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.

Upregulation of CRMP4, a new prostate cancer metastasis suppressor gene, inhibits tumor growth in a nude mouse intratibial injection model

“…Osteoprotegerin (OPG) blocks ligand binding to RANK, thereby preventing osteoclast differentiation and activation. It has been shown (47,48) that OPG plays protective role in cancer bone metastasis and RANKL promotes osteolytic bone metastasis. In our investigation, CRMP4 overexpression showed no influence on RANKL and OPG expression and the in vivo study showed both groups developed osteolytic bone destruction and no osteoclast cell difference in TRAP staining, indicating CRMP4 overexpression may have no effect on osteoclast/osteoblast balance in bone microenvironment.…”

Expression of the IL‐11 Gene in Metastatic Cells Is Supported by Runx2‐Smad and Runx2‐cJun Complexes Induced by TGFβ1

“…Both breast and prostate cancer-induced metastatic bone disease is a complex process involving interactions of tumor cells with stromal cells, osteoblasts, osteoclasts that destroy bone, resulting in disease morbidity and mortality [Sottnik and Keller, 2013; Weilbaecher et al, 2011]. TGFβ Receptor I Kinase Inhibitors are in clinical trials and drugs that inhibit osteoclastic bone resorption are clinically effective in reducing skeletal complications of malignancy, although individual patient variables must be considered [Iranikhah et al, 2014; Mathew and Brufsky, 2014].…”

“…Prostate cancer metastatic bone disease results in predominantly painful bone forming osteoblastic bone lesions, but it is now clinically recognized that osteolysis is also a component of the metastatic disease in the bone microenvironment during progression of prostate tumor growth [Morrissey et al, 2013; Sottnik and Keller, 2013]. Recent studies in mouse models have also identified the osteolytic component of prostate cancer tumor growth in bone [Akech et al, 2010; Dutta et al, 2014; Eswaraka et al, 2014; Fradet et al, 2013; Ortiz and Lin, 2012; Zhang et al, 2015].…”

“…Several interleukins are also secreted from different tumor cells and among these is the highly osteolytic cytokine IL-11 [Sottnik and Keller, 2013]. IL-11 is a cytokine secreted from mesenchymal, epithelial and tumor cells and it was found to be a valuable biomarker for tumor aggressiveness and prognosis in several cancers [Casimiro et al, 2012; Furuya et al, 2005; Necula et al, 2012; Xiang et al, 2012; Zurita et al, 2004].…”

MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways

“…In osteolytic lesions, such as those in breast cancer, bone loss predominates, while increased bone turnover in which both bone formation and bone resorption are deregulated, is characteristic of skeletal metastases in prostate cancer (8,9). More than one third of patients with SCLC develop osteolytic bone metastasis, resulting in severe pain, pathologic fractures, spinal cord compression, and loss of mobility to greatly reduce the quality of life (10,11).…”