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Carcinogenesis Advance Access published online on November 24, 2006
Carcinogenesis, doi:10.1093/carcin/bgl231
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Published by Oxford University Press 2006.
Received August 24, 2006
Revised November 6, 2006
Accepted November 17, 2006

CANCER BIOLOGY

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

Caroline S. Kim 1, Hao Ying 1, Mark C. Willingham 2, and Sheue-yann Cheng 1 *

1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
2 Department of Pathology, Wake Forest University, Winston-Salem, NC

* To whom correspondence should be addressed.
Sheue-yann Cheng, E-mail: chengs{at}mail.nih.gov


  Abstract

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 (TR{beta}PV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TR{beta}PV mice with mice lacking PTTG (PTTG-/- mice). The thyroids of TR{beta}PV/PV PTTG-/- were significantly smaller than TR{beta}PV/PV mice. Ki-67 staining showed a decrease in thyroid proliferation in TR{beta}PV/PV PTTG-/- mice. Our evaluation of the Rb-E2F pathway, a central mediator of cell growth, found that TR{beta}PV/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 TR{beta}PV/PV and TR{beta}PV/PV PTTG-/- mice which indicates that PTTG removal does not prevent the initiation of FTC. However, TR{beta}PV/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 TR{beta}PV/PV PTTG-/- versus TR{beta}PV/PV thyroids. Given the decreased vascular invasion in the PTTG knock-out mice, we studied genes involved in angiogenesis. Real-time RT-PCR showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor (VEGF). 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.

Keywords: thyroid cancer; Pituitary tumor transforming gene; thyroid hormone receptor mutants; mouse model; carcinogenesis.
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