Osteomimicry: A recurring theme in bone metastasis is the hijacking of normal bone mechanisms by tumor cells. The concept of osteomimicry is that bone metastatic prostate cells acquire the ability to produce proteins typically restricted to bone cells, such as osteoblasts, to survive and proliferate in the otherwise restrictive bone microenvironment.108
Select genes normally expressed in bone have been detected in prostate cells, including osteocalcin, osteopontin, bone sialoprotein, osteonectin, RANK, RANKL, and PTH-related protein.108-111
The expression of these genes appears to be associated with the metastatic capacity of the cells. Studies in both the PC3 and LNCaP cell lines have shown that the expression of osteonectin is highest in the more invasive and metastatic sublines, including the LNCaP metastatic variant C4-2B.109
Analysis of patient samples support these findings, showing that osteonectin staining in prostate to bone metastases was more intense than from soft-tissue metastases.109 In addition to changes in gene expression, prostate tumor cells may adopt biological activities usually specific to bone cells.
In vitro studies indicate that human C4-2B prostate tumor cells are capable of depositing hydroxyapatite and contributing to mineralization, a common feature of the sclerotic lesions observed in vivo.110
Due to the shared expression of specific bone genes between tumor and stroma cells, these common proteins could be used to simultaneously target both compartments.
Understanding that soluble factors like bone morphogenetic protein 2, RANKL, TGF-β, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor are partially responsible for inducing osteomimetic genes may also provide options to specifically target osteomimicry and establish bone outgrowths.111
It has been suggested that promoters for the common genes between the tumor and stroma cells could be utilized to drive the expression of therapeutic genes, thus targeting both the stroma and tumor cells.108
Halting the Vicious Cycle of Bone Metastases: Once the DTCs awaken and establish micrometastases, continued outgrowth arises through the interaction with multiple stromal cell types, growth factors, and enzymes in a process known as the vicious cycle model.112 Prostate to bone metastases are characterized by areas of mixed osteogenesis and osteolysis that give rise to painful lesions.113
A number of tumor-derived factors, including PTH-related protein, interleukin (IL) 1, IL-6, and IL-11, have been shown to interact with osteoblasts and stimulate the production of RANKL.114 RANKL is a crucial molecule for osteoclast differentiation; therefore, it contributes to the extensive bone remodeling seen in bone metastasis. In addition to bone destruction, osteoclast-mediated bone resorption also releases a multitude of bone-derived factors such as TGF-β, insulin growth factor, platelet-derived growth factor, and fibroblast growth factor.
These factors provide positive feedback via interaction with their respective receptors on the surface of tumor cells, thus promoting the proliferation and continued production of tumor-derived factors.114 The vicious cycle is continually evolving to include other cell types, cytokines, proteases, and therapeutics.115-118
Several studies have shown contributory roles for highly expressed host matrix metalloproteinases (MMPs) in the vicious cycle, including the regulation of latent TGF-β and VEGF-A bioavailability by MMP-2 and MMP-9, and the generation of a soluble form of RANKL by MMP-7, which promotes osteoclastogenesis and mammary tumor–induced osteolysis in vivo.119-121
In recent years, the interactions with immune cells have become an integral part of the vicious cycle. For example, T cells stimulate and inhibit the formation of osteoclasts, and the recruitment of regulatory T cells to bone marrow may inhibit osteoclastogenesis.
Myeloid-derived suppressor cells suppress T cells and release angiogenic, tumor-promoting factors. Recruited myeloid-derived suppressor cells have also been shown to differentiate into osteoclasts.118
Although the need for therapies aimed at the early stages of metastasis has been emphasized, patients will still present in the later stages of the disease; therefore, improving therapies for these patients must still remain a priority. The interactions between tumor and stromal cells in the vicious cycle model offer many opportunities to intervene.
Therapies such as zoledronic acid and denosumab interfere with the osteolytic component of the vicious cycle; however, therapies to inhibit the unique osteosclerotic component of prostate to bone metastases are lacking. Many roles for specific MMPs have been elucidated in the vicious cycle,115,120,121 and the development of MMP inhibitors with improved specificity is perhaps a promising method to modulate the vicious cycle.122
From these discoveries, it is becoming evident that the metastasis of prostate cancer is not a linear, stepwiseprocedure.
Defining the mechanisms that control CRPC metastasis may help elucidate new therapeutic targets that directly impact the cancer cells and the processes that facilitate the formation of a premetastatic niche, niche seeding, dormancy, and the vicious cycle.123 Such new discoveries are highly likely to impact the clinical treatment of patients with mCRPC.