Molecular strategies to define carcinoids and rationalize surgical intervention

定义类癌并使手术干预合理化的分子策略

• 批准号: 7467307
• 负责人: IRVIN M MODLIN
• 金额: $ 28.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467307
• 关键词: Adhesions; Appearance; Appendix; Benign; Biological; Carcinoid Tumor; Chromogranin A; Clinical; Data; Databases; Detection; Development; Disease; Early identification; Enterochromaffin Cells; Enterochromaffin-like Cells; Evaluation; Excision; Exhibits; Flushing; Freezing; Gastric Carcinoid Tumor; Gastrins; Gene Expression; Gene Proteins; Genes; Genomics; Goals; Growth; Hepatic; Histologic; Individual; Intestines; Laboratories; Lesion; Liver; Malignant - descriptor; Malignant Neoplasms; Mechanics; Metastatic Neoplasm to the Liver; Methodology; Microarray Analysis; Mitosis; Mitotic; Modality; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Negative Lymph Node; Neoplasm Metastasis; Neoplasms; Neuroendocrine Cell; Neurosecretory Systems; Non-Malignant; Obstruction; Operative Surgical Procedures; Paraffin; Paraffin Embedding; Paraffin Tissue; Pathology; Patients; Polymerase Chain Reaction; Primary Neoplasm; Principal Investigator; Proteins; Resources; Reverse Transcriptase Polymerase Chain Reaction; Serotonin; Serum; Small Intestines; Specificity; Specimen; Staging; Standards of Weights and Measures; Statistical Methods; Stomach; Stomach Neoplasms; Surgical Management; Surgical Pathology; Symptoms; Techniques; Technology; Therapeutic; Time; Tissue Microarray; Tissue-Specific Gene Expression; Tissues; Transcript; Tumor Cell Biology; Tumor Tissue; base; gastrointestinal; liver biopsy; lymph nodes; migration; mortality; novel; prognostic; programs; protein expression; tumor; tumor growth

DESCRIPTION (provided by applicant): The commonest gastrointestinal (Gl) carcinoids occur in the small intestine and appendix. Both are derived from the enterochromaffin (EC) cell, but their malignancy and propensity to metastasize vary widely. Small intestinal carcinoids (SICs) are aggressive and exhibit hepatic and lymph node (LN) metastasis; appendiceal carcinoids (APCs) are slow-growing and rarely metastasize. Gastric carcinoids (GCs) [enterochromaffin-like (ECL) cells], are slow-growing and rarely metastasize unless gastrin-independent. No biological explanation for the variable malignancy of Gl carcinoids exists. We hypothesize that a gene expression-based definition of these tumors will: 1) allow prediction of malignancy and metastasis, and 2) provide accurate staging and facilitate rational therapy. Utilizing: i) GeneChip analysis, ii) quantitative real-time PCR (Q RT-PCR), and iii) carcinoid tissue microarray (TMA) immunostaining/quantitation, we evaluated gene and protein expression in Gl carcinoids. In SICs and their metastases, the neuroendocrine marker chromogranin A (CgA); NAP1L1 (mitosis regulator); MAGE-D2 (liver metastatic predictor), and MTA1 (metastasis, migration), are over- expressed. In malignant APCs and GCs, CgA, MAGE-D2, MTA1, and NAP1L1 are all significantly over- expressed. In 30% of histologically-negative lymph nodes, molecular analysis detected CgA transcript and protein, making sensitive molecular staging of carcinoid tumors possible. This proposal seeks, using Q RT- PCR of frozen and paraffin specimens and carcinoid TMA analysis, to define the malignant potential of Gl carcinoids. The aims are: 1) Confirm the specificity of the neuroendocrine cell marker gene, CgA, in identifying Gl carcinoids, 2) Determine whether increased levels of the mitotic and metastasis-associated genes, NAP1L1, MAGE-D2 and MTA1, characterize malignant Gl carcinoids, 3) Determine whether benign and malignant appendiceal carcinoids show predictive differential gene expression, and 4) Identify occult metastasis in histologically normal lymph node or liver biopsies using Q RT-PCR. We propose that delineation and quantification of gene expression will: 1) define malignancy of an individual carcinoid and 2) identify occult metastasis. This will provide novel biological information and provide molecular data to identify occult metastasis predict spread and facilitate preemptive appropriate therapy.

描述(申请人提供)：最常见的胃肠道类癌(Gl)发生在小肠和阑尾。两者均来源于肠嗜铬细胞(EC)，但其恶性程度和转移倾向差异很大。小肠类癌(SIC)具有侵袭性，表现为肝脏和淋巴结(LN)转移；阑尾类癌(APC)生长缓慢，很少转移。胃类癌(GC)[肠嗜铬样细胞(ECL)]生长缓慢，除非不依赖胃泌素，否则很少转移。对于Gl类癌的可变性恶性，没有生物学上的解释。我们假设，基于基因表达的这些肿瘤的定义将：1)可以预测恶性肿瘤和转移，2)提供准确的分期和促进合理的治疗。利用：1)基因芯片分析，2)实时定量聚合酶链式反应(Q-RT-PCR)和3)类癌组织芯片(TMA)免疫染色/定量，我们研究了G1类癌中基因和蛋白的表达。在SIC及其转移中，神经内分泌标记物嗜铬粒蛋白A(CGA)、NAP1L1(有丝分裂调节因子)、MAGE-D2(肝转移预测因子)和MTA1(转移、迁移)过表达。在恶性APC和GC中，CgA、MAGE-D2、MTA1和NAP1L1均显著过表达。在30%的组织学阴性的淋巴结中，分子分析检测到CGA转录本和蛋白，使类癌的敏感分子分期成为可能。这项建议寻求使用冰冻和石蜡标本的Q RT-PCR和类癌TMA分析来确定G1类癌的恶性潜能。其目的是：1)确认神经内分泌细胞标记基因CgA在识别G1类癌方面的特异性；2)确定有丝分裂和转移相关基因NAP1L1、MAGE-D2和MTA1的水平升高是否表征恶性G1类癌；3)确定良、恶性阑尾类癌是否表现出预测性差异基因表达；以及4)使用Q RT-PCR确定组织学正常的淋巴结或肝活检组织中的隐匿性转移。我们认为，基因表达的描述和量化将：1)确定单个类癌的恶性程度，2)识别隐匿性转移。这将提供新的生物学信息和分子数据来识别隐匿性转移，预测扩散和促进先发制人的适当治疗。