Therapies of bone metastases in castration-resistant prostate cancer

Molecular mechanisms of bone metastases development

PCa progression to CRPC state is typically associated with development of bone metastases that rests on the seed and soil hypothesis reported for the first time by S. Paget in 1889 [ ]. Tumor cells from primary tumor present in blood (the “seed”) of patients with advanced PCa invade the bone (the “soil”), resulting in bone lesions and creating a bone microenvironment propitious to tumor growth in bone. However, the precise mechanism by which cancer cells home to bone is still unclear. Physiological and molecular mechanisms have been described explaining the predilection of metastases for bone sites, such as the blood flow [ ], or the involvement of adhesive molecules produced by cancer cells and that are able to bind bone matrix leading to tumor growth in bone [ ]. It is also well reported that bone can express chemoattractants or growth factors, including SDF-1, TGF-β, and IGF, that selectively attract tumor cells and promote tumor growth.

Bone metastases are generally a heterogeneous disease characterized by both osteolytic and osteoblastic lesions explained by a deregulation of the balance osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Disruption of this balance can lead to excessive bone loss or extra bone formation. The discovery of the triad RANK (receptor activator of nuclear factor KB), RANKL (RANK ligand), and OPG (osteoprotegerin) in 1997 has significantly improved the knowledge of the molecular mechanisms involved in the regulation of bone remodeling [ ]. In bone, OPG and RANKL are expressed by osteoblasts and bone marrow stromal cells, whereas RANK is expressed at the surface of osteoclasts precursors and mature osteoclasts. The binding of RANK/RANKL induces differentiation, maturation, and activation of preosteoclasts to mature osteoclasts leading to bone resorption. OPG is a decoy receptor able to bind RANKL, then disrupting the RANK/RANKL interaction and thus preventing bone loss.

The concept of “vicious cycle” between tumor proliferation and bone resorption defines the tumor development in bone microenvironment [ ]. Indeed, it is well known that tumor cells in bone produce factors such as IL-6, IL-11, and TNF-α that will activate bone cells leading to osteolysis, releasing growth factors (IGF-1, TGF-β) and chemoattractants (e.g., SDF-1) from bone matrix that will promote tumor growth in return [ , , ]. As example, PCa cells can produce parathyroid hormone–related peptide (PTHrP) that stimulates osteoblasts and bone marrow stromal cells to produce RANKL promoting differentiation, activation, and maturation of preosteoclasts in mature osteoclasts [ , ]. RANKL is mainly produced by osteoblasts and stromal cells but may also be produced directly by tumor cells increasing osteoclast activity and bone loss [ ].

The metastatic process is a multiple-step process in order to spread and invade distant sites, where PCa cells proliferate to develop a secondary tumor [ , ]. After the epithelial–mesenchymal transition (EMT), tumor cells are able to invade the peripheral matrix and toward blood vessels using circulation where they are called circulation tumor cells (CTCs) in order to migrate to distant organs. Then, after extravasation, the tumor cells colonize the new organ, escape the innate immune response, adapt to the microenvironment, and proliferate to form a secondary tumor. PCa tumor cells mainly metastasize into the bone because bone microenvironment represents ideal microenvironment with high attraction, or homing for tumor cells largely regulated by integrins (α4β1-vascular cell adhesion molecule 1 (VCAM1)) and chemokines (SDF-1, BMPs, Notch, and osteopontin) produced by the bone marrow stromal cells. As an example, bone marrow stromal cells and osteoblasts express CXCL12 (SDF-1) ligand that can bind the G-protein-coupled receptor CXCR4 expressed by PCa tumor cells and regulated by androgens [ ]. Colonization and expansion of tumor cells are the result of a complex series of autocrine, paracrine, and host–microenvironment interactions including endothelin 1 and its receptor [ , ], cadherin-11 [ ], matrix metalloproteinases (MMPs) [ , ], TGF-β [ , ], and parathyroid hormone–related protein (PTHrP) [ ]. Moreover, androgens play also a key role, even in an androgen-deprived state, in the bone tumorigenesis process, by inducing integrins and cell adhesion molecules needed for the homing of tumor cells in bone. Androgens also activate Wnt pathway [ ], one of the major signaling pathways in osteoblast formation, by increasing the runt-related transcription factor 2 (RUNX2) expression [ ], demonstrating a close collaboration between tumor cells and bone microenvironment in the bone metastases process.