to increased bone mass , thus paving the way for possible therapeutic
[109]