Phospho–Akt in uveal melanoma: A possible link between IGF–1R and COX–2

Abstract

Abstract: : Purpose: Insulin–like growth factor 1 (IGF–1R) and cyclooxygenase–2 (COX–2) have each been associated with poor prognosis in uveal melanoma. Studies in other human malignancies, such as pancreatic cancer, have shown COX–2 inhibitors to reduce IGF–1R expression. Phospho–Akt (p–Akt), the active form of the anti–apoptotic protein Akt, may serve as a link between COX–2 and IGF–1R. This could explain why COX–2 inhibitors have been shown to have effects in both COX–2 positive and negative tumors. The aim of this study is to investigate the expression of p–Akt in uveal melanoma and its possible relationship to the expression of IGF–1R and COX–2. Methods: Thirty–four cases of uveal melanoma were obtained from the Henry C. Witelson Eye Pathology Laboratory, McGill University, Canada. The formalin–fixed, paraffin–embedded specimens were immunostained with antibodies against IGF–1R, COX–2 and p–Akt. All immunostains were classified as negative or positive, if any cells displayed distinct immunostaining, irrespective of staining intensity. IGF–1R positive cases were further sub–classified semi–quantitatively as low (L) or high (H). Results: Thirty–two of 34 cases (94%) were classified as IGF–1R positive; 15 H and 17 L. Twenty–two of 34 cases (65%) were classified as COX–2 positive. Nineteen of 34 cases (56%) were classified as p–Akt positive. Of the 19 p–Akt positive cases, 19 (100%) were IGF–1R positive and 12 (63%) were COX–2 positive. Conclusions: To the best of our knowledge this is the first study to show p–Akt expression in uveal melanoma, with approximately half of the cases showing p–Akt positivity. P–Akt expression represents an activated pathway whereas IGF–1R expression, present to different degrees in the majority of uveal melanoma cases, only represents the presence of the receptor. P–Akt was found in uveal melanoma with and without COX–2 expression. Further studies are warranted to investigate the effects of COX–2 inhibitors on p–Akt in uveal melanoma cells with and without COX–2 expression.

Keywords: melanoma • immunohistochemistry • tumors