Guanylyl Cyclase C in Blood and Colorectal Cancer

血液和结直肠癌中的鸟苷酸环化酶 C

• 批准号: 7481026
• 负责人: SCOTT A WALDMAN
• 金额: $ 83.59万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481026
• 关键词: Adult; Age; American; Benign; Biological Markers; Blood; Blood specimen; CD34 gene; Cancer Etiology; Cancer Patient; Carcinoembryonic Antigen; Cells; Characteristics; Clinical; Clinical Data; Colitis; Colon Carcinoma; Colorectal; Colorectal Cancer; DNA; Detection; Development; Diagnostic; Diarrhea; Disease; Disease Marker; Doctor of Medicine; Doctor of Philosophy; Ectopic Expression; Epithelial Cells; Excision; Foundations; Future; Goals; Histopathology; Human; Individual; Intestines; Laboratories; Malignant Neoplasms; Measures; Medical Surveillance; Messenger RNA; Methods; Micrometastasis; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Persons; Population; Population Control; Positive Lymph Node; Postoperative Period; Range; Recurrence; Recurrent disease; Reverse Transcriptase Polymerase Chain Reaction; Risk; Serum; Site; Specificity; Staging; Standards of Weights and Measures; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Translating; Tumor Tissue; apical membrane; base; cancer cell; cancer risk; chemotherapy; enterotoxin receptor; gastrointestinal; heat stable toxin (E coli); human tissue; improved; lymph nodes; mRNA Expression; metastatic colorectal; mortality; neoplastic cell; novel; novel diagnostics; prognostic; prospective; receptor; tool; tumor

DESCRIPTION (provided by applicant): In the U.S., 50% of patients who undergo "curative" resection for colorectal cancer suffer recurrent disease. In part, this reflects the absence of techniques to detect occult micrometastases prior to clinically evident recurrence. Guanylyl cyclase C (GC-C) is specifically expressed by normal mucosal and colorectal cancer cells, but not by extra-gastrointestinal tissues and tumors. GC-C appears to be a sensitive and specific marker that can be employed to detect colorectal cancer cells in extra-intestinal sites. Preliminary studies demonstrated that GC-C RT-PCR could detect metastatic colorectal cancer cells in blood from all (34) patients examined with metastatic colorectal cancer. In addition, GC-C mRNA expression measured by RT-PCR detected occult micrometastases in lymph nodes that were free of disease by histopathology. Patients with lymph nodes positive for GC-C were at greater risk for cancer-related mortality compared to patients with lymph nodes that did not express GC-C These observations suggest that for patients undergoing post-operative surveillance for colorectal cancer, GC-C RT-PCR may be useful to detect micrometastases and recurrent disease earlier than other methods. This application will translate basic observations from our laboratory into new diagnostic tools for the management of colorectal cancer. In Specific Aim 1, GC-C expression will be examined in blood from control patients who do not have GI malignancies, with ages ranging from 40 yo to 90 yo, to establish the baseline value for GC-C RT-PCR in blood in the broad population of individuals at risk to develop colorectal cancer. In Specific Aim 2, the relationship between GC-C RT-PCR analysis in blood and metastatic colorectal cancer will be defined. It is expected that GC-C RT-PCR will be positive more often in the blood of patients with metastatic colorectal cancer compared to patients without metastatic disease. In Specific Aim 3, the temporal relationship between clinically evident recurrence and a positive GC-C RT-PCR will be compared to that of serum carcinoembryonic antigen (CEA) in serial blood samples collected prospectively from colorectal cancer patients undergoing post-operative surveillance. The prognostic value of GC-C RT-PCR will be compared to serum CEA levels in patients who recur during this study. It is anticipated that GC-C RT-PCR will be positive earlier and more frequently than CEA in the blood of patients who recur. The studies proposed will translate preliminary observations concerning the specificity of GC-C expression in human tissues and blood into clinical data which define the diagnostic utility of this novel marker for managing colorectal cancer patients during post-operative surveillance. These studies will form the foundation for future trials utilizing GC-C to identify patients at risk for recurrence who might benefit from therapeutic intervention.

描述（由申请人提供）：在美国，接受“治愈性”结直肠癌切除术的患者中有 50% 患有复发性疾病。在某种程度上，这反映出缺乏在临床明显复发之前检测隐匿性微转移的技术。鸟苷酸环化酶 C (GC-C) 在正常粘膜和结直肠癌细胞中特异性表达，但在胃肠道外组织和肿瘤中不表达。 GC-C 似乎是一种敏感且特异的标记物，可用于检测肠外部位的结直肠癌细胞。初步研究表明，GC-C RT-PCR 可以检测所有（34）名转移性结直肠癌患者血液中的转移性结直肠癌细胞。此外，通过 RT-PCR 测量的 GC-C mRNA 表达检测到组织病理学未发现疾病的淋巴结中隐匿性微转移。与淋巴结不表达 GC-C 的患者相比，淋巴结阳性 GC-C 的患者发生癌症相关死亡的风险更大。这些观察结果表明，对于接受结直肠癌术后监测的患者，GC-C RT -PCR 可能比其他方法更早地检测微转移和复发性疾病。该应用程序将把我们实验室的基本观察结果转化为用于治疗结直肠癌的新诊断工具。在具体目标 1 中，将对年龄范围为 40 岁至 90 岁的未患有胃肠道恶性肿瘤的对照患者的血液中的 GC-C 表达进行检查，以确定血液中 GC-C RT-PCR 的基线值。广大人群有患结直肠癌的风险。在具体目标 2 中，将定义血液中 GC-C RT-PCR 分析与转移性结直肠癌之间的关系。预计与无转移性疾病的患者相比，转移性结直肠癌患者的血液中 GC-C RT-PCR 更容易呈阳性。在具体目标 3 中，临床明显复发与 GC-C RT-PCR 阳性之间的时间关系将与从接受术后监测的结直肠癌患者前瞻性收集的系列血样中血清癌胚抗原 (CEA) 的时间关系进行比较。 GC-C RT-PCR 的预后价值将与本研究期间复发患者的血清 CEA 水平进行比较。预计在复发患者的血液中，GC-C RT-PCR 会比 CEA 更早、更频繁地呈阳性。拟议的研究将把关于人体组织和血液中 GC-C 表达特异性的初步观察结果转化为临床数据，从而定义这种新型标记物在术后监测期间管理结直肠癌患者的诊断效用。这些研究将为未来利用 GC-C 进行试验奠定基础，以确定可能从治疗干预中受益的有复发风险的患者。