Guanylyl Cyclase C in Blood and Colorectal Cancer

在美国，接受结直肠癌“根治性”切除的患者中有50%会复发。在某种程度上，这 反映了在临床明显复发之前缺乏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，但不在胃肠外组织和 肿瘤。GC-C是一种敏感而特异的标记物，可用于检测结直肠癌细胞外基质中的癌细胞。 肠道部位。初步研究表明，GC-C RT-PCR可以检测到结直肠癌细胞的转移。 所有34例转移性结直肠癌患者的血液。此外，通过检测GC-C mRNA的表达 RT-PCR检测到淋巴结中的隐匿性微转移，组织病理学检查没有发现这种转移。患淋巴的病人 与GC-C阳性的淋巴结患者相比，GC-C阳性的淋巴结患者癌症相关死亡的风险更大 不表达GC-C这些观察表明，对于接受结直肠手术后监测的患者 与其他方法相比，GGC RT-PCR可能有助于更早地发现微转移和复发。这 应用程序将把我们实验室的基本观察结果转化为处理结直肠疾病的新诊断工具 癌症。在特定目标1中，将检测没有GI的对照患者的血液中GC-C的表达 年龄从40岁到90岁，建立血液中GC-C RT-PCR值的基线 罹患结直肠癌的高危人群。在特定目标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将会有更多的阳性 通常在转移性结直肠癌患者的血液中与无转移性疾病的患者相比。具体而言 目的3，将临床明显复发与GC-C RT-PCR阳性之间的时间关系与 前瞻性采集的结直肠癌患者系列血样中癌胚抗原的检测 接受术后监护的患者。GC-C RT-PCR的预后价值将与血清CEA进行比较 在这项研究中复发的患者的水平。预计GGC RT-PCR将更早和更多地呈阳性 经常比CEA在血液中复发的患者。建议的研究将把初步观察结果转化为 将人体组织和血液中GC-C表达的特异性纳入定义诊断的临床数据 这一新的标志物在结直肠癌患者术后监测中的应用。这些研究将 为利用GC-C识别可能受益于以下各项的复发风险患者的未来试验奠定基础 治疗性干预。

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.