Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Laryngoscope. 2012 Jan;122(1):95-102. doi: 10.1002/lary.22345. Epub 2011 Oct 13.
OBJECTIVES/HYPOTHESIS: To establish the relevance of the bone morphogenetic protein (BMP) signaling pathway in human oral squamous cell carcinoma (OSCCA) cell lines and determine if there is a biologic impact of stimulating this pathway with recombinant human (rh) BMP-2.
In vitro laboratory investigations and in vivo analysis using an orthotopic animal model for oral cancer.
Gene expression profiles for BMP-2 and components of the BMP-signaling pathway were determined using reverse transcriptase-polymerase chain reaction. In vivo effects were evaluated using Kaplan-Meier survival analysis and studying histopathologic changes in established tumor xenografts with or without rhBMP-2 pretreatment. A phosphokinase array was used to detect levels of activation in signaling kinases.
The BMP-2 gene was expressed in 90% of the 30 OSCCA cell lines tested. Gene expression of all components of the BMP-signaling pathway was highly conserved. Tumor xenografts established with rhBMP-2-treated cells showed more rapid local growth that resulted in worse animal survival as compared to the control group. These tumors had a more poorly differentiated morphology. Changes in protein kinases suggested interactions of BMP-2 signaling with the Wnt-β-catenin, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways.
Human OSCCA cell lines frequently express BMP-2 and all necessary components of the BMP-signaling pathway. Exogenous treatment of human OSCCA cell lines with rhBMP-2 prior to engraftment in an orthotopic animal model caused the subsequent tumors to be more locally aggressive with worse survival. Continued caution should be used for considering rhBMP-2 for reconstruction of bone defects in oral cancer patients.
目的/假设：确定骨形态发生蛋白（BMP）信号通路在人口腔鳞状细胞癌（OSCCA）细胞系中的相关性，并确定用重组人（rh）BMP-2 刺激该通路是否具有生物学影响。
体外实验室研究和使用口腔癌的原位动物模型的体内分析。
使用逆转录-聚合酶链反应确定 BMP-2 和 BMP 信号通路成分的基因表达谱。使用 Kaplan-Meier 生存分析评估体内效应，并研究有无 rhBMP-2 预处理的建立的肿瘤异种移植物中的组织病理学变化。使用磷酸激酶阵列检测信号激酶的激活水平。
在测试的 30 个人 OSCCA 细胞系中，有 90%表达 BMP-2 基因。BMP 信号通路的所有成分的基因表达都高度保守。用 rhBMP-2 处理过的细胞建立的肿瘤异种移植物显示出更快的局部生长，导致动物存活率比对照组更差。这些肿瘤具有更差的分化形态。蛋白激酶的变化表明 BMP-2 信号与 Wnt-β-catenin 和 Janus 激酶/信号转导和转录激活因子（JAK/STAT）通路之间存在相互作用。
人 OSCCA 细胞系经常表达 BMP-2 和 BMP 信号通路的所有必需成分。在将人 OSCCA 细胞系植入原位动物模型之前，用 rhBMP-2 进行外源性处理会导致随后的肿瘤更具局部侵袭性，生存率更差。在考虑用 rhBMP-2 重建口腔癌患者的骨缺损时应继续谨慎。
