title: A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth.
abstract: Although increasing evidence suggests a critical role for platelet-derived growth factor (PDGF) receptor β (β-PDGFR) signaling in prostate cancer (PCa) progression, the precise roles of β-PDGFR and PDGF isoform-specific cell signaling have not been delineated. Recently, we identified the PDGF-D isoform as a ligand for β-PDGFR in PCa and showed that PDGF-D is activated by serine protease-mediated proteolytic removal of the CUB domain in a two-step process, yielding first a hemidimer (HD) and then a growth factor domain dimer. Herein, we demonstrate that the expression of PDGF-D in human PCa LNCaP cells leads to enhanced bone tumor growth and bone responses in immunodeficient mice. Histopathological analyses of bone tumors generated by PDGF-D-expressing LNCaP cells (LNCaP-PDGF-D) revealed osteolytic and osteoblastic responses similar to those observed in human PCa bone metastases. Importantly, we discovered a novel function of PDGF-D in the regulation of osteoclast differentiation, independent of the RANKL/RANK signaling axis. Although both PDGF-B and -D were able to activate β-PDGFR, only PDGF-D was able to induce osteoclastic differentiation in vitro, and upregulate the expression and nuclear translocation of nuclear factor of activated T cells 1, a master transcription factor for osteoclastogenesis. Taken together, these results reveal a new function of PDGF-D as a regulator of osteoclastic differentiation, an activity critical for the establishment of skeletal metastatic deposit in PCa patients.
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Fridman
authors.forename: R D
authors.initials: RD
authors.lastname: Bonfil
authors.forename: C V
authors.initials: CV
authors.lastname: Ustach
authors.forename: M K
authors.initials: MK
authors.lastname: Conley-LaComb
authors.forename: C
authors.initials: C
authors.lastname: Wiesner
authors.forename: A
authors.initials: A
authors.lastname: Saliganan
authors.forename: M L
authors.initials: ML
authors.lastname: Cher
authors.forename: H-R C
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D041681:NIH 3T3 Cells; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D007527:Isoenzymes; D008222:Lymphokines; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D053245:RANK Ligand; D011994:Recombinant Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase