MOLECULAR CYTOLOGY IN HUMAN PANCRETIC CANCER

人类胰腺癌的分子细胞学

基本信息

批准号：
3191224
负责人：
JAMES Douglas JAMIESON
金额：
$ 16.93万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-05-10 至 1991-04-30
项目状态：
已结题

项目摘要

Pancreatic cancer continues to present a major cause of cancer mortality in this country in that of the -25,000 new cases diagnosed each year, nearly all will succumb within a few months of detection. This bleak outlook is due to the absence of specific and sensitive diagnostic markers for the early stages of the disease and the lack of decisive means of tumor eradication at the later stages of progression and metastasis. The long range goal of this proposal is to utilize a battery of molecular probes that recognize normal human exocrine pancreatic cell constituents, several of which may be expressed specifically by subsets of pancreatic tumor cells of similar morphology. Poorly- differentiated and moderately-well differentiated pancreatic adenocarcinomas, for example, may be found to resemble several phases of normal tissue differentiation or a number of forms of transformed cells deriving from a particular normal cell type. Several lines of evidence indicate that pancreatic tumors can exhibit phenotypes that correspond to stages of the normal differentiation program. In these studies we plan to use riboprobes for several classes of mRNA: major cell structural components, enzymes involved in metabolism and secretion, hormone receptors, and protein kinases and substrates; antibodies specific for protein kinases and their substrates will be used in consort with gene probes for these molecules. Freshly fixed and snap-frozen pancreatic adenocarcinoma resections and biopsies and normal tissue will be analyzed using the techniques of Northern analysis of tissue extracts and in situ hybridization of tissue sections, as well as light microscopic immunocytochemistry for proteins of interest. Electron microscopy of sections of Epon- embedded fixed tissues will be done for refined morphological analysis. These specimens will be classified pathologically and the patients' clinical course correlated with the data. Sections of pathologic specimens embedded in paraffin from patients with pancreatic adenocarcinoma previously treated in our institution will be similarly examined in order to provide a retrospective clinical-pathologic correlation with new information gained in this study. At the same time, we plan to examine the normal embryonic rat pancreas with the same gene probes and immunologic probes in order to compare the human tumors with an accessible pancreatic developmental system. This analytical scheme should enable us to test the hypothesis that human pancreatic neoplasms reflect aberrant stages in the normal differentiation process and should allow us to identify potential cells of origin and developmental stages that may be the targets of the carcinogenic process in the pancreas.

胰腺癌仍然是癌症的主要原因该国新增病例的死亡率为-25,000 每年确诊，几乎所有人都会在几个月内死亡的检测。这种黯淡的前景是由于缺乏具体的以及早期阶段敏感的诊断标志物疾病和缺乏根除肿瘤的决定性手段进展和转移的后期阶段。长期目标是该提议是利用一组分子探针识别正常人外分泌胰腺细胞成分，其中一些可以具体地由子集表示胰腺肿瘤细胞形态相似。可怜—— 分化型和中分化型胰腺例如，腺癌可能类似于几种正常组织分化的阶段或多种形式源自特定正常细胞类型的转化细胞。多项证据表明胰腺肿瘤可以表现出与正常阶段相对应的表型差异化计划。在这些研究中我们计划使用用于几类 mRNA 的核糖探针：主要细胞结构参与新陈代谢和分泌的成分、酶，激素受体、蛋白激酶和底物；抗体特定于蛋白激酶及其底物将用于与这些分子的基因探针配合。刚固定好并速冻胰腺腺癌切除和活检正常组织将使用以下技术进行分析组织提取物的 Northern 分析和原位杂交组织切片以及光学显微镜免疫细胞化学对于感兴趣的蛋白质。 Epon-切片的电子显微镜将进行包埋固定组织以进行精细形态学分析。这些标本将进行病理学分类并患者的临床病程与数据相关。的部分石蜡包埋的患者病理标本曾在我们机构接受过治疗的胰腺腺癌将进行类似的审查，以便提供回顾性的与在此获得的新信息的临床病理相关性学习。同时，我们计划检查正常情况具有相同基因探针的胚胎大鼠胰腺免疫学探针，以便将人类肿瘤与一个可访问的胰腺发育系统。本次分析的该计划应该使我们能够检验人类的假设胰腺肿瘤反映了正常情况下的异常阶段差异化过程应该让我们能够识别潜在的可能是目标的起源和发育阶段的细胞胰腺的致癌过程。