title: Endogenous expression of the sodium iodide symporter mediates uptake of iodide in murine models of colorectal carcinoma.
abstract: The sodium iodide symporter (NIS) mediates iodide uptake into the thyroid. Because of this mechanism, differentiated thyroid cancer is susceptible for radioiodine therapy. Functional NIS expression in extrathyroidal tumors has been reported mainly in breast cancer. We screened colorectal tumors for NIS expression and investigated the mechanisms regulating NIS activity. Cell lines were screened for iodide uptake in vitro and NIS expression was evaluated by real-time RT-PCR, immunocytochemistry and immunoblotting. Iodide and pertechnetate uptake were evaluated in allograft tumors by biodistribution studies and scintigraphy. Tumors of transgenic mouse models for colorectal cancer harboring mutations in the oncogenes KRAS, beta-catenin or the tumor-suppressor gene adenomatous-polyposis coli (APC) were screened for NIS expression by RT-PCR. In vitro, functional NIS activity was detected in murine CMT93 rectal carcinoma cells and NIS expression was verified on mRNA and protein level. Inhibition of tyrosine kinases increased iodide uptake. Inhibition of tyrosine phosphatases decreased iodide uptake. In vivo, functional NIS expression was preserved in CMT93 tumors and tumor uptake could be enhanced by treatment of mice with tyrosine kinase inhibitors. In transgenic murine models of colorectal cancer, 14% of endogenous tumors expressed elevated levels of NIS mRNA. We conclude that NIS is functionally expressed in a subset of murine colorectal tumors and its activity is regulated by tyrosine phosphorylation. Therefore, with specific tyrosine kinase inhibition, these tumors might be susceptible for radioiodine treatment. Further studies are justified to identify the specific pathways regulating NIS activity and to transfer these findings to human cell lines and tissues.
authors: Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universitaet Muenchen, Ismaninger Str. 22, Muenchen 81675, Germany.
authors: Florian C
authors: FC
authors: Gaertner
authors: Franziska
authors: F
authors: Rohde
authors: Jan
authors: J
authors: Mueller
authors: Birgit
authors: B
authors: Blechert
authors: Klaus-Peter
authors: KP
authors: Janssen
authors: Markus
authors: M
authors: Essler
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017491:Genes, APC / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D007454:Iodides / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099209:Sodium-Iodide Symporters
chemical_list: D007454:Iodides; D007457:Iodine Radioisotopes; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D027981:Symporters; D051176:beta Catenin; D000099209:Sodium-Iodide Symporters; C495971:Hras protein, mouse