OR16-5 Development of a Series of Knockout Mice to Model the Stages of Follicular Thyroid Cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 206 (Moscone Center)
Daphne R Pringle1, Vasyl Vasko2, Lianbo Yu1, Albert F Parlow3, Motoyasu Saji4, Matthew David Ringel5, Krista M.D. La Perle1 and Lawrence Steven Kirschner*5
1The Ohio State University, 2USUHS, Bethesda, MD, 3Harbor - UCLA REI, Torrance, CA, 4The Ohio State Univ, Columbus, OH, 5Ohio State Univ, Columbus, OH
Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising.  In most patients, this cancer is easily treated and most patients have an excellent prognosis; however, there remains a subset of these patients whose disease proves incurable by standard therapies.  Well-differentiated thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC).  Although FTC is less common, patients with this condition have an  increased incidence of metastatic disease and have a poorer prognosis than those with PTC. Thus, it remains important to characterize molecular changes which lead to aggressive and metastatic FTC.  Our lab has recently demonstrated that thyroid specific ablation of the Carney Complex gene, Prkar1a, leads to hyperthyroidism and FTC in mice.   However, while these animals develop cancer, none developed distant metastases.  In order to better study the molecular basis for aggressive FTC formation, we have generated a new mouse model harboring thyroid specific deletion of both Prkar1a and Pten, DRP-TpoKO mice (double R1a Pten knockout).  Longitudinal analysis of these mice by thyroid ultrasonography demonstrates marked enlargement of the glands as early as two months which progresses throughout the animal’s life and leads to tracheal compression necessitating euthanasia. DRP-TpoKO mice are also hyperthyroid as manifest by elevated hormone levels and decreased weight compared to control littermates. Histopathologically, 100% of DRP-TpoKO mice develop FTC at six months of age.  Additionally, ~30% of these animals develop FTC derived lung metastases, suggesting that two genetic hits are required for the development of metastatic FTC.  Comparison of these tumors to human FTC demonstrates significant similarities, and, interestingly, ~60% of these cancers show areas of squamous metaplasia of uncertain significance. Analysis of gene expression indicates alteration of multiple developmental and differentiation pathways in these cancers, suggesting the molecular changes driving cancer formation are also leading to squamous metaplasia. The combination of Pten KO (follicular adenomas), Prkar1a KO (locally invasive FTC) and the double KO’s (metastatic FTC) provide an important and reliable new tool for the study of molecular mechanisms which drive the formation of distant metastases in FTC and may lead directly to the development and testing of novel FTC therapies.

Nothing to Disclose: DRP, VV, LY, AFP, MS, MDR, KMDL, LSK

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported in part by NIH grants: CA112268 (to LSK), PO1CA124570 (DRP, LY, KMDL, MDR, LSK) and CA16058 (to the OSU Comprehensive Cancer Center).  DRP was supported by the 2011 Jeffery J. Seilhamer Memorial Fellowship and the 2012 Pelotonia Graduate Fellowship.