Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Mihama-ku, Chiba 261-8502, Japan.
Int J Oncol. 2010 Jun;36(6):1387-94. doi: 10.3892/ijo_00000623.
Bone invasion is a critical prognostic factor for patients with oral squamous cell carcinoma (OSCC). We established an orthotropic implantation model using the murine OSCC cell line, SCCVII, showing direct invasion of the mandible by OSCC. Using this model, we examined the molecular mechanisms of bone invasion and the role of parathyroid-related protein (PTHrP). We established PTHrP, stable, knock-down SCCVII cells. Knock-down of PTHrP caused decreased osteoclast formation in vitro relative to expression levels of PTHrP. In vivo models showed dramatic suppression of bone invasion in PTHrP knock-down cells, and the degree of suppression was more pronounced than the level of PTHrP knock-down. We looked at an additive role of transforming growth factor-beta (TGF-beta) in PTHrP-mediated bone invasion. TGF-beta induced mRNA expression of PTHrP, showed no inhibitory effect on SCCVII cell proliferation, and caused epithelial mesenchymal trans-differentiation such as changes in the cells. Sections of resected mandibles from patients with invasive OSCC showed a great number of osteoclasts at bone invasion sites, strong expression of PTHrP, and decreased expression of E-cadherin in the tumour cells. Cancer-derived PTHrP appears to play a critical role in bone invasion by OSCC, mediated by osteoclasts. Moreover, TGF-beta appears to act synergistically to accelerate mandibular bone invasion.
骨侵袭是口腔鳞状细胞癌（OSCC）患者的一个关键预后因素。我们使用鼠 OSCC 细胞系 SCCVII 建立了一个原位种植模型，该模型显示 OSCC 直接侵袭下颌骨。使用该模型，我们研究了骨侵袭的分子机制以及甲状旁腺相关蛋白（PTHrP）的作用。我们建立了 PTHrP 稳定敲低的 SCCVII 细胞。与 PTHrP 的表达水平相比，PTHrP 敲低导致体外破骨细胞形成减少。体内模型显示 PTHrP 敲低细胞的骨侵袭明显受到抑制，抑制程度比 PTHrP 敲低水平更为显著。我们研究了转化生长因子-β（TGF-β）在 PTHrP 介导的骨侵袭中的附加作用。TGF-β诱导 PTHrP 的 mRNA 表达，对 SCCVII 细胞增殖没有抑制作用，并导致上皮间质转化，如细胞形态改变。侵袭性 OSCC 患者下颌骨切除标本的切片显示，在骨侵袭部位有大量破骨细胞，PTHrP 表达强烈，肿瘤细胞中 E-钙黏蛋白表达减少。癌源性 PTHrP 似乎通过破骨细胞在 OSCC 的骨侵袭中发挥关键作用。此外，TGF-β似乎协同作用以加速下颌骨的骨侵袭。
