title: Differences in the cytokine profiles associated with prostate cancer cell induced osteoblastic and osteolytic lesions in bone.
abstract: Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It is hypothesized that osteoclastogenesis is a critical component in the development of skeletal metastases. These findings, however, were generally noted in predominantly osteolytic lesions. The pathophysiology of osteoblastic lesions remains unknown but the type of bone lesion formed may be influenced by the cytokines produced by prostate tumors. To test this theory, we implanted PC-3 and LAPC-9 cells into the tibias of SCID mice. These mice were sacrificed at 1, 2, 4, 6, and 8 weeks after implantation and histologic analysis was performed on these tibias. PCR analysis was also performed on bulk tumors. The results showed that the PC-3 implanted tibias developed pure osteolytic lesions while the LAPC-9 implanted tibias developed pure osteoblastic lesions on radiographs. Analysis of tibias after injection with PC-3 cells revealed progressive osteolytic lesions with abundant osteoclast activity at 2 weeks and destruction of the proximal tibia at 6 weeks after cell implantation. In contrast, the LAPC-9 cells formed osteoblastic lesions six weeks after cell injection. There were rare osteoclasts prior to the establishment of the osteoblastic lesions but greater osteoclast activity was noted with remodeling of the osteoblastic lesion 8 weeks after implantation of the tumor cells. PCR analysis revealed that PC-3 cells produced RANKL, IL-1, and TNF-alpha, which are associated with osteoclastogenesis. In contrast, LAPC-9 cells produced osteoprotegerin, which blocks osteoclast production and no detectable levels of RANKL or IL-1 and only minimal amounts of TNF-alpha were noted. These cells secreted BMP-2, -4, -6, and IL-6, which are associated with bone formation. These results suggest that the role of the osteoclast in the development of a metastatic lesion is variable depending on the phenotype of the prostate cancer cells, and that tumor-induced osteolysis may not be required for osteoblastic metastases.
authors.affiliation: Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: E
authors.initials: E
authors.lastname: Schwarz
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: M
authors.initials: M
authors.lastname: Jo
authors.forename: J
authors.initials: J
authors.lastname: Gates
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J R
authors.initials: JR
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics*; D015870:Gene Expression / Q000276:immunology; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000276:immunology / Q000473:pathology*; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D053244:Osteoprotegerin; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000150:complications / Q000556:secondary*; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor; D013977:Tibia / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse