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Molecular Strategies for Gastric Carcinoid Surgery

胃类癌手术的分子策略

基本信息

批准号：
6933139
负责人：
IRVIN M MODLIN
金额：
$ 21.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-22 至 2006-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The biological behavior of gastric enterochromaffin (ECL) cell tumors remains an enigma and their clinical management a source of controversy and concern. As a result, surgical management is often disparate and based upon relatively arbitrary concepts (size, primary lesions, and number of lymph nodes) and the inability to define whether the lesions are simply hyperplastic cell aggregates that are gastrin-dependent for their growth or gastrin-autonomous neoplastic cells. The aims of this grant are to identify molecular markers that can be utilized to assess whether the ECL cell is gastrin-responsive or when the lesion has become gastrin-autonomous. A unique rodent model (Mastomys) has been developed in our laboratory to investigate ECL cell tumor biology. This rodent is unique in being the only known model of rapid (< 4 months) ECL cell tumor transformation. Numerous studies have indicated that its gastric carcinoid lesion is similar to that of human disease. Our preliminary data utilizing a number of molecular strategies in ECL cell tissue from rats, Mastomys and human demonstrate several conserved gene alterations particularly associated with AP-1 activity. Our hypothesis is that a biological rationale for surgical therapy for ECL cell carcinoids may be derived from studying and defining the evolution of ECL cell proliferation and neoplastic transformation in the Mastomys and applying these findings to humans. The most promising initial gene target pathway is AP-1 transcription. The aims of the proposal are 1) identify whether fos/jun expression is a marker of ECL cell autonomy in Mastomys exposed to variable periods of hypergastrinemia, 2) define the gene pattern expression pathways associated with gastrin autonomy in the ECL cell using gene chip technology to examine alterations in gene expression as the ECL cell converts from normal to gastrin dependent and gastrin-autonomous neoplasia, 3) examine the human relevance of gastrin autonomous genes using tissue microarray technology. A pre-operative determination of the neoplastic ECL cell gene expression relating to gastrin responsiveness will improve the rationale for therapeutic gastric or antral resection.

描述（由申请人提供）：胃肠嗜铬细胞瘤（ECL）的生物学行为仍然是一个谜，其临床管理是争议和关注的来源。因此，外科治疗通常是不同的，并且基于相对任意的概念（大小，原发性病变和淋巴结数量），并且无法确定病变是否只是生长依赖于胃泌素的增生细胞聚集体或胃泌素自主性肿瘤细胞。这项资助的目的是确定可用于评估ECL细胞是否对胃泌素有反应或病变何时成为胃泌素自主的分子标志物。我们实验室开发了一种独特的啮齿动物模型（乳鼠属）来研究ECL细胞肿瘤生物学。这种啮齿动物是唯一已知的快速（< 4个月）ECL细胞肿瘤转化模型。大量研究表明其胃类癌病变与人类疾病相似。我们的初步数据，利用一些分子策略，在ECL细胞组织从大鼠，乳鼠和人类证明了几个保守的基因改变，特别是与AP-1的活性。我们的假设是，ECL细胞类癌手术治疗的生物学原理可能来自研究和定义的ECL细胞增殖和肿瘤转化的Mastomys的演变，并将这些研究结果应用于人类。最有希望的初始基因靶向途径是AP-1转录。该提案的目的是1）鉴定fos/jun表达是否是暴露于不同时期的高胃泌素血症的乳鼠属中ECL细胞自主性的标志物，2）使用基因芯片技术定义ECL细胞中与胃泌素自主性相关的基因模式表达途径，以检查ECL细胞从正常转化为胃泌素依赖性和胃泌素自主性瘤形成时基因表达的改变，3）利用组织微阵列技术检测胃泌素自主基因的人类相关性。术前测定肿瘤性ECL细胞与胃泌素反应性相关的基因表达将改善治疗性胃或胃窦切除术的基本原理。