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Mouse Knockout Resembles Human Renal Cell Cancer

Date:
April 10, 2007
Source:
Cell Press
Summary:
A new mouse model is providing valuable insight into the biochemical pathways that are associated with development of renal cysts and renal cell cancer. The research, published in the April issue of the journal Cancer Cell, published by Cell Press, provides new information about the relationship between hypoxia and cancer progression. In addition, it is likely that this mouse model may prove to be a useful tool for testing therapeutic strategies for renal cell cancer.

A new mouse model is providing valuable insight into the biochemical pathways that are associated with development of renal cysts and renal cell cancer. The research, published in the April issue of the journal Cancer Cell, published by Cell Press, provides new information about the relationship between hypoxia and cancer progression. In addition, it is likely that this mouse model may prove to be a useful tool for testing therapeutic strategies for renal cell cancer.

Mutations in the Krebs cycle enzyme fumarate hydratase (FH) tumor suppressor gene are present in individuals with renal cysts and renal cell cancer (HLRCC). These mutations are also linked to overexpression of hypoxia-inducible factor (HIF), a transcription factor that is activated when cells are exposed to an environment that is deficient in oxygen. In order to provide a model of HLRCC as well as to further examine the role of Krebs cycle dysfunction in cancer initiation and progression, Dr. Patrick J. Pollard 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. The researchers propose that activation of the hypoxia pathway is likely to be the cause of the cysts in the mice and that if the cysts had not caused renal failure, progression to malignancy may have occurred.

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. "Our mouse model advances the understanding of biochemical pathways linking mitochondrial dysfunction and tumorigenesis and will allow testing of potential therapies for renal neoplasms," says Dr. Pollard.

Pollard et al.: "Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway." Publishing in Cancer Cell 11, 311--319, April 2007. DOI 10.1016/j.ccr.2007.02.005


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The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


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Cell Press. "Mouse Knockout Resembles Human Renal Cell Cancer." ScienceDaily. ScienceDaily, 10 April 2007. <www.sciencedaily.com/releases/2007/04/070409121654.htm>.
Cell Press. (2007, April 10). Mouse Knockout Resembles Human Renal Cell Cancer. ScienceDaily. Retrieved September 16, 2014 from www.sciencedaily.com/releases/2007/04/070409121654.htm
Cell Press. "Mouse Knockout Resembles Human Renal Cell Cancer." ScienceDaily. www.sciencedaily.com/releases/2007/04/070409121654.htm (accessed September 16, 2014).

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