Title:Understanding and Targeting Osteoclastic Activity in Prostate Cancer Bone Metastases
VOLUME: 13 ISSUE: 4
Author(s):J.L. Sottnik and E.T. Keller
Affiliation:Department of Urology, RM 5308 CCGC, University of Michigan, Ann Arbor, MI 48109-8940, USA.
Keywords:Bisphosphonates, bone microenvironment, Denosumab, IL-6, OPG, osteoblast, osteoclast, prostate
cancer, RANKL
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.
