Risk factors for site-specific metastasis in esophageal cancer

描述（由申请人提供）：这个职业发展奖申请的主要目标是为我提供适当的指导环境，以进步和发展成为一个成功的独立研究人员在食管肿瘤进展的风险因素。食管癌尤其是腺癌的发病率在西方国家迅速上升，并且绝大多数食管癌患者死于转移性疾病的并发症。然而，影响位点特异性转移的因素尚未得到很好的描述。我们的初步研究表明，在食管癌患者中，吸烟可能会增加肺转移的风险，而酒精可显著降低肝转移的风险。研究提案的具体目的是：（1）确定吸烟是否增加食管癌肺转移的风险;（2）确定酒精是否降低食管癌肝转移的风险;（3）确定吸烟和酒精是否通过对原发肿瘤（“种子”），转移部位（“土壤”）或两者的影响来影响特定部位的转移风险。为了实现目标1和2，我建议进行巢式病例对照研究，从食管癌患者的队列，以确认吸烟和酒精的转移模式的网站特定的影响。病例将定义为伴有肺或肝转移的食管癌患者，对照组定义为没有肺或肝转移的患者。为了实现目标3，将对原发性肿瘤和转移部位进行探索性分析。将分析原发性肿瘤组织的高迁移率族蛋白A1和A2（转移行为的潜在标志物）的表达。肺损伤将通过用力呼气量（1秒）和主要的尿中前列腺素-E2代谢产物（烟草诱导的肺损伤的实验测量）进行定量。将使用由三种血清标志物（透明质酸、前胶原III和TIMP-1）组成的算法估计肝纤维化。识别位点特异性转移的生活方式风险因素及其作用位点（“种子”或“土壤”）将：改善食管癌扩散风险患者的预测模型;识别未来化学预防和治疗药物的新靶点;并作为研究位点特异性转移风险因素的模型。

DESCRIPTION (provided by applicant): The primary objective of this career development award application is to provide me with the proper mentored environment to progress and develop into a successful independent researcher in risk factors for progression in esophageal neoplasia. The incidence of esophageal cancer, particularly adenocarcinoma, is rising rapidly in western countries, and the large majority of esophageal cancer patients die from complications of metastatic disease. However, factors that affect site-specific metastasis have not been well described. Our preliminary research indicates that, in patients with esophageal cancer, smoking may increase the risk of lung metastasis, while alcohol significantly reduces the risk of liver metastasis. The specific aims of the research proposal are to: (1) determine whether smoking increases the risk of lung metastasis from esophageal cancer; (2) determine whether alcohol decreases the risk of liver metastasis from esophageal cancer; and (3) determine whether smoking and alcohol impact site-specific metastatic risk via effects on the primary tumor (the "seed"), the site of metastasis (the "soil"), or both. In order to accomplish Aims 1 and 2, I propose to conduct a nested case-control study from a cohort of esophageal cancer patients to confirm the site-specific effects of smoking and alcohol on patterns of metastasis. Cases will be defined as esophageal cancer patients with lung or liver metastases, and controls as those patients without lung or liver metastases. In order to accomplish Aim 3, exploratory analyses will be performed of the primary tumor and of sites of metastasis. Primary tumor tissue will be analyzed for expression of high mobility group proteins Al and A2, potential markers of metastatic behavior. Lung damage will be quantified by forced expiratory volume (one second) and by the major urinary prostaglandin-E2 metabolite, an experimental measure of tobacco-induced lung injury. Liver fibrosis will be estimated using an algorithm comprised of three serum markers (hyaluronic acid, procollagen III, and TIMP-1). The identification of lifestyle risk factors for site-specific metastasis and their site of action ("seed" or "soil") will: improve predictive modeling of patients at risk for spread of esophageal cancer; identify novel targets for future chemopreventive and therapeutic agents; and serve as a model to study risk factors for site-specific metastasis.