title: Blockade of transforming growth factor-beta (TGFβ) signaling inhibits osteoblastic tumorigenesis by a novel human prostate cancer cell line.
abstract: BACKGROUND
  The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The role of transforming growth factor-beta (TGFβ) signaling in prostate cancer-induced osteoblastic metastasis is not clear. We investigated the role of TGFβ signaling in prostate cancer-induced bone metastasis using a novel human prostate cancer cell line, PacMetUT1.
  
  
  METHODS
  We injected PacMetUT1/Luc-GFP cells in male nude mice by intracardiac and intratibia injections and then investigated the effect of TGFβ signaling abrogation on osteoblastic tumor growth and incidence in vivo by using fluorescence and bioluminescence imaging analysis and quantifying bone and tumor volume by histomorphometry analysis. Osteoclasts were counted using TRAP assay.
  
  
  RESULTS
  Osteoblastic bone metastasis in skull, rib, and femur was detected after 10-16 weeks of intracardiac injection of the PacMetUT1 cells. Stable knockdown of TGFβ1 with an shRNA resulted in decreased tumor incidence and bone formation when the cells were directly injected into the tibiae. Systemic administration of either a small inhibitor of TGFβ type I receptor kinase or a pan TGFβ binding protein (BG(E) RII) also decreased bone tumor growth and osteoblastic bone formation in vivo after 7 weeks of treatment.
  
  
  CONCLUSIONS
  Our results for the first time indicate that blockade of TGFβ signaling in the PacMetUT1 model significantly inhibits osteoblastic bone formation and tumor incidence. Thus, TGFβ signaling pathway may be a viable target for the prevention and treatment of prostate cancer-induced bone metastasis.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
authors.forename: Sweta
authors.initials: S
authors.lastname: Mishra
authors.forename: Yuping
authors.initials: Y
authors.lastname: Tang
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Linda
authors.initials: L
authors.lastname: deGraffenried
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Sherry
authors.initials: S
authors.lastname: Werner
authors.forename: Dean
authors.initials: D
authors.lastname: Troyer
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D051899:Smad2 Protein; D016212:Transforming Growth Factor beta