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Interference with TGF-β1 and -β3 in Tumor Stroma Lowers Tumor Interstitial Fluid Pressure Independently of Growth in Experimental Carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2002 (English)In: International Journal of Cancer, ISSN 0020-7136, Vol. 102, no 5, 453-462 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 102, no 5, 453-462 p.
Identifiers
URN: urn:nbn:se:uu:diva-94344OAI: oai:DiVA.org:uu-94344DiVA: diva2:168165
Available from: 2006-04-28 Created: 2006-04-28 Last updated: 2017-11-10Bibliographically approved
In thesis
1. Taking Pressure of Anaplastic Thyroid Carcinoma: Molecular Studies of Apoptosis and Interstitial Hypertension
Open this publication in new window or tab >>Taking Pressure of Anaplastic Thyroid Carcinoma: Molecular Studies of Apoptosis and Interstitial Hypertension
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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-β inhibitor in an ATC model in athymic mice. Tumor IFP was lowered in TGF-β 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-β inhibition. A decreased protein leakage together with an increased coverage of α-smooth-muscle actin (SMA)-expressing cells indicated vessel normalization. An adjuvant treatment with the TGF-β inhibitor resulted in an increased treatment efficacy of doxorubicin. Thus, TGF-β 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 thyroglobulin promoter together with an inducible Cre recombinase (creERT2) was used. Two transgenic founder lines were identified expressing cre mRNA solely in the thyroid. Functional activity of the CreERT2 protein was demonstrated by using a ROSA26-LacZ reporter mouse.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 143
Keyword
Medicine, Anaplastic thyroid carcinoma, Apoptosis, Cre recombinase, 2-Methoxyestradiol, Transforming growth factor-β, Transgenic mouse, Tumor-associated macrophages, Tumor interstitial fluid pressure, Medicin
Identifiers
urn:nbn:se:uu:diva-6804 (URN)91-554-6538-2 (ISBN)
Public defence
2006-05-20, Rudbecksalen, Rudbecklaboratoriet, Sjukhusvägen 10, Uppsala, 09:15
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Available from: 2006-04-28 Created: 2006-04-28Bibliographically approved

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