The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in bone.
Adenocarcinoma of the prostate exhibits a clear propensity for bone and is associated with the formation of osteoblastic metastases. It has previously been suggested that osteoclast activity may be necessary for the development of these osteoblastic metastases based on data from lytic and mixed lytic-blastic tumors. Here we investigate the effects of complete in vivo osteoclast depletion via the blockade of receptor activator of NF:kappaB (RANK) on the establishment and progression of purely osteoblastic (LAPC-9 cells) bone lesions induced by human prostate cancer cells using a SCID mouse intratibial injection model. The subcutaneous administration of the RANK antagonist (15 mg/kg) RANK:Fc did not prevent the formation of purely osteoblastic lesions, indicating that osteoclasts may not be essential to the initial development of osteoblastic metastases. However, RANK:Fc protein appeared to inhibit the progression of established osteoblastic lesions, suggesting that osteoclasts may be involved in the subsequent growth of these tumors once they are already present. In contrast, RANK:Fc treatment effectively blocked the establishment and progression of purely osteolytic lesions formed by PC-3 cells, which served as a positive control. These results indicate that in vivo RANK blockade may not be effective for the prevention of osteoblastic metastasis but may potentially represent a novel therapy that limits the growth of established metastatic CaP lesions in bone.
Whang
Peter G
PG
Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences 76-134, 10833 LeConte Avenue, Los Angeles, CA 90095, USA.
Schwarz
Edward M
EM
Gamradt
Seth C
SC
Dougall
William C
WC
Lieberman
Jay R
JR
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology* / Q000556:secondary*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010006:Osteoblasts / Q000473:pathology*; D010010:Osteoclasts / Q000502:physiology*; D010014:Osteolysis; D053244:Osteoprotegerin; D011471:Prostatic Neoplasms / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse