Immune–Expression of Hypoxia–Inducible Factor –1 in an Animal Model of Uveal Melanoma

Abstract

Abstract: : Purpose: Hypoxia inducible factor–1α (Hif–1α) is an inducible transcription factor induced in response to hypoxia. It plays a key role in the induction of genes required for the angiogenic process and has been shown to enhance tumor survival through inhibition of apoptosis. Furthermore, it may regulate the expression of genes involved in invasion and has been implicated in the pathological progression of various malignancies including bladder, breast, colon and lung cancer. This study examined the expression of Hif–1α in primary uveal melanoma tumors and their corresponding lung metastases over the course of 5 weeks in an animal model of uveal melanoma. Methods: The immune–expression of Hif–1α was investigated in nine specimens of ocular tumors and lung metastases collected from immunosuppressed rabbits in an animal model of uveal melanoma. The rabbits used in this study were sacrificed between four and nine weeks after inoculation of uveal melanoma cells. Immunohistochemistry for Hif–1α expression was performed using a monoclonal antibody (clone H1α67) on formalin–fixed, paraffin–embedded sections. Three observers examined the slides and ranked the immunohistochemical staining in four categories: negative, low, medium, or high. Results: All 9 of the ocular tissue sections were positive for expression of Hif–1α. Seven out of these 9 samples showed high levels of expression while the remaining 2 showed low levels of expression. Of the 9 lung metastases, 1 was negative for expression of Hif–1α, 3 showed low levels of staining, 4 showed medium levels of staining and 1 showed high levels of staining. The intensity of staining in the metastasis did not correlate with staining intensity in the primary tumor. Similarly, the intensity of staining did not increase over the course of the disease progression in this study. Conclusions: Expression of Hif–1α was found within all primary tumors that had disseminated and metastasized to the lung. However, the immunoexpression of Hif–1α in the lung metastases suggests that the melanoma cells continue to exhibit a high metabolic rate, perhaps in preparation for further haematogenous dissemination.

Keywords: immunohistochemistry • melanoma