FH-deficient mouse models overexpressed hypoxia-inducible factor and developed potentially cancerous cysts.

Researchers found that fumarate hydratase (FH) inactivation leads to renal cysts and renal cell cancer (HLRCC) in mice models. FH inactivation is caused in humans by mutations in the krebs cycle enzyme FH tumor suppressor gene.

Kreb cycle mutations have previously been linked to overexpression of hypoxia-inducible factor (HIF) in HLRCC tumors.

To provide a model of HLRCC as well as to further examine the role of Krebs cycle dysfunction in cancer initiation and progression, Patrick J. Pollard, Ph.D. from the Molecular and Population Genetics Laboratory at the London Research Institute and colleagues created a kidney-specific Fh1-deficient mouse model.

The researchers observed that, like humans, the Fh1-deficient mice developed clonal and proliferative renal cysts that exhibited a characteristic overexpression of HIF. The animals eventually succumbed to renal failure. Additional studies went on to show that Fh1 inactivation in mouse embryonic stem cells leads to upregulated HIF.

Results from these studies demonstrate that inactivation of FH in the kidney causes activation of the hypoxia pathway and formation of numerous cysts. The researchers conclude that FH deficiency is a direct cause of the increased HIF expression observed in HLRCC tumors and that it is plausible that, in some situations, inactivation of FH initiates formation of simple cysts followed by more complex cysts and eventually carcinoma.

The paper will be published in the April issue of Cancer Cell.

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