Journal Article

The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer

Caroline S. Kim, Hao Ying, Mark C. Willingham and Sheue-yann Cheng

in Carcinogenesis

Volume 28, issue 5, pages 932-939
Published in print May 2007 | ISSN: 0143-3334
Published online November 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl231
The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer

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Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular thyroid cancer (FTC) with distant metastasis (TRβPV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TRβPV mice with mice lacking PTTG (PTTG−/− mice). The thyroids of TRβPV/PV PTTG−/− mice were significantly smaller than TRβPV/PV mice. Ki-67 staining showed a decrease in thyroid proliferation in TRβPV/PV PTTG−/− mice. Our evaluation of the Rb–E2F pathway, a central mediator of cell growth, found that TRβPV/PV PTTG−/− mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRβPV/PV and TRβPV/PV PTTG−/− mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRβPV/PV PTTG−/− mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease in vessel density in TRβPV/PV PTTG−/− versus TRβPV/PV thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genes involved in angiogenesis. Real-time reverse transcription–polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.

Journal Article.  6048 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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