Introduction Uveal melanoma (UM) cells and neurohormone-producing cells both originate from the neural crest. Somatostatin receptors subtype 2 (SSTR2) are overexpressed in several tumors, often from neuroendocrine origin, and synthetic antagonists like octreotide and octreotate are being used as diagnostic or therapeutic agents. We investigated the SSTR2 expression in UM, and determined whether this expression was related to prognosis of the disease. Materials and methods UM cell lines and fresh primary UM samples were tested for SSTR2 expression by autoradiography (AR) using 125I-Tyr3-octreotate. Furthermore, UM cell lines were analyzed for SSTR2 mRNA expression with quantitative real-time RT-PCR. Results Using AR, cell-surface SSTR2 expression was demonstrated in two UM metastatic cell lines, but no expression was detected in three cell lines derived from primary UM. However, all primary and metastatic UM cell lines showed mRNA expression levels for SSTR2 using quantitative real-time RT-PCR. Only three of 14 primary UM demonstrated moderate SSTR2 expression, and this expression was not significantly associated with tumor-free survival or any tested prognostic factor. Conclusions Based on the rare and low expression of SSTR2 found in primary UM specimens and in UM cell lines, we conclude that SSTR2 is not widely expressed in UM. Furthermore, SSTR2 expression was not associated with tumor-free survival and prognostic factors. Therefore SSTR2 is not suited as prognostic marker or therapeutic target in UM.
Purpose Uveal melanoma patients that present a tumor with monosomy 3 have a high propensity to develop metastases. Based on the two‐hit hypothesis, one might expect that the remaining copy of chromosome 3 contains a genetically‐modified gene and that loss of this gene is responsible for malignant progression. Identification of the gene and the genetic or epigenetic mechanisms that influence genes on chromosome 3 will enlighten the pathway(s) that determine uveal melanoma progression. In addition, studying epigenetics may result in useful molecular markers: whereas analysis of monosomy 3 is useful in primary tumors, it is useless in the detection of spreading tumor cells in the blood. We propose that a molecular marker in the form of a (tumor specific) genetic or epigenetic modification will be more helpful in this respect. Methods We have analyzed genes on chromosome 3 for epigenetic regulation that may suffice in non‐invasive testing for spreading tumor cells. Results We have identified RASSF1a methylation as a predictor of metastasis in uveal melanoma based on analysis of uveal melanoma tissues. In order to detect disseminating tumor cells in the bloodstream of uveal melanoma patients we have developed a very sensitive assay for methylation of RASSF1a. The detection limit of RASSF1a methylation exceeds 1/10,000 and in combination with isolation cell‐free DNA we are able to detect tumor DNA in the background of a vast excess of normal blood cells. With this assay we will test patient blood and validate the prognostic and diagnostic value of this marker. Conclusion With this assay we will test patient blood and validate the prognostic and diagnostic value of this marker.
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