Effect of YM529 on a model of mandibular invasion by oral squamous cell carcinoma in mice
Effect of YM529 on a model of mandibular invasion by oral squamous cell carcinoma in mice
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DOI：
10.1158/1078-0432.ccr-04-1767
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发表时间：
2005-04-01
影响因子：
11.5
通讯作者：
Shibahala, T
中科院分区：
文献类型：
--
作者：
Cui, NH;Nomura, T;Shibahala, T
目的：本研究探讨口腔鳞状细胞癌（OSCC）模型中破骨细胞介导的骨侵袭机制，将SCC VII细胞接种到C3H/HeN小鼠咬肌区，建立口腔鳞状细胞癌下颌骨侵袭的动物模型。实验设计：将小鼠分为三组：对照组，每日皮下注射给药。注射生理盐水；第1组，每只小鼠每天给予2μg双膦酸盐YM529；第2组，每只小鼠每天给予10微克YM529。治疗3周后，通过微型计算机断层扫描对病变进行研究。经过抗酒石酸酸性磷酸酶（TRAP）染色后，破骨细胞很容易被识别，并且通过计算机计算每个样品的破骨细胞所占面积的百分比。通过RT-PCR分析肿瘤，测定白细胞介素6（IL-6）、甲状旁腺激素相关蛋白（PTHrP）、肿瘤坏死因子-α（TNF-α）、核因子κB受体激活剂（RANK）、RANK配体（RANKL）和骨保护素的mRNA表达。结果：SCC VII细胞快速 在小鼠的咬肌中繁殖。显微计算机断层扫描仅在对照组中出现明显的骨侵袭。在TRAP染色切片上，第1组和第2组破骨细胞的百分比显着低于对照组。随着YM529浓度的增加，IL-6、PTHrPTHF-α和RANK的mRNA表达降低。结论：我们得出结论，各种癌症来源的细胞因子在OSCC骨侵袭中发挥重要作用。 YM529 是第三代双膦酸盐，可以抑制破骨细胞介导的 OSCC 骨侵袭。这种作用的机制可能涉及 YM529 对 IL-6、PTHrP、TNF-α 和 RANK 等细胞因子的抑制。
Purpose: 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.Experimental Design: The mice were divided into three groups: a control group, given daily s.c. injections of saline; group 1, given 2 mu g per mouse per day of the bisphosphonate YM529; and group 2, given 10 mu g 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-kappa B (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, PTHrPTHF-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.