Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

Abstract

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT -PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours.

Expression and prognostic relevance of endothelin-B receptor in vulvar cancer

“…Prognostic relevance of ET B R has been described in uveal melanoma where reduced ET B R expression correlated with death from metastatic disease (17) Our results indicate a potential role of ET B R in cancer progression with overexpression in patients with disease progression and decreased expression with longer relapsefree survival. The significantly worse outcome in stage pT1 and pT2 patients with ET B R overexpressing tumours suggests that analysing ET B R expression in vulvar cancer at the time of diagnosis might help to identify patients with an unfavourable prognosis.…”

“…With respect to ET B R expression in human malignancies contradictory data have been reported. Whereas ET B R seems to function as a possible survival factor in oligodendrogliomas (16), decreased ET B R expression was associated with poorer clinical outcome (17)(18)(19) in other cancer entities (e.g., malignant melanoma or prostate cancer).…”

Proteomics in uveal melanoma research: opportunities and challenges in biomarker discovery

“…Metalloproteinases: MMP-2, 9 Epithelioid cell type/metastasis risk [123][124][125][126][127] TIMP-2/3 MMPs inhibitors Loss of expression [125,128,129] VEGF Synthesis and secretion by uveal melanoma cells/present in aqueous humor and serum [130][131][132] Membrane receptors EGF-R Metastasis risk [133,134] Endothelin receptor B Downregulation related to metastasis risk [135] HGF-R Cell invasion-related [136,137] IGF-1R Cell invasion-related [137][138][139] HMB-45 (gp100) Melanoma-specific silver/tumor rejection [140] Somatostatin receptor Better prognosis [141] Other 5-S-cysteinyldopa Present in intraocular fluids and serum [142,143] COX-2 Poor prognosis [144] Vimentin and cytokeratins 8/18 (interconverted phenotype) Cell invasion related [145,146] affected involving the lung, bone and skin [5]. In those cases, systemic chemotherapy is applied with very disappointing results [6].…”

Gene expression profiling identifies tumour markers potentially playing a role in uveal melanoma development

“…ET2 can act as a mitogen in many cancer systems, and ETs in general stimulate melanocyte proliferation and differentiation (Reid et al, 1996). Recently, Smith et al (2002) associated decreased ENRB expression in large primary uveal melanoma with early clinical metastasis and short survival. These results, together with the high expression levels of ET2 in our tumour samples, might support investigation of the expression of endothelin receptors and their ligands in uveal melanoma.…”