BIOLOGIC EFFECTS OF BONE MORPHOGENETIC PROTEINS ON ORAL CANCER

骨形态发生蛋白对口腔癌的生物学作用

• 批准号: 7146548
• 负责人: Brian Nussenbaum
• 金额: $ 7.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146548
• 关键词: bone; bone morphogenetic proteins; cell line; human; mouth neoplasms; proteins; squamous cell carcinoma

DESCRIPTION (provided by applicant): Project Summary: There are many etiologies for segmental bone loss in the maxillofacial and mandibular regions, but the vast majority of defects that require bone grafting arise from ablative cancer surgery. Although advances in surgical technique and plate technology have improved the functional and cosmetic restoration of these patients, there are still significant limitations that make a novel approach using osteoinductive molecules quite appealing. Bone morphogenetic protein-2 and -7 (BMP-2, -7) are morphogens known to stimulate bone regeneration through endochondral ossification. These proteins are commercially available and FDA-approved for orthopedic applications based on randomized clinical trials proving equivalence to autologous bone grafts but with the added advantage of avoiding a donor site. Preclinical data and limited patient experience suggest that this approach will also successfully regenerate bone in maxillofacial bone defects and it is the Principal Investigator's long term objective to use BMPs rather than bone grafts to reconstruct these defects. Very little is known about the biologic effects of BMPs on cancer, however. Preliminary work using three oral squamous carcinoma (OSCCA) cell lines suggests that tumor cell proliferation and secretion of proangiogenic molecules are unaffected by treatment with BMP- 2 and -7. The purpose of this application is to follow up on these results and study whether these BMPs activate specific molecular pathways in oral cancer cells and the consequence, if any, on in vivo tumor growth. Specific Aim 1 will establish the potential relevance of BMPs in tumorigenesis by determining which pathway-related molecules are being expressed and determining whether the pathway is functional by examining activation of a downstream target gene. Specific Aim 2 will study the in vivo biologic effects of stimulating or inhibiting the BMP-pathway on OSCCA using an orthotopic nude mouse model of oral cancer. The primary endpoint will be tumor growth, with secondary endpoints of local invasiveness, metastasis, and survival also being studied. The impact of baseline BMP expression on the observed biologic effects will be determined by using cell lines identified in Specific Aim 1 with unique BMP expression profiles. Relevance to Public Health: Patients with bone defects in the maxillofacial and mandibular areas suffer devastating functional (speech, swallowing), cosmetic, and emotional consequences. The limitations of current reconstructive options will likely be overcome by rapidly emerging bone regeneration approaches using a growth factor molecule called bone morphogenetic protein. This study will form the necessary foundation for determining if this molecule can be used safely in patients with defects caused by removal of oral cancers without stimulating the cancer cells to grow or become more aggressive.

描述（由申请人提供）：项目摘要：上颌面和下颌区域中有许多病因，但是绝大多数需要骨骼嫁接的缺陷是由消化的癌症手术引起的。尽管手术技术和板技术的进步改善了这些患者的功能和外观恢复，但仍然存在重大局限性，可以使用骨诱导分子进行新的方法，这非常有吸引力。骨形态发生蛋白-2和-7（BMP -2，-7）是已知的形态剂，可通过内软骨软骨骨化刺激骨骼再生。这些蛋白质是商业上可用的，并且基于随机临床试验的骨科应用，证明与自体骨移植物相等，但还具有避免供体部位的额外优势。临床前数据和有限的患者经验表明，这种方法还将成功再生颌面骨缺损的骨骼，并且使用BMP而不是骨移植物重建这些缺陷是主要研究者的长期目标。但是，关于BMP对癌症的生物学影响知之甚少。使用三种口腔鳞状癌（OSCCA）细胞系的初步工作表明，肿瘤细胞的增殖和促肌生成分子的分泌不受BMP -2和-7处理的影响。该应用的目的是跟进这些结果，并研究这些BMP是否激活了口腔癌细胞中的特定分子途径以及在体内肿瘤生长中的结果（如果有的话）。具体目标1将通过确定表达哪些途径相关的分子并确定该途径是否通过检查下游靶基因的激活来确定该途径是否功能来确定BMP在肿瘤发生中的潜在相关性。具体目标2将研究使用口腔癌的原位裸小鼠模型刺激或抑制OSCCA的BMP-Pathway的体内生物学效应。主要终点是肿瘤生长，还研究了局部侵入性，转移和生存的次要终点。基线BMP表达对观察到的生物学效应的影响将通过使用具有独特的BMP表达谱的特定AIM 1中的细胞系来确定。与公共卫生有关：上颌面和下颌区域中骨缺损的患者遭受毁灭性功能（语音，吞咽），化妆品和情感后果。使用称为骨形态发育蛋白的生长因子分子快速出现的骨再生方法，可能会克服当前重建方案的局限性。这项研究将构成确定该分子是否可以安全地用于由去除口服癌症引起的缺陷的患者而不刺激癌细胞生长或变得更具侵略性的患者的必要基础。