Understanding and targeting osteoclastic activity in prostate cancer bone metastases

Abstract

Bone metastasis is a debilitating side effect of advanced prostatic carcinoma impacting nearly all of the men developing this disease. Even though a majority of these lesions are considered osteoblastic, it is believed that there is an underlying osteolytic component. Lytic processes are governed primarily by osteoclasts, the primary bone resorptive cell. Osteolysis has been implicated in tumor cell seeding and nourishment of tumor growth via development of pro-tumorigenic changes in the microenvironment. Herein, we provide a current view of the processes involved in regulating osteolysis in the presence of prostate cancer bone metastases. Several factors have been implicated in the division, differentiation, and activation of osteoclasts, including, but not limited to, interleukin-6, receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), and parathyroid hormone-related protein (PTHrP). Effector molecules in bone resorption play a significant role, such as matrix metalloproteinases (MMPs), cathepsins, and acid secretion. The primary method for treating skeletal events associated with prostate cancer bone metastases has been bisphosphonates. However, a new therapeutic, denosumab, a monoclonal antibody that inhibits RANKL in a mechanism similar to that attributed to the endogenous mediator OPG, has received approval for treatment of skeletally associated metastases. Additional novel targets are continuously being developed for bone metastases. In this review, we describe the processes involved in osteolysis of the prostate cancer bone microenvironment, and introduce therapeutics that may play a role in inhibiting tumor growth leading to increased survival and quality of life.

Figure 1. Osteoclast differentiation

Important cytokines are listed at relevant points of differentiation. Legend: CFU-GM=Colony forming unit-granulocyte monocyte; OC=Osteoclast; RANK=Receptor activator of nuclear factor kappa B; RANKL=Receptor activator of nuclear factor kappa B ligand; M-CSF=macrophage colony stimulating factor; OPG=Osteoprotegerin. CFU-GM are the earliest precursor in the osteoclast lineage. Presence of M-CSF leads to expansion of the CFU-GM pool and initiation of differentiation. The presence of RANKL and M-CSF leads to increased expression of genes characteristic of osteoclast. Continued presence of RANKL leads to continued differentiation into mature osteoclasts and promotes bone resorption by converting cells to an active phenotype. Throughout this process, OPG can mitigate the effects of RANKL leading to lack of differentiation and/or the bone resorptive phenotype. The presence of TGF-β is associated with osteoclast apoptosis and helps mitigate bone lysis.

Figure 2. Therapeutic targeting the microenvironment of prostatic bone metastases

Novel therapeutics are important for the targeting of osteoclastogenesis through osteoclasts themselves and relevant effectors. A snapshot of the prostatic bone microenvironment is shown with the location and impact of important therapeutics. There is significant crosstalk and overlap concerning the mechanisms by which PCa can alter bone homeostasis and promote not only an osteolytic, but an osteoblastic environment. Legend: CFU-GM=Colony Forming Unit Granulocyte-Macrophage; PCa=Prostate Cancer Cell; PTHrP=Parathyroid Hormone Related Protein; RANKL; Denosumab; Anti-IL-6 Ab=Anti-IL-6 Antibody; Interleukin-1,-4,-6=IL-1, -4, -6; OPG=Osteoprotegerin; OB=Osteoblast; Acid=Acid Secretion; MMP=Matrix Metalloproteinase; MMP-I=MMP inhibitor CAI=Carbonic Anhydrase Inhibitor; Bisphos=Bisphosphonates; OC=Osteoclast.