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Carcinogenesis Advance Access originally published online on November 24, 2006
Carcinogenesis 2007 28(5):932-939; doi:10.1093/carcin/bgl231
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Published by Oxford University Press 2006.

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

Caroline S. Kim, Hao Ying, Mark C. Willingham1 and Sheue-yann Cheng*

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, MD 20892-4264, USA
1 Department of Pathology, Wake Forest University, Winston-Salem, NC 27157-3001, USA

* To whom correspondence should be addressed. Tel: +301 496 4280; Fax: +301 402 8262; Email: chengs{at}mail.nih.gov

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 (TRßPV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TRßPV mice with mice lacking PTTG (PTTG–/– mice). The thyroids of TRßPV/PV PTTG–/– mice were significantly smaller than TRßPV/PV mice. Ki-67 staining showed a decrease in thyroid proliferation in TRßPV/PV PTTG–/– mice. Our evaluation of the Rb–E2F pathway, a central mediator of cell growth, found that TRßPV/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 TRßPV/PV and TRßPV/PV PTTG–/– mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRßPV/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 TRßPV/PV PTTG–/– versus TRßPV/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.

Abbreviations: FGF, fibroblast growth factor; FTC, follicular thyroid cancer; PTTG, pituitary tumor-transforming gene; PBS, phosphate-buffered saline; RTH, resistance to thyroid hormone; TSH, thyroid-stimulating hormone; VEGF, vascular endothelial growth factor

Received August 24, 2006; revised November 6, 2006; accepted November 17, 2006.


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