Effect of YM529 on a model of mandibular invasion by oral squamous cell carcinoma in mice.
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.
Cui
Nianhui
N
The First Department of Oral and Maxillofacial Surgery, Stomatology School, Peking University, Beijing, China.
Nomura
Takeshi
T
Noma
Hiroyasu
H
Yokoo
Keiko
K
Takagi
Ryo
R
Hashimoto
Sadamitsu
S
Okamoto
Masato
M
Sato
Mitsunobu
M
Yu
Guangyan
G
Guo
Chuanbin
C
Shibahala
Takahiko
T
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
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