Diagnosis, Pathophysiology And Molecular Biology Of Pheo

Pheo 的诊断、病理生理学和分子生物学

• 批准号: 7209915
• 负责人: Karel Pacak
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7209915
• 关键词: catecholamines; children; chromaffin cells; clinical research; fluorine; gene mutation; genetic markers; human subject; human tissue; microarray technology; molecular biology; neoplasm /cancer diagnosis; neoplasm /cancer relapse /recurrence; pathologic process; phenylethylamines; pheochromocytoma; positron emission tomography; proteomics; radionuclides; tissue /cell culture

The Unit emphasizes bedside to bench projects and multidisciplinary and multi-institutional collaborations. The studies focus on 3 objectives: (1) development and testing of novel methods and criteria to diagnose and localize pheochromocytoma cost-effectively; (2) development of better treatments for malignant pheochromocytoma; (3) identification of molecular and genetic mechanisms of pheochromocytoma tumorigenesis and clinical manifestations of disease. It is anticipated that studies directed at the last objective will have the most far-reaching consequences by leading to new strategies for diagnosis and therapy of pheochromocytoma, particularly of metastatic disease. Recently, we have described that plasma concentrations of free metanephrines are relatively independent of renal function and therefore more suitable for diagnosis of pheochromocytoma among patients with renal failure than measurements of deconjugated metanephrines. We also found that measurements of plasma free metanephrines not only provide information about the likely presence or absence of a pheochromocytoma, but when a tumor is present, can also help to predict tumor size and location. Recently, we have introduced the O-methylated metabolite of dopamine, methoxytyramine, as an additional biochemical blood test to detect these tumors. Currently, we are also attempting to determine the diagnostic utility of measurements of plasma free metanephrines in patients with metastatic pheochromocytoma before and after treatment. We are also performing a large prospective study to compare 6-[18F]-fluorodopamine PET scanning with [123I]-MIBG, Octreoscan, and [18F]-Fluorodeoxyglucose PET scanning to find out whether 6-[18F]-fluorodopamine PET scanning may be considered as the ?first-line? imaging methods in the diagnosis of various pheochromocytomas, especially in patients in whom this tumor cannot be localized by other currently available imaging modalities. Metastasis suppressor genes affect the spread of several cancers and, therefore, may provide promise as prognostic markers or therapeutic targets for malignant pheochromocytoma. We applied quantitative real-time polymerase chain reaction to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancer-related cell events, such as cell growth regulation and apoptosis (nm23-HI, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRSM-1), invasion (CRMP-1), and cell adhesion (E-Cad and KiSS1). Following cross-validation, the non-linear rule produced 0 errors in 10 malignant samples and 3 errors in the 15 benign samples, with overall error rate of 12%. These results suggest that down-regulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. We have also found that many of the genes over-expressed in VHL compared to MEN 2 tumors are clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter (GLUT1), vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, and VEGF receptors, VEGFR-2 and neuropilin-1. Successful treatment of any metastatic cancer depends on its early detection and localization. Despite excellent improvements in various imaging techniques, small metastatic lesions are often not detected due to suboptimal spatial resolution of current anatomical and functional imaging modalities. This also applies for animal models of metastatic cancer. These models are crucial for the development of new therapeutic approaches and treatments. For the first time, we show that microCT using hepatobillary specific contrast reveals liver metastasis as small as 0.35mm and can be detected as early as 4 weeks after initial injection of tumor cells. Furthermore, we introduced a new model of metastatic pheochromocytoma resulting from tail vein injected mouse pheochromocytoma cells that reproducibly generated multiple tumors. This model may be utilized for studies on the in vivo molecular biology and therapeutic strategies for treatment of malignant pheochromocytoma. We established the Pheochromocytoma Research Support Organization (Pressor; www.pressor.org) that has currently about 140 members throughout the world. We also organized the 1st International Meeting on Pheochromocytoma that was held in Bethesda, October 20?23, 2005 under NIH sponsorship.

该股强调床边项目以及多学科和多机构协作。这些研究集中于三个目标：(1)开发和测试新的方法和标准，以经济有效地诊断和定位嗜铬细胞瘤；(2)开发更好的治疗恶性嗜铬细胞瘤的方法；(3)鉴定嗜铬细胞瘤发生的分子和遗传学机制以及疾病的临床表现。预计针对最后一个目标的研究将产生最深远的后果，导致诊断和治疗嗜铬细胞瘤的新策略，特别是转移疾病的诊断和治疗。 最近，我们描述了血浆中游离的甲肾上腺素浓度相对独立于肾功能，因此比测定去结合的甲肾上腺素更适合于诊断肾功能衰竭患者的嗜铬细胞瘤。我们还发现，血浆游离偏肾上腺素的测量不仅提供了有关嗜铬细胞瘤可能存在或不存在的信息，而且当存在肿瘤时，还可以帮助预测肿瘤的大小和位置。最近，我们引入了多巴胺的O-甲基化代谢物甲氧基酪胺，作为检测这些肿瘤的附加生化血液测试。目前，我们还试图确定在转移性嗜铬细胞瘤患者治疗前和治疗后测定血浆游离甲肾上腺素的诊断价值。 我们还进行了一项大型前瞻性研究，将6-[18F]-氟多胺PET扫描与[123I]-MIBG、Octreoscan和[18F]-氟脱氧葡萄糖PET扫描进行比较，以了解6-[18F]-氟多胺PET扫描是否可以被视为一线？影像方法在各种嗜铬细胞瘤的诊断中的应用，特别是在目前其他可用的成像方法无法定位该肿瘤的患者中。 转移抑制基因影响几种癌症的扩散，因此有望成为恶性嗜铬细胞瘤的预后标记物或治疗靶点。我们应用实时定量聚合酶链式反应对11个转移抑制基因进行了检测。这些基因参与了重要的肿瘤相关细胞事件的调控，如细胞生长调控和细胞凋亡(nm23-HI、TIMP-1、TIMP-2、TIMP-3、TIMP-4、TXNIP和CRSP-3)、细胞间通讯(BRSM-1)、侵袭(CRMP-1)和细胞黏附(E-Cad和Kiss1)。经过交叉验证，非线性规则在10个恶性样本中产生0个错误，在15个良性样本中产生3个错误，总体错误率为12%。这些结果表明，转移抑制基因的下调反映了恶性嗜铬细胞瘤的高度敏感性。我们还发现，与男性2肿瘤相比，VHL中许多过度表达的基因明显与VHL相关肿瘤发生过程中被激活的缺氧驱动的血管生成途径有关。这些基因包括葡萄糖转运蛋白(GLUT1)、血管内皮生长因子(VEGF)、胎盘生长因子、血管生成素2、Tie-1、以及血管内皮生长因子受体、VEGFR-2和Neuropilin-1。 转移性癌症的成功治疗有赖于其早期发现和定位。 尽管各种成像技术有了很大的进步，但由于当前解剖和功能成像方式的空间分辨率不够理想，小的转移灶往往无法被发现。这也适用于转移性癌症的动物模型。这些模型对于开发新的治疗方法和治疗方法至关重要。我们首次发现，使用肝胆管特异性对比剂的MicroCT可以显示0.35 mm的肝脏转移，并且最早可以在最初注射肿瘤细胞后4周发现。此外，我们介绍了一种新的转移性嗜铬细胞瘤模型，该模型是由尾静脉注射小鼠嗜铬细胞瘤细胞导致的，该细胞可复制产生多个肿瘤。该模型可用于恶性嗜铬细胞瘤体内分子生物学和治疗策略的研究。 我们建立了嗜铬细胞瘤研究支持组织(Pressor；www.pressor.org)，该组织目前在世界各地拥有约140名成员。我们还组织了首届嗜铬细胞瘤国际会议，会议由美国国立卫生研究院主办，于2005年10月20日至23日在贝塞斯达举行。