title: Effect of YM529 on a model of mandibular invasion by oral squamous cell carcinoma in mice.
abstract: OBJECTIVE
  This study examined the mechanisms of osteoclast-mediated bone invasion in a model of oral squamous cell carcinoma (OSCC). C3H/HeN mice were inoculated with SCC VII cells into the masseter region to establish an animal model of mandibular invasion by OSCC.
  
  
  METHODS
  The mice were divided into three groups: a control group, given daily s.c. injections of saline; group 1, given 2 microg per mouse per day of the bisphosphonate YM529; and group 2, given 10 microg per mouse per day of YM529. After 3 weeks of treatment, the lesions were studied by micro-computed tomography. After tartrate-resistant acid phosphatase (TRAP) staining, the osteoclasts were easily identified, and the percentages of the area occupied by osteoclasts were calculated by computer for each sample. The tumors were analyzed by RT-PCR to determine the mRNA expression of interleukin-6 (IL-6), parathyroid hormone-related protein (PTHrP), tumor necrosis factor-alpha (TNF-alpha), receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), and osteoprotegerin.
  
  
  RESULTS
  SCC VII cells rapidly multiplied in the masseter muscle of the mice. Bone invasion was evident only in the control group on micro-computed tomography. On TRAP-stained slices, the percentages of osteoclasts in groups 1 and 2 were significantly lower than that in the control group. The mRNA expressions of IL-6, PTHrP, THF-alpha, and RANK decreased as the concentration of YM529 increased.
  
  
  CONCLUSIONS
  We conclude that various cancer-derived cytokines play important roles in the invasion of bone by OSCC. YM529, a third-generation bisphosphonate, can suppress osteoclast-mediated bone invasion by OSCC. The mechanism of this effect might involve inhibition of cytokines such as IL-6, PTHrP, TNF-alpha, and RANK by YM529.
authors.affiliation: The First Department of Oral and Maxillofacial Surgery, Stomatology School, Peking University, Beijing, China.
authors.forename: Nianhui
authors.initials: N
authors.lastname: Cui
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nomura
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Noma
authors.forename: Keiko
authors.initials: K
authors.lastname: Yokoo
authors.forename: Ryo
authors.initials: R
authors.lastname: Takagi
authors.forename: Sadamitsu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Sato
authors.forename: Guangyan
authors.initials: G
authors.lastname: Yu
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Guo
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shibahala
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001862:Bone Resorption / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics; D021621:Imaging, Three-Dimensional; D007093:Imidazoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008334:Mandible / Q000187:drug effects* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics; D053245:RANK Ligand; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004164:Diphosphonates; D006023:Glycoproteins; D007093:Imidazoles; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C087958:YM 529