Novel pathways promoting thyroid tumourigenesis and growth
Lead Research Organisation:
University of Birmingham
Department Name: Clinical and Experimental Medicine
Abstract
Thyroid cancers are the most common endocrine malignancies in England and Wales and their incidence is rising. Since these tumours have a tendency to recur following surgery, patients are often offered treatment with radioiodine (131I) to prevent tumour re-growth. In addition, benign thyroid gland enlargements (goitres) affect up to 50% of the population and 131I therapy is increasingly used in their management.
Although we remain unsure which mechanisms control the growth of these thyroid tumours, our studies have shown that a cancer-causing gene called pituitary tumor transforming gene (PTTG) plays a role. PTTG stimulates tissue growth through interactions with growth promoting molecules and our preliminary findings demonstrate that PTTG directly affects the uptake of radioiodine by thyroid cells. We propose to assess the ways in which PTTG interacts with a number of growth factors and which mechanisms are involved in this process using thyroid cells in culture. Additionally we will study the in vivo effects of reduced and increased PTTG expression in the thyroid using mouse models. Finally we propose to investigate if the effects of PTTG on radioiodine uptake can be inhibited in order to improve the treatment of thyroid diseases. These investigations will be carried out by researchers who have made significant contributions to characterising the role of PTTG in thyroid disease.
Although we remain unsure which mechanisms control the growth of these thyroid tumours, our studies have shown that a cancer-causing gene called pituitary tumor transforming gene (PTTG) plays a role. PTTG stimulates tissue growth through interactions with growth promoting molecules and our preliminary findings demonstrate that PTTG directly affects the uptake of radioiodine by thyroid cells. We propose to assess the ways in which PTTG interacts with a number of growth factors and which mechanisms are involved in this process using thyroid cells in culture. Additionally we will study the in vivo effects of reduced and increased PTTG expression in the thyroid using mouse models. Finally we propose to investigate if the effects of PTTG on radioiodine uptake can be inhibited in order to improve the treatment of thyroid diseases. These investigations will be carried out by researchers who have made significant contributions to characterising the role of PTTG in thyroid disease.
Technical Summary
Thyroid neoplasia (cancers) and hyperplasia (goitres) are common clinical entities and interactions between oncogenes and growth factors are pivotal in their pathogenesis. We have identified the pituitary tumor transforming gene (PTTG) as a novel molecular indicator of prognosis for thyroid cancers. PTTG has a dual role in thyroid tumourigenesis firstly by inducing genetic instability and subsequently by promoting tumour growth and angiogenesis. Interactions between PTTG and growth factors (e.g.FGF-2) are well described and we have demonstrated that this is regulated via PTTG‘s SH3-interacting domain. Recently mitogenic factors implicated in thyroid tumourigenesis (IGF-1, TGF?, HGF and EGF) were found to regulate PTTG in breast cancer and astrocytoma cells. Of particular clinical relevance are our preliminary findings that PTTG and its binding factor (PBF) repress expression and function of the sodium iodide symporter (NIS) thereby potentially affecting the treatment of thyroid diseases with radioiodine.
We hypothesise (i) that PTTG promotes the growth of thyroid tumours through paracrine/autocrine interactions with growth factors and (ii) that this is regulated via PTTG‘s SH3-interacting domain. (iii) Additionally, we propose that PTTG under-and overexpression affects thyroid gland growth and (iv) that amelioration of PTTG-induced NIS repression may improve treatment of thyroid diseases with radioiodine.
To test our first hypothesis we propose to use a number of in vitro techniques to unravel the autocrine/paracrine pathways of interaction between PTTG and growth factors such as IGF-1, EGF, HGF and TGF? in thyroid cells to identify potential therapeutic targets. Additionally we will relate the expression of these mitogens in our thyroid tissue cohort to our existing molecular and clinical findings to determine their role as prognostic markers. Secondly, we will explore the mechanism of growth factor-PTTG interaction using a mass spectrometry proteomics approach to identify functionally relevant proteins determining this interaction. Thirdly we will investigate the effects of PTTG under- and targeted overexpression on thyroid growth in mouse models. We will attempt to induce goitres in PTTG knockout mice (provided by Professor Melmed, University of California) and develop a thyroglobulin-driven PTTG transgenic mouse model in collaboration with Professor Fagin (University of Cincinnati). We will examine effects on thyroid specific gene expression and thyroid cell differentiation and function in both models. Finally we will investigate if amelioration of PTTG‘s effects could lead to improvements in the treatment of patients with thyroid disease with radioiodine. We will investigate the effects of PTTG/PBF on subcellular localisation and function of NIS and determine if disruption of PTTG-induced NIS repression represents a potential means of modulating the treatment of thyroid diseases with radioiodine.
We hypothesise (i) that PTTG promotes the growth of thyroid tumours through paracrine/autocrine interactions with growth factors and (ii) that this is regulated via PTTG‘s SH3-interacting domain. (iii) Additionally, we propose that PTTG under-and overexpression affects thyroid gland growth and (iv) that amelioration of PTTG-induced NIS repression may improve treatment of thyroid diseases with radioiodine.
To test our first hypothesis we propose to use a number of in vitro techniques to unravel the autocrine/paracrine pathways of interaction between PTTG and growth factors such as IGF-1, EGF, HGF and TGF? in thyroid cells to identify potential therapeutic targets. Additionally we will relate the expression of these mitogens in our thyroid tissue cohort to our existing molecular and clinical findings to determine their role as prognostic markers. Secondly, we will explore the mechanism of growth factor-PTTG interaction using a mass spectrometry proteomics approach to identify functionally relevant proteins determining this interaction. Thirdly we will investigate the effects of PTTG under- and targeted overexpression on thyroid growth in mouse models. We will attempt to induce goitres in PTTG knockout mice (provided by Professor Melmed, University of California) and develop a thyroglobulin-driven PTTG transgenic mouse model in collaboration with Professor Fagin (University of Cincinnati). We will examine effects on thyroid specific gene expression and thyroid cell differentiation and function in both models. Finally we will investigate if amelioration of PTTG‘s effects could lead to improvements in the treatment of patients with thyroid disease with radioiodine. We will investigate the effects of PTTG/PBF on subcellular localisation and function of NIS and determine if disruption of PTTG-induced NIS repression represents a potential means of modulating the treatment of thyroid diseases with radioiodine.
People |
ORCID iD |
| Kristien Boelaert (Principal Investigator / Fellow) |