Priority Programme: THYROID TRANS ACT
Translation of Thyroid Hormone Actions beyond Classical Concepts

Prof. Dr. Christine Spitzweg, Prof. Dr. Peter Nelson

Plasma membrane-mediated non-genomic effects of T4, T3 and thyroid hormone metabolite Tetrac on the tumor microenvironment

LEERIn the recent years we and others have shown that mesenchymal stem cells (MSCs) are actively recruited into growing tumor stroma where they play a major role in supporting tumor vasculature and forming the tumor’s fibrovascular network. Upon their homing to the tumor stroma, MSCs differentiate into carcinoma-associated fibroblast-/pericyte-like cells and secrete pro-angiogenic growth factors. This tumor tropism of MSCs makes them uniquely suited to act as tumor stroma-selective gene delivery vehicles, which has been convincingly demonstrated by our previous work using the sodium iodide symporter (NIS) or herpes simplex virus thymidine kinase as therapy genes. NIS as a potent and well characterized reporter gene allowed detailed non-invasive in vivo tracking of MSC homing and engraftment at the tumor site by 123I-scintigraphy/SPECT and 124I-PET imaging. There is now growing evidence that thyroid hormones T4 and T3 play a critical role in regulation of tumor stroma formation by stimulation of angiogenesis, proliferation and inflammation in tumors. This is mediated through non-genomic mechanisms via integrin avb3, which can be effectively inhibited by Tetrac, a deaminated T4 derivative. Based on our previous work using MSCs as delivery vehicles for NIS as reporter and therapy gene, in the current grant proposal we will make use of NIS as well characterized reporter gene to investigate the non-genomic effects of T4 and T3 versus Tetrac on (I) the recruitment of MSCs to the tumor stroma in liver cancer mouse models, (II) MSC differentiation potential in vitro and in vivo, (III) MSC-mediated neovascularization by in vivo imaging, and (IV) transcriptional activity of HIF-1a in the tumor microenvironment using a HIF-1a-specific NIS reporter gene system.

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Project Coordinator(s):

Prof. Dr. Christine Spitzweg
Klinikum der Universität München - Grosshadern
LMU München, Medizinische Klinik II
Marchioninistr. 15
81377 München
Phone: +49 89 7095 0
Fax: +49 89 7095 8737

Prof. Dr. Peter Nelson
Klinikum der Universität München - Grosshadern
Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, AG Klinische Biochemie
Schillerstr. 42
80336 München
Phone: +49 89 2180 75845
Fax: +49 89 2180 75860