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Cancer

 

Iodine and Liver Cancer

 

Faivre

 

Sodium Iodide Symporter Is Expressed at the Preneoplastic Stages of Liver Carcinogenesis and in Human Cholangiocarcinoma.

Liu B, Herve J, Bioulac-Sage P, Valogne Y, Roux J, Yilmaz F, Boisgard R, Guettier C, Cales P, Tavitian B, Samuel D, Clerc J, Brechot C, Faivre J.

Gastroenterology. 2007 Jan 26; [Epub ahead of print]

[abstract only]

 

"BACKGROUND & AIMS: The ability of thyroid cells to take up iodide, which enables (131)I radiotherapy for thyroid cancer, is due to the expression of the sodium iodide symporter at their plasma membrane. Expression of this symporter has been found in some nonthyroid cancers. However, it is mostly accumulated in the cytoplasm, and its functionality has not been demonstrated. We have investigated sodium iodide symporter expression and functionality in human liver cancer, and in a diethylnitrosamine induced Wistar rat model of primary liver cancer at different stages of carcinogenesis.

 

METHODS: Sodium iodide symporter mRNA and protein were studied in tissues from patients with hepatocellular- or cholangio-carcinomas using reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemistry. We studied the dynamics of hepatic iodine uptake in the animal model using nuclear imaging.

 

RESULTS: Sodium iodide symporter expression showed up in all 20 cholangiocarcinomas, but in only 2 of the 26 hepatocellular carcinomas, investigated. It was also found in normal bile duct cells and in the ductular reaction present in cirrhotic tissues. It was located at the plasma membrane in 10 of 20 cholangiocarcinoma. In rat liver cancer, a functional sodium iodide symporter expression was triggered as from the early preneoplastic steps, and was amplified during clonal tumor cell expansion, allowing complete tumor suppression after (131)I radiotherapy.

 

CONCLUSIONS: A significant proportion of human cholangiocarcinomas expresses membrane sodium iodide symporter, which may permit radioiodine therapy. Our data also suggest that (131)I acts on a crucial target for liver cancer development."

 

 

Long-term radioiodine retention and regression of liver cancer after sodium iodide symporter gene transfer in wistar rats.

Faivre J, Clerc J, Gerolami R, Herve J, Longuet M, Liu B, Roux J, Moal F, Perricaudet M, Brechot C.

Cancer Res. 2004 Nov 1;64(21):8045-51. Erratum in: Cancer Res. 2004 Dec 15;64(24):9230.

 

"Radioiodine therapy of nonthyroid cancers after sodium iodide symporter (NIS) gene delivery has been proposed as a potential application of gene therapy. However, it seems to be precluded by the rapid efflux of taken up iodine from most transduced xenografted tumors. We present an in vivo kinetic study of NIS-related hepatic iodine uptake in an aggressive model of hepatocarcinoma induced by diethylnitrosamine in immunocompetent Wistar rats. We followed the whole-body iodine distribution by repeated imaging of live animals. We constructed a rat NIS (rNIS) adenoviral vector, Ad-CMV-rNIS, using the cytomegalovirus (CMV) as a promoter. Injected in the portal vein in 5 healthy and 25 hepatocarcinoma-bearing rats and liver tumors in 9 hepatocarcinoma-bearing rats, Ad-CMV-rNIS drove expression of a functional NIS protein by hepatocytes and allowed marked (from 20 to 30% of the injected dose) and sustained (>11 days) iodine uptake. This contrasts with the massive iodine efflux found in vitro in human hepatic tumor cell lines. In vivo specific inhibition of NIS by sodium perchlorate led to a rapid iodine efflux from the liver, indicating that the sustained uptake was not attributable to an active retention mechanism but to permanent recycling of the effluent radioiodine via the high hepatic blood flow. Radioiodine therapy after Ad-CMV-rNIS administration achieved a strong inhibition of tumor growth, the complete regression of small nodules, and prolonged survival of hepatocarcinoma-bearing rats. This demonstrates for the first time the efficacy of NIS-based radiotherapy in a relevant preclinical model of nonthyroid human carcinogenesis."

 
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