Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, theseanalogs could be considered for the LHRH receptor-based treatment of uveal melanoma.
Highlights
Uveal melanoma is very rare, it is the most common primary intraocular malignancy in adults.Its incidence in the Western world seems to be relatively stable with about 7 new cases per year per 1 million individual
[6] Since both cutaneous melanoma and uveal melanoma have the same neuroectodermal origin, but the presence of luteinizing hormone-releasing hormone (LHRH) receptors has never been studied in uveal melanoma, we investigated the expression of mRNAs for LHRH-I ligand and for type I LHRH receptor in specimens of human uveal melanoma
Patients with uveal melanoma face a dismal prognosis as eventually about 45% of them die of metastasis, regardless of the fact that the tumor is most often diagnosed and locally cured before any signs of clinical disseminated disease appear
Summary
Uveal melanoma is very rare, it is the most common primary intraocular malignancy in adults. [1,2] Treatment by systemic or intra-hepatic chemotherapy or partial hepatectomy only rarely prolongs the survival [3], emphasizing the need to develop more efficacious therapies. Recent progress in our understanding of the molecular processes underlying uveal melanoma should enable us to advance the diagnosis, prognosis and treatment of this malignancy. The discovery of specific receptors for peptide hormones on cancer cells has led to the development of cytotoxic and radiolabeled hormone analogs that are useful for tumor localization and targeted therapy. Various preclinical studies have shown that chemotherapy based on cytotoxic peptide conjugates targeted to receptors on tumors can improve the effectiveness of treatment and reduce general side effects. [5] Recently, it has been shown that various cancer cell lines, including cutaneous melanoma, xenografted into nude mice, can be inhibited by the targeted cytotoxic LHRH analog AN-152 (AEZS-108). The presence and binding characteristics of LHRH receptor protein were examined
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