Expression of hypoxia inducible factor-1 alpha and 2 alpha in genetically distinct early renal cortical tumors

Purpose: The role of the HIF class of transcription factors has been implicated to be a critical step in clear cell kidney tumorigenesis. To assess if HIF over expression is a prominent feature of other renal cell carcinoma histological subtypes we characterized the expression of HIF-1 alpha and HIF-2 alpha in genetically distinct early renal cortical tumors. Materials and Methods: Nascent renal tumors of distinct histology from patients with a hereditary renal tumor syndrome were characterized for HIF expression using high amplification immunohistochemistry. In addition, indirect immunofluorescence and confocal microscopy were used for subcellular localization of HIF-1 alpha and 2 alpha in clear cell renal carcinoma cells. Results: Clear cell RCC tumors from patients with von Hippel-Lindau disease strongly expressed HIF-1 alpha and HIF-2 alpha (10 of 12 and 12 of 12 tumors, respectively). Chromophobe tumors from patients with Birt-Hogg-Dube syndrome expressed predominantly HIF-2 alpha with weaker HIF-1 alpha expression (12 of 12 and 6 of 12 tumors, respectively). Consistent HIF-1 alpha expression was not seen in type I papillary tumors from patients with hereditary papillary renal carcinoma (3 of 12 tumors). However, half of the type I papillary tumors (6 of 12) expressed HIF-2 alpha. Conclusions: Differential patterns of HIF-1 alpha and HIF-2 alpha protein over expression were found among the 3 human kidney tumor types associated with multifocal hereditary kidney tumor syndromes. Consistent, simultaneous over expression of HIF-1 alpha and HIF-2 alpha appears to be specific to VHL negative clear cell renal cell carcinoma. Consistent HIF-2 alpha expression was found in all 3 renal cortical tumor subtypes, suggesting a pivotal role in renal cortical tumorigenesis. Differential function of HIF-1 alpha vs HIF-2 alpha is suggested by the distinct subcellular localization pattern of HIF-1 alpha and HIF-2 alpha in clear cell renal carcinoma cells.

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