| First Author | Roswall P | Year | 2006 |
| Journal | PhD Thesis - Uppsala University | Mgi Jnum | J:267412 |
| Mgi Id | MGI:6267354 | Citation | Roswall P (2006) Taking pressure of anaplastic thyroid carcinoma: Molecular studies of apoptosis and interstitial hypertension (Doctoral dissertation). PhD Thesis - Uppsala University |
| abstractText | Rosewall, P. 2006. Taking Pressure of Anaplastic Thyroid Carcinoma. Molecular Studies of Apoptosis and Interstitial Hypertension. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 143. 50 pp. Uppsala. ISBN 91-554-6538-12. Molecular mechanisms in the development and progression of thyroid carcinomas are still not fully understood. In the present thesis the highly malignant anaplastic thyroid carcinoma (ATC) was used to study regulation of apoptosis and tumor interstitial fluid pressure (IFP). Addition of a natural estrogen metabolite, 2-Methoxyestradiol (2-ME) induced a G2/M cell cycle arrest and apoptosis in five out of six human ATC cell lines. Treatment with 2-ME induced DNA-fragmentation as well as activation of caspase-3. Inhibitors of JNK and p38 MAPKs activity decreased the effect of 2-ME suggesting involvement in the induction of apoptosis. Solid tumors have an elevated IFP. High IFP forms or reflects a barrier for exchange of molecules between microvessels and surrounding tissue. The mechanisms for the generation of the high IFP were investigated using a specific TGF-beta inhibitor in an ATC model in athymic mice. Tumor IFT was lowered in TGF-beta inhibitor-treated compared to control mice. Affymetrix microarray analysis showed a decreased expression of macrophage-associated genes in treated tumors. Furthermore, the number and activity of tumor-associated macrophages was reduced after TGF-beta inhibition. A decreased protein leakage together with an increased coverage of alpha-smooth-muscle actin (SMA)-expressing cells indicated vessel normalization. An adjuvant treatment with the TGF-beta inhibitor resulted in an increased treatment efficacy of doxorubicin. Thus, TGF-beta inhibitor-treatment suggests improved microvessel function which results in a lowering of tumor IFP and increased tumor drug uptake. To create a model for specific inactivation of genes in the thyroid, a transgenic mouse with a thyrocyte-specific expression of Cre recombinase was generated. The thryroglobulin promoter together with an inducible Cre recombinase (creER<T2>) was used. Two transgenic founder lines were identified expression cre mRNA solely in the thyroid. Functional activity of the CreER<T2> protein was demonstrated by using a ROSA26-LacZ reporter mouse. |
