Expression of Phospho–Akt and Human Uveal Melanoma Progression in an Animal Model

Abstract

Abstract: : Purpose: Avoiding apoptosis is essential to malignant cell survival. Akt is an anti–apoptotic serine/threonine kinase that regulates cell survival by acting as a downstream target in the PI3 kinase pathway. In addition to its anti–apoptotic role Akt also acts to block anti–proliferative signaling, promote cell growth and mediate angiogenesis. Previous studies have used immunohistochemistry to show a correlation between positive staining for phoshpo–Akt (the active form of Akt) and tumor progression or poorer prognosis in various cancers. The purpose of this study is to characterize the immunohistochemical expression of phospho–Akt in different stages of human uveal melanoma progression in a rabbit animal model. Methods: Twenty–eight New Zealand albino rabbits were inoculated with the 92.1 human uveal melanoma cell line in the suprachoroidal space and immunossupressed with cyclosporine–A throughout a 10–week experiment. Animals were submitted to fundoscopy weekly, and at least 1 animal was autopsied per week during the experiment. Eye, lungs and liver were excised and submitted to histopathology and immunohistochemistry for phospho–Akt. Results:Histopathology revealed that each of the 28 rabbits in the experiment developed ocular tumors. Lung metastases were found in each of the 24 rabbits that were autopsied from week 4 and after, and liver metastases were found in 3 rabbits autopsied in weeks 8 and 9. In terms of phospho–Akt expression, of the 19 interpretable eye samples, 13 (68.4%) were found to be positive and expression was first detected on week 4. After week 4, 13 out of 15 eye samples (86.7%) were found to be positive; of the 23 interpretable lung metastasis cases, only 2 (8.7%) stained positively; and of the 3 liver metastasis cases all (100%) were negative. Conclusions: The majority of eye tumors expressed phospho–Akt, however expression was low in lung metastases and negative in liver metastases. These findings suggest that phospho–Akt plays a role in protection from apoptosis until neoplastic cells escape from the intraocular tumor. This study shows that phospho–Akt should be investigated as a potential target for treatment of uveal melanoma.

Keywords: melanoma • tumors