Diagnosis, Pathophysiology And Molecular Biology Of Pheo

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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.