title: Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration.
abstract: Lung cancer metastases to bone produce a primarily mixed osteolytic/osteoblastic lesion. The purpose of this study was to determine if blockade of both pathways would inhibit the formation these lesions in bone. Inhibition of the osteoblastic lesion with noggin and the osteolytic lesion with RANK:Fc was a successful treatment strategy to inhibit progression of mixed lung cancer lesions in bone.
  
  
  BACKGROUND
  Approximately 9-30% of patients with lung cancer develop bone metastases, leading to significant morbidity and mortality. A549 is a non-small-cell lung cancer (NSCLC) line that produces a mixed metastatic lesion in bone. We sought to determine if blockade of key components in both osteolytic and osteoblastic pathways would result in a reduction of a NSCLC tumor progression in a murine model of bony metastasis.
  
  
  METHODS
  The study used a retroviral vector overexpressing noggin (RN), a specific inhibitor of BMP, and RANK:Fc, a chimeric protein that inhibits the RANK-RANKL interaction. A549 cells were transduced with RN before implantation in SCID mice. Cells were implanted in a subcutaneous model and tibial injection model. RANK:Fc was administered twice weekly at 15 mg/kg. There were five treatment groups: A549; A549 + RN; A549 + RANK:Fc; A549 + empty vector; and A549 + RN + RANK:Fc (n = 10/group).
  
  
  RESULTS
  In SCID mice who underwent subcutaneous A549 tumor cell injection, animals treated with A549 + RN had significantly smaller subcutaneous tumor size at 8 weeks. In an intratibial model of bony metastasis, animals injected with A549 cells developed a mixed lytic/blastic lesion with cortical destruction at 8 weeks. Treatment with RANK:Fc inhibited the formation of osteoclasts, led to a smaller tumor volume in bone, and inhibited the lytic component of the mixed lesion. Animals treated with A549 + RN had a decreased number of osteoblasts in bone lesions, smaller tumor volume, and inhibition of the blastic component of the mixed lesions. Combination treatment inhibited both the lytic and blastic components of the lesion.
  
  
  CONCLUSIONS
  The NSCLC cell line A549 forms a mixed osteolytic/osteoblastic lesion in vivo. Noggin overexpression inhibited the formation of the osteoblastic aspect of the lesion in bone and the tumor growth in vivo. Treatment with RANK:Fc limited the formation of the lytic aspect of the mixed lesion and also inhibited the rate of in vivo tumor growth. Inhibition of both pathways is necessary to effectively inhibit the progression of mixed metastatic lesions in bone.
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Feeley
authors.forename: Nancy Q
authors.initials: NQ
authors.lastname: Liu
authors.forename: Augustine H
authors.initials: AH
authors.lastname: Conduah
authors.forename: Lucie
authors.initials: L
authors.lastname: Krenek
authors.forename: Kevin
authors.initials: K
authors.lastname: Roth
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
authors.forename: Steve
authors.initials: S
authors.lastname: Dubinett
authors.forename: Jay R
authors.initials: JR
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010014:Osteolysis / Q000378:metabolism; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013977:Tibia / Q000000981:diagnostic imaging / Q000473:pathology; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D000099176:Noggin Protein; C517736:Rank-Fc