Abstract
Purpose: :
Despite the high accuracy of clinical diagnosis of Uveal Melanoma (UM) and advances in local treatment, approximately 40% of UM patients develop metastasis within ten years of initial diagnosis. Metastasis Suppressor Genes (MSGs) have recently emerged as putative therapeutic targets in numerous malignancies. KISS1 is one such MSG that is believed to be involved in tumor dormancy since its reduced expression has correlated with high metastatic potential in various cancers. The purpose of this study was to validate an established UM rabbit animal model as a baseline for testing KISS1-altering drugs, such as imatinib mesylate
Methods: :
As previously described, fourteen immunosuppressed albino rabbits were injected with the 92.1 UM cell line in the suprachoroidal space of the right eye. Previously, this cell line was shown to express KISS1. Primary tumors from all rabbits and five lung metastases were immunostained with a KISS1 monoclonal antibody using the Ventana BenchMark fully automated machine. The immunostaining was evaluated based on the extent and intensity of staining by double blind analysis. In addition, circulating malignant cells obtained from peripheral blood of the rabbits were immunostained for KISS1 using immunofluorescence. Moreover, quantitative real-time PCR was used to determine mRNA transcript levels of KISS1 of the 92.1 UM cell line before and after treated with imatinib mesylate
Results: :
Immunostaining was positive and cytoplasmic in 94% of the primary tumors (13 out of 14). Furthermore, all metastatic lesions were negative for KISS1 expression. Circulating malignant cells obtained from the blood were positive for KISS1. Quantitative real-time PCR analysis showed upregulation of KISS1 mRNA levels in UM melanoma cell lines treated with imatinib mesylate
Conclusions: :
The presence of KISS1 in both primary tumors and circulating malignant cells coupled with the absence in metastatic lesions suggests a prominent role for KISS1 as a metastasis suppressor of uveal melanoma. Furthermore, the observation that imatinib mesylate increases KISS1 expression in uveal melanoma cell lines suggests that clinical trials investigating the use of imatinib mesylate in preventing metastic development in this particular tumor are warranted.
Keywords: melanoma • immunohistochemistry • tumors