Downregulation of metastasis suppressor genes in malignant pheochromocytoma

Abstract

There is no reliable method currently available to predict malignant potential of pheochromocytoma based on conventional histology or genetic, molecular or immunohistochemical markers. Metastasis suppressor genes affect the spread of several cancers and, therefore, may provide promise as prognostic markers or therapeutic targets for malignant pheochromocytoma. We hypothesized that the downregulation of metastasis suppressor genes in malignant pheochromocytoma may play a role in malignant behavior. We applied quantitative real-time polymerase chain reaction (QRT-PCR) to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancerrelated cellular events, such as cell growth regulation and apoptosis (nm23-H1, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRMS-1), invasion (CRMP-1) and cell adhesion (E-Cad and KiSS1). The study included 15 benign and 10 malignant pheochromocytomas. Six metastasis suppressor genes (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3 and E-Cad) were downregulated significantly in malignant compared to benign pheochromocytoma (p < 0.05, Mann-Whitney U-test). We applied a non-linear rule using median malignant value (MMV) as a threshold to use metastasis suppressor genes to distinguish malignant from benign samples. After cross-validation, the non-linear rule produced no errors in 10 malignant samples and 3 errors in the 15 benign samples, with an overall error rate of 12%. These results suggest that downregulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. Thus, we conclude that altered function of these metastasis suppressor gene pathways may play an important role in the malignant behavior of pheochromocytoma. Published 2004 Wiley-Liss, Inc. † Key words: pheochromocytoma; metastasis; real-time PCR A total of 13-36% of patients with sporadic pheochromocytoma develop malignant disease with an overall 5-year survival rate of 50%. [1][2][3] Because there are no reliable histological criteria for malignancy, malignant pheochromocytoma can only be diagnosed by the presence of metastatic lesions at sites where chromaffin tissue is normally absent. 4 The most common sites for metastasis are lymph nodes, bones, lungs and liver. 2 Currently, there is no cure for malignant pheochromocytoma.The lack of histological criteria for malignancy has initiated many studies to find a marker for metastatic behavior of pheochromocytoma. Markers such as p53, MIB-1/Ki-67 and telomerase, alone or in combination, have been tested for their usefulness, with some showing promising results. 5-7 Staining MIB-1 was higher in approximately 50% of malignant pheochromocytomas and was negative in all benign tumors. 5,8 Boltze et al. 7 demonstrated recently that the expression of hTERT is upregulated in 100% of malignant tumors vs. 7% of benign tumors. This gene may be a promising marker to identify malignant pheochromocytoma.Recent studies have demonstrated that altered cell cycle pathways are import...

Kisspeptin is released from human prostate cancer cell lines but plasma kisspeptin is not elevated in patients with prostate cancer

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High frequency of SNAIL-expressing cells confirms and predicts metastatic potential of phaeochromocytoma

“…Ohta et al (2005) has investigated, with real-time quantitative PCR, the RNA expression of 11 genes in phaeochromocytoma. Six of these were downregulated in malignant versus benign tumours.…”

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