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: 7474877
• 负责人: SCOTT A WALDMAN
• 金额: $ 5.42万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474877
• 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

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, GGC 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 mafignancies, 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 GGC 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 GGC 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.

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。部分地，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) 由正常粘膜和结直肠癌细胞特异性表达，但不由胃肠道外组织和 肿瘤。 GC-C 似乎是一种敏感且特异的标记物，可用于检测体外结直肠癌细胞。 肠道部位。初步研究表明GC-C RT-PCR可以检测转移性结直肠癌细胞 来自所有（34）名转移性结直肠癌患者的血液。此外，GC-C mRNA 表达通过 RT-PCR 检测到组织病理学检查未发现疾病的淋巴结中存在隐匿性微转移。有淋巴的患者 与淋巴结阳性的患者相比，GC-C 淋巴结阳性的患者发生癌症相关死亡的风险更大 不表达 GC-C 这些观察结果表明，对于接受术后结直肠监测的患者 对于癌症，GGC RT-PCR 可能比其他方法更早地检测微转移和复发性疾病。这 该应用程序将把我们实验室的基本观察转化为用于结直肠管理的新诊断工具 癌症。在具体目标 1 中，将检查没有 GI 的对照患者的血液中 GC-C 的表达 年龄范围从 40 岁到 90 岁的恶性肿瘤，以建立广泛血液中 GC-C RT-PCR 的基线值 有患结直肠癌风险的人群。在具体目标 2 中，GC-C RT-PCR 之间的关系 血液和转移性结直肠癌的分析将被定义。预计GGC RT-PCR阳性更多 与没有转移性疾病的患者相比，经常存在于转移性结直肠癌患者的血液中。具体来说 目标 3，临床明显复发与 GC-C RT-PCR 阳性之间的时间关系将与 前瞻性地从结直肠癌采集的系列血液样本中血清癌胚抗原 (CEA) 的含量 接受术后监测的患者。 GC-C RT-PCR 的预后价值将与血清 CEA 进行比较 在本研究期间复发的患者中的水平。预计GGC RT-PCR阳性的时间会更早、更多 复发患者血液中的 CEA 频率高于 CEA。拟议的研究将转化初步观察结果 将人体组织和血液中 GC-C 表达的特异性转化为定义诊断的临床数据 这种新型标记物在术后监测期间管理结直肠癌患者的效用。这些研究将 为未来的试验奠定基础，利用 GC-C 来识别有复发风险的患者，这些患者可能会受益 治疗干预。